The comatose patient

THE COMATOSE PATIENT

THE COMATOSE PATIENTSECOND EDITION

Eelco F. M. Wijdicks, MD, PhD, FACP, FNCS, FANAProfessor of Neurology, Mayo Clinic College of MedicineChair, Division of Critical Care NeurologyConsultant, Neurosciences Intensive Care UnitMayo Clinic Hospital, Saint Marys CampusMayo Clinic, Rochester, Minnesota

1

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Library of Congress Cataloging-in-Publication DataWijdicks, Eelco F. M., 1954– author.The comatose patient / Eelco F. M. Wijdicks.—Second edition. p. ; cm.Includes bibliographical references and index.ISBN 978–0–19–933121–5 (alk. paper)I. Title.[DNLM: 1. Coma. 2. Neurologic Examination. WB 182]RB150.C6616.8′49—dc232013047124

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FOR BARBARA, COEN, AND MARILOU

CONTENTS

Collection of Videoclips (VC) xvii

Preface to the Second Edition xix

Preface to the First Edition xxi

PART I: UNDERSTANDING, DIAGNOSING, AND CARE OF COMATOSE STATES

1. A History of Coma: Evolution of Ideas 3

Understanding Brain Herniation 4Concepts and Benchmarks 4Revision of a Paradigm 15

Understanding the Role of Increased Intracranial Pressure 18

Understanding Localization and Key Clinical Signs in Coma 21Decerebrate Rigidity 21Fixed Dilated Pupil 23Oculovestibular Reflex 26Breathing Patterns 27

Understanding the Mechanisms of Metabolic and Diffuse Encephalopathies 29

Understanding Psychogenic Unresponsiveness 32

Understanding the Spectrum of Prolonged Comatose States 35

Classification of Coma and Major Works 47

Prognostication of Coma 53

Conclusions 56

2. The Neuroscience of the Awake State 60

Early Studies 61

viii / / CONTENTS

The Anatomy of the Awake State 64

The Chemistry of the Awake State 70

The Physiology of the Awake State 75

Translation into Clinical Practice 76

Conclusions 78

3. Neurologic Examination of the Comatose Patient and Localization Principles 81

Definitions 82Locked-in Syndrome 82Hypersomnia 82Acute Confusional State and Delirium 83Stupor and Coma 83

The Clinical Examination of a Comatose Patient 84Fundamentals of Functional Anatomy 85Physical Examination 88Neurologic Examination: Coma Scales and the FOUR Score 89Neurologic Examination: Clinical Observations 94

Breathing Patterns 94Cranial Nerve Examination 95Spontaneous Movements 100

Localization Principles and Brain Displacement Syndromes 100

Conclusions 107

4. The Clinical Diagnosis of Prolonged Impaired Consciousness 111

Categories of Outcome 112

Persistent Vegetative State 113

Minimally Conscious State and Akinetic Mutism 116

Laboratory Investigations 119

Prediction of Outcome 124

Conclusions 126

5. The Clinical Diagnosis of Brain Death 131

Code of Practice 132

CONTENTS / / ix

The Clinical Examination 134Prerequisites and Major Confounders 134The Bedside Examination 138Confirmatory Tests 142Documentation 144

Special Issues 147

Pathophysiological Response to Brain Death 150

Organ Procurement 151

Conclusions 152

6. Neuroimaging, Neurophysiology, and Neuropathology 156

Neuroimaging in Coma 157Diagnostic Imaging of Brain Tissue Shift 160Diagnostic Imaging of Gray and White Matter Disorders 168

Neurophysiology of Coma 175EEG Patterns in Coma 176Continuous EEG Monitoring 182Evoked Potentials 183

Neuropathology of Coma 184

Specific Types of Injury 184Hypoxemia and Ischemia 184Infarction and Hemorrhage 186Trauma and Abuse 188Infection 190Demyelination 193Neurotoxicity 194

Disease States 195Pathology of Brain Herniation 195Persistent Vegetative State 197Brain Death 199

Conclusions 201

7. Clinical Diagnosis and Decisions 205

Clinical Decisions in the Comatose Patient 206Respiratory and Hemodynamic Stabilization 206Further Questions to Family or Bystanders 208

x / / CONTENTS

Consolidation of Neurologic Findings 209Interpretation of Neuroimaging: Abnormal CT Scan Findings

and Their Consequences 210Interpretation of Neuroimaging: Normal CT Scan Findings

and Their Consequences 215

The Comatose Patient in Various Hospital Locations 216Coma in the Emergency Department 217Coma in the ICU 223Coma on the Ward 225

Conclusions 226

8. Medical Care of the Comatose Patient 229

Supportive Care of the Comatose Patient 230Systematic Approach to Care 230Infection Control 230Blood Glucose Control 232Temperature Control 233Eye and Mouth Care 234Airway and Pulmonary Care 235Cardiac Care 240Circulation Care 243Gastrointestinal Care 243Bladder Care 245

Medical Complications of Immobilization 246

Communication With the Family 249

Clinical Practice of Withdrawal of Support 253

Conclusions 255

9. Recovery and Rehabilitation 260

Early Interventions 261Physiotherapy 262Pharmaceutical Interventions 262Stimulation Programs 266Other Adjunctive Therapies 267

Neurorehabilitation 269Metrics in Neurorehabilitation 270Technology and New Options 272

Conclusions 274

CONTENTS / / xi

10. Law and Bioethics 278

The Court Cases in the United States 279The Quinlan Case 279The Jobes Case 280The Brophy Case 281The Cruzan Case 281The Wendland Case 283The Schiavo Case 283Lessons Learned From the Court Cases 286Legal Aspects of Withdrawal of Support 288

Applied Ethics 289Spirituality and Health Care 289Comatose States as a Bioethical Controversy 291

Ethics in Organ Donation After Cardiac Death 294

Conclusions 296

11. Media and Popular Culture 299

News Writing on Coma 299

The Newspaper and Coverage of Coma 301

Television and Coma 304

The Internet and Coma 306

Cinema and Coma 307

Conclusions 309

PART II: THE CLINICAL APPROACH TO THE COMATOSE PATIENT

12. An Introduction to 100 Vignettes 313

13. Comatose and Traumatic Brain Injury 315

14. Comatose and Gunshot Wounds 322

15. Comatose and Traumatic Brainstem Lesion 327

16. Comatose and Shaken-Impact Syndrome 331

17. Comatose and Acute Epidural Hematoma 336

xii / / CONTENTS

18. Comatose and Acute Subdural Hematoma 340

19. Comatose and Cerebral Hematoma 345

20. Comatose and Intraventricular Hemorrhage 352

21. Comatose and Pontine Hemorrhage 356

22. Comatose and Cerebellar Hemorrhage 360

23. Comatose and Aneurysmal Subarachnoid Hemorrhage 366

24. Comatose and Cerebral Venous Thrombosis 372

25. Comatose and Hemispheric Stroke 378

26. Comatose and Bihemispheric Stroke 383

27. Comatose and Basilar Artery Occlusion 386

28. Comatose and Bacterial Meningitis 391

29. Comatose and Brain Abscess 397

30. Comatose and Empyema 401

31. Comatose and Herpes Simplex Encephalitis 405

32. Comatose and H1N1 Influenza 411

33. Comatose and Rabies Encephalitis 415

34. Comatose and Mumps Encephalitis 419

35. Comatose and Acute Necrotizing Encephalitis 423

36. Comatose and Zoonotic Disease 427

37. Comatose and Opportunistic Infections (I) 432

38. Comatose and Opportunistic Infections (II) 436

39. Comatose and High-Grade Astrocytoma 441

40. Comatose and CNS Lymphoma 445

41. Comatose and Metastasis 449

42. Comatose and Gliomatosis Cerebri 453

CONTENTS / / xiii

43. Comatose and Paraneoplastic Encephalitis 456

44. Comatose and Autoimmune Encephalitis 461

45. Comatose and Acute Disseminated Encephalomyelitis 465

46. Comatose and Fulminant Multiple Sclerosis 470

47. Comatose and Osmotic Demyelination 474

48. Comatose and Acute Hydrocephalus 478

49. Comatose and CSF Hypotension 483

50. Comatose and Convulsive Status Epilepticus 487

51. Comatose and Nonconvulsive Status Epilepticus 492

52. Comatose in the Recovery Room 496

53. Comatose After Organ Transplantation 500

54. Comatose After Coronary Artery Bypass Surgery 505

55. Comatose on ECMO 509

56. Comatose After Brain Biopsy and Craniotomy 514

57. Comatose After Epilepsy Surgery 519

58. Comatose After Cerebral Angiography 523

59. Comatose After Clipping of a Ruptured Cerebral Aneurysm 527

60. Comatose After Endovascular Treatment of Ruptured Cerebral Aneurysm 531

61. Comatose and Accidental Hypothermia 536

62. Comatose and Carbon Monoxide Inhalation 541

63. Comatose and Heatstroke 545

64. Comatose and Near-Drowning 549

65. Comatose After Cardiopulmonary Resuscitation 554

66. Comatose After Therapeutic Hypothermia 561

67. Comatose After Near-Hanging 565

68. Comatose After Fat Embolism Syndrome 569

xiv / / CONTENTS

69. Comatose and Air Embolism 573

70. Comatose and Status Asthmaticus 577

71. Comatose and Acute Uremia 581

72. Comatose and Hypertensive Crisis 585

73. Comatose and Fulminant Hepatic Failure 591

74. Comatose and Chronic Liver Disease 596

75. Comatose and Thyroid Disease 601

76. Comatose and Sepsis 607

77. Comatose and Endocarditis 611

78. Comatose After Aortic Dissection 615

79. Comatose and Hypoglycemia 619

80. Comatose and Hyperglycemia 623

81. Comatose and Hyponatremia 629

82. Comatose and Hypernatremia 634

83. Comatose and Hypercalcemic Crisis 638

84. Comatose and Hypercapnia 642

85. Comatose and Pituitary Apoplexy 646

86. Comatose and Systemic Lupus Erythematosus 651

87. Comatose and Central Nervous System Vasculitis 656

88. Comatose and Acute Thrombocytopenia 662

89. Comatose and Acute Leukemia 666

90. Comatose and Acute Porphyria 670

91. Comatose and Urea Cycle Disorder 675

92. Comatose and Wernicke-Korsakoff Syndrome 679

93. Comatose and MELAS 683

94. Comatose and Preterm Newborn 688

CONTENTS / / xv

95. Comatose and Fulminant Cerebral Vasoconstriction 692

96. Comatose and Puerperium 696

97. Comatose and Chemotherapy Toxicity 701

98. Comatose and Baclofen Toxicity 705

99. Comatose and Cefepime Toxicity 708

100. Comatose and Acetaminophen Toxicity 711

101. Comatose and Tricyclic Antidepressant Toxicity 715

102. Comatose and SSRI Toxicity 719

103. Comatose and Alcohol Intoxication 723

104. Comatose and Ethylene Glycol Ingestion 728

105. Comatose and Salicylate Toxicity 732

106. Comatose and Opioid Toxicity 736

107. Comatose and Benzodiazepine Toxicity 740

108. Comatose and Lithium Toxicity 743

109. Comatose After a Rave Party 747

110. Comatose and Rapid Dementing Illness 752

111. Comatose and Malignant Catatonia 757

112. Comatose and Conversion Disorder 762

Index 767

xvii

COLLECTION OF VIDEOCLIPS (VC) (First number refers to chapter)

VC 3-1: Locked-in syndromeVC 3-2: Locked-in (plus) syndromeVC 3-3: FOUR score (instruction)VC 3-4: Breathing in Coma

Central Neurogenic HyperventilationCheyne-Stokes BreathingCluster Breathing

VC 3-5: Eye Movements in ComaOcular BobbingPing-PongForced Downward GazeRapid VOR with Downward MovementNormal Oculovestibular ResponsesAbsent Oculovestibular ResponsesInternuclear Ophthalmoplegia

VC 3-6: Movements in ComaArc de CercleChoreiform FidgetsMyoclonus Status EpilepticusSpontaneous Triple Flexion Responses

VC 3-7: Status Myoclonus (muted with propofol)VC 3-8: Shivering due to brainstem injuryVC 3-9: Ping-pong eye movementsVC 3-10: See-Saw NystagmusVC 4-1: Persistent Vegetative StateVC 4-2: Akinetic Mutism

xviii / / COLLECTION OF VIDEOCLIPS (VC)

VC 4-3: Minimally Conscious StateVC 5-1: Clinical Diagnosis of Brain Death (instruction)

Neurologic ExaminationApnea TestPitfalls and Concerns

VC 5-2: Thumb extension with noxious stimulus in Brain DeathVC 5-3: Leg flexion with forceful neck flexion in Brain DeathVC 5-4: “Babinski” sign in Brain DeathVC 8-1: Paroxysmal Sympathetic Hyperactivity Syndrome (Autonomic Storm)VC 51-1: Nonconvulsive Status EpilepticusVC 112-1: Pseudo Status Epilepticus

xix

PREFACE TO THE SECOND EDITION

This new edition has benefitted from the encouragement I received. The opportunity to do a second edition of this work allowed me to correct, rewrite, and expand.

All chapters have been updated and many have been expanded with new sections, and thus the book has grown by nearly 200 pages. In this edition you will find new sections on classic books on coma and the historical development of prognostication in coma. With renewed interest in EEG monitoring there are new and expanded sections on elec-trophysiology. The cause of coma depends on where the patient is seen. There is a new section on common problems found in evaluating coma in the emergency department and sorting out the cause of coma in various other hospital locations. The purpose of this chapter is to take the clinical approach outlined in the book into a specific location. It provides a practical approach to separate the wheat from the chaff and to rapidly come to a conclusion.

I have included an expanded chapter on neurorehabilitation. The chapter also pro-vides an overview of therapeutic claims that range from pure quackery to potentially promising. Many patients and families are seeking treatments that are not only unproven but also ruinously costly. The chapter will give useful information for physicians who have to judge these unrealistic approaches.

As expected, the field of “coma” may progress slowly with few new breakthroughs or novel ideas. (Some of my colleagues have bitingly and amusingly asked me, “So what is new in coma?”) Most of the “progress” has been made in functional neuroimaging, although the consequences of this newly acquired knowledge may not be known for some time. A comprehensive (and critical) assessment of the usefulness and validity of functional MRI is therefore included in this edition.

I have added 25 additional clinical vignettes based on recent observations. This book now has 100 case descriptions on presenting causes of coma, which should include all possible clinical scenarios. Other causes—and there are a few more exotic ones in devel-oping countries—should be mostly considered variations on the themes presented here.

xx / / PREFACE TO THE SECOND EDITION

The first edition had a separate DVD with video clips on neurologic examination and neurologic manifestations seen in comatose patients. These videos are now directly linked to the text in the electronic edition. All video recordings have been reformatted and remastered where needed. I have added several more video clips of patients seen over the last few years.

I strived to write a full-length work on coma—a single clinical neurologic sign of great importance. It provides all a clinician should know (or wants to know) to feel confident when assessing and treating comatose patients but also to sincerely help family members. So what will be new in coma? I hope we will be able to better predict outcome and pro-vide surviving patients with the best opportunity for recovery. We are far from that goal. The evaluation and management of coma remains one of the most difficult medical tasks for clinicians, and I hope this book will guide them in the right direction.

Eelco F. M. Wijdicks

xxi

PREFACE TO THE FIRST EDITION

Coma is derived from the Greek word κώμα, meaning deep sleep. That is not what it is. For the most part, a comatose state is a result of a calamity and severe brain injury. This clinical condition, for understandable reasons, raises apprehension in physicians. To many of us it is troubling when the cause of coma is unclear and—if not found and treated—may result in an undesirable outcome. The recent medical interest with pro-longed comatose states has brought it due prominence. These matters would in them-selves justify a separate monograph about coma.

The basic principles of neurologic examination and localization have not changed, and one could argue, all of which has been written about extensively and in tedium. However, the role of neuroimaging, in particular CT and MRI, has become hugely impor-tant, and these studies are now widely integrated in medical and surgical decision making and determination of prognosis. Moreover, the concepts underlying brain tissue shift and herniation have changed. Medical and neurosurgical treatment of the comatose patient has been better defined. Therefore, a new clinical and practical book on management of the comatose patient would be useful.

How can one present a fresh and contemporary look and avoid shopworn approaches? I believe there are distinguishing ways of doing that. The book is divided into two major parts. One section presents current clinical knowledge of comatose states and the other presents causes of coma in clinical vignettes.

In the first part of the book, current ideas of brain tissue shift syndromes are presented and contrasted with earlier descriptions. Such a historical homage will help the reader understand how certain ideas came to be (Chapter 1). I realized that any book on uncon-sciousness must have a chapter on consciousness. Basic principles of awareness will be discussed, but for want of more definitive answers, this practical clinical book will not delve into the field of the neurobiology of consciousness and cognitive neurosciences. A comprehensive understanding of the theories underlying consciousness in my view is not needed for clinicians who are more interested in the ills of the brain (Chapter 2).

xxii / / PREFACE TO THE FIRST EDITION

The clinical evaluation of comatose patients is discussed in three core chapters (Chapters 3, 4, and 5), and is followed by a discussion on the role of neuroimaging and neuropathology in assessment of coma (Chapter 6). A separate chapter deals not only with the initial approach to a comatose patient but also with all aspects of emergent medi-cal and long-term supportive care and has a separate section on how to lead an effective family conference (Chapter 7).

The diagnosis and care of patients in a prolonged comatose state may be challenged in court and receive considerable media attention. The main legal and ethical issues, with-drawal of support, religious positions on persistent vegetative state and brain death, and increasing use of organ donation after cardiac death protocols are addressed in a sepa-rate chapter (Chapter 8). This includes an attempt to interpret the cases that came to court but with a focus on physician opinions and involvement. Finally, the effect of the media (eg, newspapers, television, and movies) on the public’s attitude toward prolonged coma is critically evaluated (Chapter 9). I think in discussing the broader social and legal implications it brings an additional perspective, and hopefully a multidimensional representation.

In the second part of the book, causes of coma are described (Chapter 10). Here, the book transitions from the general to the particular. I think further clarity can be achieved by presenting comatose patients according to specific causes. I decided to present com-mon and uncommon causes of coma in 75 clinical vignettes. Carefully chosen, all cases have been personally consulted upon in the past 15 years. This section has a unique for-mat. Each clinical vignette starts with a conversation. This is simply because diagnostic evaluation and the early management are usually discussed during rounds or during phone calls from the emergency department or even outside the hospital. The "fly on the wall" reader is able to immediately get involved with the challenges of the case as it hap-pens. In these narrative lines, I have tried to create a climate of collegiality and seriousness and used wit sparingly. The vignette follows a standard template and the introduction is followed by an explanation, a treatment plan and prognosis, and a final concluding note summarizing the major points made in the conversation segment. This collection can be dipped into or read as a whole.

This textbook includes a DVD with five narrated chapters. The video clips were col-lected over a short period (2-3 years), taping patients in the NICU. This DVD is there-fore not a lifelong collection of clinical observations but includes clinical features that most likely can be seen at any time, in any place, by any clinician. All patients, but more often proxy, granted permission. In this DVD the new coma scale (FOUR score) is fur-ther explained and taught using multiple patient examples. The DVD also shows key fea-tures of the neurologic examination and patient examples of known states of impaired

PREFACE TO THE FIRST EDITION / / xxiii

consciousness. The clinical determination of brain death has been animated using 3D Studio Max and Poser software and provides a detailed instruction. A Spanish transla-tion is included. The DVD stands alone and can be watched separately. I hope it will also facilitate the understanding of the text and I have included cross-references.

I hope this new clinical book on coma—part practical knowledge and part tutorial using modern technology—will find its way to all physicians, medical and nursing stu-dents, residents, and fellows confronted with comatose patients. I hope it will be used by neurologists, neurosurgeons, neuroradiologists, psychiatrists, anesthesiologists, emergency physicians, intensivists, and physiatrists responsible for the immediate and long-term management. It has also been written for the dedicated nursing staff involved with the care of the comatose patient who gives so much comfort to the family.

Eelco F. M. Wijdicks

/ / / / / / / / / / / / / / / / / / PART ONE / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / /

UNDERSTANDING, DIAGNOSING, AND CARE OF COMATOSE STATES

3

We need to go back to the last century, a productive period that led to notable advances in our understanding of coma. If we go back earlier to the classic monographs in medicine, little nuance is found, but coma had been recognized as a signa mali ominis. One of the first works describing coma in some detail using clinical signs was by Wepfer in Historiae Apoplecticorum (1658 edition). His patient with a cerebral hemorrhage was “deprived of all sensation” and developed “laborious” irregular breath-ing with “body shaken albeit by a movement.” Thomas Willis, in his work De Anima Brutorum (1672), reported coma, carus, and lethargy, and even mentioned coma vigil. The physician and taxonomist Boissier de Sauvages de La Croix, in his work Nosologia Methodica Sistens Morborum Classes, Genera et Species (1763), defined coma as typho-mania (awake but not aware), lethargus (easily awoken and responding to questions), cataphora (responding but falling asleep when unstimulated), carus (hard to awaken), and apoplexia (deep sleep and limbs flaccid).

In the 19th and early 20th centuries, disorders of consciousness were mentioned in medical texts, but attention was directed to their relation with organ failure.67 Likewise, coma as a clinical condition was only dealt with sporadically in neurology textbooks. Open up Romberg’s Lehrbuch der Nervenkrankheiten des Menschen (1840 edition), and coma is mentioned only as a sign preceding death. Open up Hammond’s Treatise on Diseases of the Nervous System (1872 edition), and you will find coma referred in the “apo-plectic form of cerebral congestion” and other catastrophes. Open up Bing’s Lehrbuch der Nervenkrankheiten (1913 edition), and you will generally find coma associated with epileptic fits, apoplectic stroke, and traumatic head injury.

A History of Coma: Evolution of Ideas

/ / / 1 / / /

4 / / THE ComATosE PATIEnT

Separate book chapters on coma appeared in the early 1950s (e.g., Russell DeJong, The Neurologic Examination, 1950), and they emphasized the value of noxious stimuli to look for responsiveness, brainstem reflexes, compensatory eye reflexes with head turning, and significance of decerebrate responses. In the early 1960s, several works appeared that focused on general patient care with recommendations on head positioning, ventilation and tracheostomy, fluid management, and temperature control.94

As technology advanced, better laboratory tests became available, but groundbreaking changes came with novel neuroimaging. Rapidly establishing the cause of coma accelerated with the widespread availability of computed tomography (CT) scanning in the late 1970s. This assisted neurologists, but mostly neurosurgeons, who could now eliminate emergency cerebral angiograms and stop performing blind exploratory burr holes for acute subdural hematomas.37 A decade later magnetic resonance imaging (MRI) allowed even better visu-alization of the damaged and displaced brain structures. More recently, functional MRI showed brain activation when certain tasks were asked of a patient with impaired conscious-ness. None of this was apparent during neurologic examination, and these findings provoca-tively implied that these patients were “disconnected” from the external environment.

Given the large body of work, it is important to identify distinguishable strands. Explaining the background to all of this requires not only a discussion of laboratory experiments, but also an exploration of clinical concepts and pathological observations.53 This chapter will review how the clinical features of coma, its clinical course, and its out-come became known and how it became part of neurologic knowledge and practice.

UNDERSTANDING BRAIN HERNIATION

As with so many other gradually unraveling medical syndromes, it will be difficult to trace the very first complete description of brain herniation in the medical literature. A possible time line is shown in Table 1-1.

Concepts and Benchmarks

Two milestones can be archived—the observation that coma could be due to compression of the brain, and the notion that it could lead to brainstem injury. One of the earliest clini-copathological correlations comes from Rostan from the Salpêtrière Hospital, who noted in the beginning of the 19th century that in patients with cerebral softening, coma was a sign of later deterioration. At autopsy, he noted compression of the brain, and clinically, he found dilation of the pupils, which then became fixed, and a respiration that was compa-rable to a very deep sleep.74 It became clear that when brain tissue shifted, the brainstem

A History of Coma: Evolution of Ideas / / 5

carried the brunt of the injury. In fact, pontomedullary hemorrhages were linked to acute space-occupying intracranial lesions. Later, Duret found these lesions in 30% of traumatic and spontaneous cerebral hemorrhages and they would carry his name.21

In a series of dog experiments, Duret described in considerable detail the clinical and pathological features of les phénomènes de choc after injection of water or gelatin into the cranium. These original studies became part of a medical doctorate thesis in 1878 (Fig. 1-1).21 The signs included sudden acceleration of blood pressure, respiratory arrest, slow pulse, and tétanisme. Duret hypothesized that a shock wave in the cerebrospinal fluid (CSF) was augmented in the aqueduct of Sylvius, causing hemorrhage under the fourth ventricle. (This explanation was based on Bernoulli’s law, which states that hydrostatic pressure is the greatest in the immediate post-stenotic area.)

The earliest pathology account of brain herniation is probably herniation of the cortex into the arachnoid villae, particularly under the surface of the temporal lobe as an attempt to absorb pressure. Other accounts are on brain herniation from missile wounds show-ing extrusion outside the bone defect. Cushing was one of the first clinicians to describe tonsillar herniation and to warn of the risk of lumbar puncture.

Not a few instances of disaster in consequence of lumbar puncture have been recorded

in the literature, and six have come under my personal observation. Three of them were

fatalities in the medical ward after puncture in cases of unsuspected cerebellar lesions.

If the brain, after such an incident, is removed from the cranial chamber soon after death

and particularly hard in situ, it will show the imprint of the foraminal ring about the

protrusion that has been tightly jammed into the open ring.19

Cushing mentioned tonsillar herniation in his Mutter lecture of 1901. In this paper, he also cited Quincke, who had already called attention to the dangers of lumbar puncture.

TABLE 1–1 Early Historical Landmarks in Understanding Brain Herniation

Key Observation Year Author(s)

Pontine hemorrhages 1878 Duret21

Tonsillar herniation 1901 Cushing19

1904 Collier17

Herniation of temporal lobe through tentorial

opening

1920 Meyer56

Contralateral pyramidal signs due to

displacement of brainstem

1929 Kernohan and Woltman42

Occipital lobe infarction 1938 Moore and Stern58

Third-nerve involvement 1939 Reid and Cone;71 Sunderland and Bradley80

Dysautonomic manifestations 1941 Schwarz and Rosner76


20

Tensionarterielle

18

16

14

12

A10

8

6

xxx injection

H Duret PL . XVII.

FIGURE 1-1 Henri Duret. Duret’s thesis on traumatic brain injury describing brainstem lesions.

The tracing shows the development of an hypertensive surge with his brain injection experi-

ments and drawings of the lesions in the brainstem. (Some were found in the medulla oblon-

gata.) Reproduced from Duret.21


Cushing named it protrusion of the brainstem and actual hernia cerebelli. These accounts of the tentorial pressure cone found at autopsy were the first clinical-pathological cor-relations, and they highlighted the dangers associated with sudden changes in the CSF compartments.53,65

Other papers more specifically described tonsillar herniation. Collier, in his article in Brain in 1904, noted that supratentorial tumors can press not only the tentorium down-ward but also the brainstem and cerebellum. The cerebellum was deeply indented by the edge of the foramen magnum, forming a so-called conical plug. Collier described his observations of cerebellar herniation as follows:

In many cases of intracranial tumor of long duration, it was found postmortem that the

posterior inferior part of the cerebellum had been pushed down and backwards into the

foramen magnum and the medulla itself being somewhat caudally displaced, two struc-

tures together forming a cone-shaped plug tightly filling up the foramen magnum.17

Alquier reported, in Revue Neurologique, two cases that he designated as heterotopie du cervelet dans le canal rachidien.6 Autopsy in two cases with brain tumors showed tissue displacement, “forced to migrate,” because of the pressure effect of the tumor. Alquier could not choose between two hypotheses; one supported a developmental anomaly and the other favored herniated cerebellar tissue compressing the brainstem. The concluding remarks of his mentor, Pierre Marie, are interesting but he dismissed it as a postmortem artifact.

The earliest anatomical description of uncal herniation can be attributed to Adolf Meyer in 1920.56 The article comprised of a pathology series with virtually no explana-tory text. The author declared at the outset: “The falx and tentorium constitute an impor-tant protection against any sudden impacts of pressure by keeping apart heavy portions of the brain, but they also provide an opportunity for trouble in case of swelling or need of displacement.”

Meyer’s article was rich in photographs (Fig. 1-2), but it drew few practical conclu-sions. Importantly, however, he described hemianopia as a false localizing sign of uncal herniation, resulting from compression of the posterior cerebral artery.

Other evidence of displacement was discovered at autopsy. Following a brief case report by Groeneveld and Schaltenbrand32 (Fig. 1-3A), pathologist Kernohan and neu-rologist Woltman42 published a seminal pathology work in 1929 on ipsilateral hemiplegia accompanying cerebral mass lesions. It provided the first comprehensive pathological observation that a groove of the shifted crus cerebri occurred on the side contralateral to a brain tumor (Fig. 1-3B). Pathological proof was provided: “herniation and displacement


may be evidenced by a groove sweeping over the uncinate gyrus on the side of the tumor.” They concluded: “Notching of the crus cerebri by the free margin of the tentorium could, we believe, explain the homolateral signs of the pyramidal tract noted in most of our cases” (Fig. 1-3C).

Ipsilateral pyramidal signs with uncal herniation had puzzled physicians, and more than a few unnecessary craniotomies had been performed on the wrong side. Since it was now possible to explain homolateral hemiplegia, it could possibly reduce clinical error. Over the years, this observation has been referred to as the Kernohan-Woltman syndrome or Kernohan’s notch. However, even now, the mechanism by which this V-shaped indenta-tion or groove is produced, whether by displacement of the brainstem at a diencephalic level or pushed by the herniating uncus, remains unclear. Moreover, this “notching” is more common as a result of gradual tumor growth and compression.

The anatomical relations of the tentorial hiatus were studied in greater detail in the following years. In 1938, Sir Geoffrey Jefferson36 summarized it as follows:

The temporal lobes lie on the tentorium, which slopes away laterally as a gently inclined

plane, so that pressure from above will tend to make them slide away from the midline.

However if one lobe is enlarged it cannot escape overhanging the free edge. For this rea-

son, a tumor of the temporal lobe will be the surest way of bringing it more firmly into

contact with the midbrain and squeezing its inner border over the sharp edge of the falx,

into a situation in which it can herniate downward into the posterior fossa.36

FIGURE 1-2 Sagittal depressions of the uncus on either side marking the line of tentorium; also

moderate wedging of the cerebellum into the foramen magnum. Reproduced from Meyer.56


FIGURE 1-3 Tentorial groove described by Groeneveld32 and later by Kernohan and Woltman.42


Sir Geoffrey Jefferson (familiar to neurosurgeons by the eponym Jefferson’s fracture, a burst fracture of the atlas vertebra) also coined the term tentorial pressure cone or tem-poral pressure cone. This term introduced the word “pressure” in the dynamics of the process, but Jefferson was not quite able to pinpoint the main variables. Pathological findings of these cases seen at autopsy included compression of cranial nerves travers-ing the subarachnoid space, mesencephalic hemorrhages, and kinking of the posterior cerebral arteries.

In the same year, Moore and Stern58 described 14 consecutive patients with brain tumors or abscesses that were specifically examined for evidence of vascular lesions. They described calcarine infarction and hemorrhages in the midbrain and pons. The hemorrhages in the brainstem were considered terminal events and were explained by reduced outflow, thus causing arterial congestion predisposing to hemorrhages. Acute increased intracranial pressure (ICP) was emphasized as a mechanism. Because the hemorrhages in the pons had major similarities to hypertension-induced hemorrhages, a similar mechanism was suggested with increased blood pressure causing hemorrhage in a fragile artery, the so-called locus minoris resistentiae. These secondary midbrain and pontine hemorrhages were not commonly seen in patients with transtentorial hernia-tion and were topographically different from those described by Duret, who had noted them to be predominantly surrounding the fourth ventricle. Van Gehuchten,83 Wolman,96 and Friede and Roessmann29 interpreted these lesions as ischemic of arterial origin and

FIGURE 1.3 Continued. Peduncle V-shaped indentation (“notch”).42


a consequence of prolonged tentorial coning. Wolman found thrombosed arteries in the same region, strengthening this concept.96

An important advance came in 1939, when Reid and Cone71 published their exper-imental study. They induced acute compressive brain lesions in anesthetized Macacus Rhesus monkeys by infusing Ringer’s solution through trephine holes in the skull, with simultaneous measurement of ICPs. At will, they could induce and reverse pupillary dila-tation through manipulation of the ICP (Fig. 1-4A–C). The animals were sacrificed after they developed pupillary changes. The oculomotor nerves were found to be compressed by the extruded hippocampal gyrus in most cases (Fig. 1-4C). The article additionally contained a description of clinical cases published in the literature and personal observa-tions to augment the experimental findings.

(A)

FIGURE 1-4 (A) Title page, Reid and Cone’s monkey experiment demonstrating uncal herniation.


Each clinical and experimental case that we have included has presented such a lesion in

the form of a herniated hippocampal gyrus pressing on the third nerve. In some of our

cases, the nerve was flattened or stretched and in one instance discolored . . . The amount

of pressure necessary to produce the herniation in the normal animal may give some

idea of the pressures in cases in human beings . . . In some of the animals, it was almost

as high as systolic blood pressure and this may aid in the explanation of the infarctions

that occur in man.71

This study was unable to duplicate findings such as the Kernohan-Woltman notch phe-nomenon or midbrain hemorrhages seen in human beings in similar circumstances. Nevertheless, the role of sudden elevation of ICP in the genesis of brain shift and uncal herniation was herein established. By demonstrating the reversible nature of the alleged signs of temporal lobe herniation, Reid and Cone were able to suggest the possible ben-efit of early surgery. Reid and Cone also described animal experiments reproducing the compressed third nerve with bilateral uncal herniation. Although they considered dam-age to the nucleus of the third nerve, they found that the herniated hippocampal gyrus flattened the third nerve in all monkeys and was considered the main mechanism.

(B) (C)

FIGURE 1.4 Continued. (B) Monkey experiment showing fixed pupil with acute mass effect.

(C) Monkey experiment with pathological confirmation of uncal herniation.71


Further refinement came in 1941, when Schwarz and Rosner76 described a clinical-pathological study of herniation of the gyrus of the hippocampus derived from 43 cases, and with one detailed case study demonstrating the unraveling and sequence of clinical signs. These clinical findings included nuchal rigidity with resistance to lat-eral movement of the head and thermoregulatory disturbances. Often, the temperature reached 40°C, indicating that hippocampal herniation disturbed the blood supply to the midbrain. Lateral displacement of the brainstem was noted, with flattening of the aqueduct

(A)

(B)

Substantianigra Substantia

nigra

NORMAL BRAIN SWOLLEN BRAIN

Sections 8mm. from midlineDentate ligament

FIGURE 1-5 (A) Upper brainstem compression—Howell35 title page. (B) Brainstem compression

and buckling with central herniation. (Reproduced from Howell.35)


of Sylvius causing obstructive hydrocephalus. Oddly, the clinical signs were then used to extrapolate a temporal course, with the implicit assumption that such a course existed. Six stages were described: (1) fluctuation in state of consciousness, (2) anisocoria with or without disturbance in the light reflex, (3) nuchal rigidity, (4) impairment of extraoc-ular muscles, (5) cardiorespiratory and thermoregulatory changes, and (6) paradoxical pyramidal tract signs followed by decerebrate rigidity.

Displacement of the brainstem itself was emphasized by Scheinker in 1945, who noted vertical shift and buckling for the first time. He stated that herniation of the hippocampal gyrus cannot be responsible for “gravity and danger of the clinical syndrome.” In his view—although not corroborated by data—occlusion of the aqueduct of Sylvius and intraventric-ular fluid pressure would rise, pushing the brainstem deeper into the tentorial opening.75

In 1953, disturbances of ocular motor function were described in considerable detail by Sunderland and Bradley.80 In patients with acute epidural hemorrhages, they found that the pupil on the affected side dilated. This was explained by the susceptibility of pupilloconstrictor fibers to deformation and pressure on the upper surface of the third nerve where the pupilloconstrictor fibers are located. Fixed pupils occurred, followed by loss of function of extraocular muscles. The changes in the opposite pupil were then explained by downward displacement of the basilar artery, pulling the posterior cerebral artery into the upper surface of the third nerve lying just below it and thus impairing pupil responses. In their reconstruction of events, central origin of a third nerve palsy was dismissed as an explanation because the extraocular eye mechanism would suffer and the opposite pupil was not affected until the signs were well advanced on the ipsilateral side.

Johnson and Yates,41 in 1956, also were interested in the pressure changes at the ten-torium. This paper made two major contributions. First, it suggested that, with uncal herniation, the third nerve may be angulated across the petroclinoid ligaments, produc-ing varying degrees of injury. Second, they described bilateral posterior herniation of the temporal occipital lobes, expanding cerebral hemispheres, gently sliding medially across the flat middle section, causing a pear-shaped compression, and compressing the dorsal midbrain, causing upward gaze palsy. It was of interest to the authors that upward gaze palsy produced a false localizing sign. It would suggest tumor in the pineal region, but, in fact, it was frontal and bilateral.

In 1959, Howell described upper brainstem compression and claimed a separate syn-drome (Fig. 1-5).35 He wrote:

Though the syndrome was complex and variable, its main features were sufficiently

constant for it to be accurately distinguished from other diseases causing coma, in the

majority of cases.


He correlated changes in respiration from noisy and labored breathing to apneic pauses followed by slow and gasping breathing, with heavy congested edematous lungs. Loss of pupil reflex (pupils were small or contracted) was a constant observation. Decerebrate rigidity was also common.

Similarly, the observations by McNealy and Plum,55 examining 52 patients with supratentorial mass lesions (Fig. 1-6), distinguished herniation from displacement of the uncus into the tentorium from another syndrome that they felt was more frequently observed and named it central syndrome or bilateral diencephalic impairment. The discus-sion stated that “throughout this study the predictable inexorable manner in which decay-ing brainstem function followed an orderly rostrocaudal pattern has been emphasized, for this orderly deterioration greatly assisted the accurate clinical diagnosis of coma after supratentorial disease.” This central syndrome was characterized by the development of Cheyne-Stokes breathing; small reactive pupils; hyperactive oculocephalic responses; and bilateral motor changes, with the development of paratonia (resistance to passive movement) or decorticate rigidity in several stages, from an early diencephalic to late diencephalic, midbrain upper pons, lower pontine, and upper medullary stage. Key clini-cal features that include respiration, pupillary responses, oculocephalic responses, and motor responses could help in recognizing this syndrome. They further emphasized that “orderly progression of signs was invariable unless intraventricular hemorrhage or ill advised lumbar puncture rapidly altered cephalocaudal pressure gradients to produce medulla ischemia failure.” Key to its progression—named rostrocaudal deterioration—was a loss of function of the diencephalon, followed consecutively by loss of function of midbrain, pons, and terminally, the medulla oblongata. In their view uncal herniation also may progress with a rostrocaudal course with third-nerve compression but no impaired consciousness (due to sparing of the diencephalon structures). Signs of midbrain or pons involvement were noted in a subsequent stage when shift progressed. The downward dis-placement was facilitated by three factors: (1) arterial compression followed by infarc-tion and edema (anterior cerebral artery under the falx and posterior cerebral artery from uncal compression), (2) venous compression followed by increased ICP (due to com-pression of the great cerebral vein), and (3) obstructive hydrocephalus at the aqueduct, further increasing ICP. According to the authors, these factors create a vertical force that could explain the rostrocaudal direction.

Revision of a Paradigm

The clinical signs of brain herniation provided a touchstone that would remain the con-ventional standard. Questions of validity were raised most prominently by Finney and


Or

Central Syndrome—Early Diencephalic

Oº C

FIGURE 1-6 McNealy and Plum—Central herniation paper with clinical signs that recognize this

entity. Reproduced from McNealy and Plum.55


Walker in their monograph on transtentorial herniation.23 It was only in the 1980s that Fisher26 and Ropper72 challenged this dogma and surmised that many of the arguments used were unsatisfactory. Ropper felt that the uncal herniation was more a passive process than an active one as the mesencephalon was moved by the expanding cerebral mass and the ipsilateral ambient cisterns widened.26 The main wrangling of Fisher was “the claim is being made that the aperture cerebellar herniation is an incidental late byproduct, a harmless telltale of increased posterior fossa content on the diffuse elevated pressure and not a special instrument for adding to the damage by throttling the brain stem.”26 Fisher noted two findings. He found that extreme cerebellar herniation can be asymptomatic and described an autopsy case of a 3- to 4-cm cerebellar herniation with hemorrhagic necrotic tips, proving that it had been present for several days. Secondly, in a pathological study, Fisher found cerebellar hemorrhage with posterior fossa compression and respiratory failure, but no pressure cone, in 17 of 18 patients. Fisher said in a passage of some impor-tance, “displacement of cerebellar tissue into the foramen magnum may even afford per-haps some relief from crowding rather than being harmful.”26 He also questioned whether urgent decompression could rescue these patients from respiratory arrest. “Our concern is how often we see respiratory arrest before loss of brainstem reflexes. Acute respira-tory failure causing death in this condition may be rare.”26 The concept of uncal hernia-tion was also considered disputable. Autopsy cases were described with horizontal shift and secondary brainstem hemorrhages, but absent temporal lobe herniation. Clinicians did note that hyperosmolar solution could reverse the clinical course, but it was hard to imagine that tissue wedged in the tentorial opening would become dislodged. An alter-native explanation was that the lateral shift could deform the midbrain and stretch the extra-axial third nerve. His provocative, but ultimately correct, conclusion was that lateral displacement of the brainstem is the prime mover, not transtentorial herniation. Ropper added to this concept in an influential paper in 1986, in which lateral displacement of the brain tissue and level of consciousness were closely correlated72 (Figs. 1-7A, B). This work revisited the major tenets of brain herniation, with some CT scans showing a later-ally displaced and rotated brainstem opening up the ambient cistern, but without the presence of herniated hippocampal tissue. This correlation of horizontal shift on CT scan and level of consciousness could be clinically relevant. If the degree of horizontal shift did not correlate with the level of consciousness, neurosurgical evacuation may not improve consciousness.

These observations correctly de-emphasized or even refuted brain tissue herniation as a clinical phenomenon. It is a fact that the pathologist always turned more attention to the herniation of brain tissue through openings rather than to the damage done to the thalamus and upper brainstem from displacement or compression.


UNDERSTANDING THE ROLE OF INCREASED INTRACRANIAL PRESSURE

At the end of the 19th century, investigators interested in the role of increased ICP in coma became more prolific. Earlier surgical pioneers who explained cerebral pressure fol-lowing trauma included Von Bergmann.84 His experiments described animals that devel-oped clonic spasms when pressure was suddenly applied to the brain. A slow heartbeat,

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16

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Awake Drowsy Stupor Coma

Aqueduct



Septum pellucidum

Pineal

(mm) (mm)

(mm)

(A)

(B)

FIGURE 1-7 (A) Ropper’s challenge of herniation. (B) Ropper’s displacement concepts. Note the

correlation between shift and categories of consciousness. Reproduced from Ropper.72


deep and snoring respirations, vomiting, and incontinence were other remarkable symp-toms. These symptoms were not seen when pressure was slowly increased. To produce death, ICP must equal the carotid pressure.84 Immediately after the injury, the blood pres-sure rises and then falls. There is a paralysis of the respiratory center; however, if mechani-cal ventilation is applied, the pulse remains strong. Hill suggested that these early effects were due to diminished flow in the bulbar centers.34 Hill also suggested that death occurs when ICP equals the system blood pressure in the carotid arteries.

Cushing is already acknowledged for his astute observation of brain herniation, and any historical account on the role of ICP must begin with Cushing’s contributions to its physiology. Cushing performed his animal experiments in Kocher’s laboratories (Figs. 1-8A,B). (A general surgeon, Theodor Kocher in Berne, Switzerland, received the Nobel Prize in 1909 for his work on goiters.) Cushing worked through the winter of 1900 on the following question given to him by Kocher: “To decide if incompression of the brain, the small veins and capillary vessels are dilated by stasis or compressed.” Increase in blood pressure with brain compression became known as “Cushing’s law” or “Cushing’s response” (Fig. 1-9), but this phenomenon had been observed earlier by other research-ers. The work was first published in German in 190218 and was notably followed by an acidic comment by Bernhard Naunyn, who claimed to have made the same observations 20 years earlier and felt undercredited. However, Cushing’s original experiments in dogs were highly important, and he introduced the measurement of intra-arterial blood pres-sure. ICP was increased by infusing saline in a rubber cannula, and Cushing documented

FIGURE 1-8 (A) Cushing’s portrait (when working on his seminal laboratory experiments).

(B) Kocher’s portrait.


this with increase of ICP; blood pressure would increase above the pressure that was applied to the vasomotoric center in the medulla.

With rapidly increased ICP, there was vagal activity with a decrease in pulse, some-times asystole and shallow breathing. With further increased ICP, the regulatory function of the vasomotor center and medulla would become “paralyzed” and would not respond to hypoxemia of the medulla oblongata, and this would then result in hypotension. Therefore, these findings were best understood as the increase in systolic blood pressure due to increase of ICP as a result of increased activity of the vasomotor center in the medulla, in turn resulting from a decreased cerebral perfusion and ischemia. He could also document that after the vagal nerve and the spinal cord were cut, the blood pressure and pulse did not change with rising ICP. When only the vagal nerves were cut, the blood pressure would simply follow ICP.

Cushing’s work came to be treated with respect and even awe, despite attacks and futile attempts to discredit the findings. However, it became clear in subsequent papers that these changes in systemic blood pressure, pulse rate, and respiration were not dem-onstrated until the ICP reached or surpassed the level of diastolic pressure. Kocher and Cushing made substantial advances in the field by proposing the following stages of medullary compression: (1) First stage: accommodation—kompensation. In this stage, the CSF is displaced out of the cranial vault, followed by encroachment upon the cere-bral venous bed with little change in the systemic circulation. (2) Second stage: stage of early manifest symptoms—anfangsstadium des manifesten hirndruckes. In this stage, blood from the capillaries has been expelled, and “anoxemia” of the vital bulbar cen-ters results in rise of the systemic blood pressure. The pulse rate is retarded, but the pulse has a full quality. The respiratory rate is also reduced. (3) Third stage: stage of advanced manifest symptoms—hohe stadium des manifesten hirndruckes. In this stage,

FIGURE 1-9 Original graphs in Cushing’s paper18 and later in Kocher’s book “Hinnerschütterung.”

It shows increased blood pressure (blutdruck), increased intracranial pressure (Hirndruck),

absent breathing (athmung), and spasms (krämpfe).


the respirations are more snoring and rhythmic and may be of the Cheyne-Stokes type. Papilledema is seen, and pupils become irregular. (4) Fourth stage: stage of medullary collapse—lähmungs stadium. In this stage, the “vital centers are exhausted.” The blood pressure is decreasing, and the patient is in shock, with all reflexes abolished, pupils dilated, and with irregular respirations with apneic episodes. These postulates, based on experimental findings, were accepted, and clinicians had no difficulty in putting them into practice and instructing nurses about them. In his work Hinnerschütterung, Kocher clearly recognized the lifesaving effects of decompression or trepanation in patients with increased ICP.

There were other important contributions, particularly on the consequences of increased ICP.81 Taylor and Page felt that arterial hypertension due to increased ICP was a combination of ischemia and mechanical compression. Others opted more for axial distortion of the brainstem to explain this vasopressor response.82 Langfitt, among oth-ers, documented that traumatic brain injury can cause a marked increase in ICP even without mass effect from a contusional lesion. Two major periods were observed: first, a brief rise in ICP due to the impact; second, a rise associated with cerebrovascular dila-tion from reduced cerebrovascular tone, resulting in an increase of cerebral blood vol-ume.46,88 Despite these landmark findings, the physiological changes in brain tissue shift with increased ICP remain incompletely understood.

UNDERSTANDING LOCALIZATION AND KEY CLINICAL SIGNS IN COMA

One would like to believe that small pieces of a puzzle were gradually discovered, which led to the emergence of an easily recognizable clinical picture. However, clinical patterns are far from coherent. In this section, the basic clinical signs are further discussed.

Decerebrate Rigidity

Extensor rigidity with head retraction had been noted by clinicians in comatose patients and most notably in patients with cerebral hemorrhage extending into the ventricles. Sir Charles Sherrington, a Nobel laureate in medicine and physiology, described decerebrate rigidity in his animal experiments.13 Transection experiments in cats demonstrated the existence of a conceptional transverse plane at the level of the corpora mammillaria, red nucleus, and between anterior and posterior colliculi (line A in Fig. 1-10). Transection would produce decerebrate rigidity. Rigidity disappeared when a transection occurred caudal to that plane at the level of the vestibular nuclei (line B in Fig. 1-10). These findings were confirmed by others.69


One of the first descriptions of decerebrate rigidity in man was by Walshe in 192387 (Fig. 1-11). He described that

the patient lay motionless and unconscious on her back with the head in a median posi-

tion. There was no trace of head retraction. The arms lay across the chest, semiflexed at

the elbows, with the forearm slightly pronated and the wrists and digits flexed. The legs

lay extended and adducted with the feet plantar-flexed. There was spasticity of moderate

degree in all 4 limbs, definitely more pronounced in the arms than in the legs.

In addition, the article described an abnormal tonic neck reflex of Magnus and De Kleijn (normal in neonates, known as the tonic neck reflex; Fig. 1-12).

To translate these experiments to clinical observations is difficult, but Walshe sug-gested that next to a midbrain lesion, a lesion of the forebrain or a ventricular hemor-rhage could interfere with the activity of the midbrain centers87 Walshe noted: “yet the lesion does not end here and in almost all of them, there is clear evidence of a pro-gressive and ultimate fatal interference with the function of the vital medullary cen-ters.” Decerebrate posturing became mostly recognized after traumatic brain injury and was recognized as a poor prognosticating sign.20 In Fulton’s studies, decorticate responses with grasp reflexes were found in animals after removal of both motor and premotor cortices.31

comm.

MR.

VIII.

Ch.

c.m

B

A

Bulb. Olfact.

cop

8.9.a

FIGURE 1-10 Sherrington’s transection experiments (see text).13


Its localizing value in humans is less understood, and it can be observed in midbrain lesions or lesions involving injury to both hemispheres without evidence of brainstem injury or displacement. Moreover, worsening to flaccidity or change to withdrawal or decorticate responses is not clearly correlated with outcome. Both decorticate (patho-logical flexion) and decerebrate (pathological extension) responses indicate a high likeli-hood of a severe structural injury. There are many patients with a decorticate response on one side and a decelerate response on the other or even alternating in the acute stage. Often the “worse” response correlates with the hemispheric lesion. We can only conclude that it is more likely that the responses are different manifestations of a similar lesion rather than being precisely localizable.

Fixed Dilated Pupil

The observation that pupils dilate and become fixed to light came first from experimental studies. In the early 1800s the German internists and surgeons Von Leyden, Naunyn, and Bergmann all noted in their ICP studies that pupils dilate with increasing ICP. The pupillary

FIGURE 1-11 Walshe’s paper; original clinical description of rigidity.87


changes were considered a result of medulla oblongata ischemia because their appearance was so closely related to the appearance of hypertension and periodic breathing.

Changes in pupils have fascinated clinicians and their significance sweeps far beyond any other sign in coma. The earliest clues to this time-honored sign can be traced back to 1867, when Sir Jonathan Hutchinson observed unilateral pupillary dilatation in a patient, although he dismissed its significance. It was forgotten for two decades before Sir William Macewen51 recognized its import in a treatise on the pupil (Fig. 1-13): “the patient was generally insensible at the onset when both pupils were dilated and fixed. As the patient recovered consciousness, one pupil became normal while the other remained dilated and fixed; this being on the side of the lesion.”

The surgeon Bergmann was convinced the lesion was located in the cortex. In his classic work (Deutsche Chirurgie: Die Lehre von den Kopfverletzungen, 1880) he located oculomotor dysfunction in the frontal eye field. His clinical observations also described widening of the pupil ipsilateral to the lesion.

Collier argued that oculomotor palsies were “always of peripheral type.”65 Plum and Posner67 suggested that downward movement of the posterior cerebral artery compresses

FIGURE 1-12 Decorticate responses and Magnus-De Kleijn tonic neck reflex. The text reads as

follows: “The following tonic reactions were observed: When the head was rotated so that the

face looked over the right shoulder the right arm, after a latent period of about 2 seconds, slowly

extended at the elbow the whole limb abducted. The forearm went into increased pronation. The

wrist and digits remained immobile. The right lower limb slowly and actively extended the foot

plantar flexing. The left arm, the one on the side to which the occiput was directed, simultane-

ously went into full flexion at the elbow so that the hand came into the neighborhood of the

neck. The forearm supinated and the wrist and digits remained immobile.”87


the third nerve. As mentioned before, the correlation between fixed dilatation of the pupil and herniation was clearly described by the classic studies by Reid and Cone,71 and by Jennett and Stern,40 who replicated the experiment in cats. Jennett and Stern had pos-tulated the following:

The rapidity with which cardiorespiratory pupil and electroencephalographic changes

usually return to normal on releasing the pressure; although, the hernia clearly per-

sists—calls into question the rationale for splitting the tentorium in patients with per-

sisting symptoms after removal of mass lesions.

The authors also stated that

the tentorium was removed in certain animals, and the changes were observed different

from those that were noted with the tentorium intact; namely the severe respiratory

changes were seen prior to pupillary dilation suggesting perhaps that with the tent gone,

there was more ready transmission of the distorting effect to the lower brain stem.40

Out of conformity, Fisher-Brugge coined the term Das Klivus Kanten Syndrome (the edge of the clivus syndrome). This syndrome largely consisted of unilateral or bilateral dilated fixed pupils and decreased consciousness; it was no different clinically than uncal hernia-tion, but no compression by the uncus was found. Abnormal consciousness was attrib-uted to compression or ischemia of the mesencephalon. Fisher-Brugge was convinced that the uncus of the hippocampus played no role in the cause of the fixed pupil.24 The third nerve could be damaged owing to its position—wedged in between the edge of the clivus and the tentorial ridge. Petechial hemorrhages in the nerve were put forward as additional proof. It could also explain enlargement of the pupil on the opposite side of the mass.

FIGURE 1-13 One of the first observations of fixed dilated pupil.51


Ropper suggested acute angulation of the third nerve over the clivus due to displace-ment of the brainstem in an autopsy study.73 Therefore, the mechanism of pupillary enlargement has not been definitively explained, and more than one mechanism may be operative. How the opposite pupil enlarges with transtentorial herniation remains an ana-tomical mystery, with bilateral central (at the nucleus level) third-nerve damage being a more likely mechanism.

Oculovestibular Reflex

The initial discovery that the oculovestibular reflex is impaired in coma was by Klingon, who demonstrated disorders of the conjugate movements of the eyes after stimulation with cold water.43 Disconjugate ocular responses (abduction of the eye at the stimulated site with the opposite eye frozen) correlated in a comatose patient with demyelination in the tegmentum (Fig. 1-14). Nathanson and colleagues60 described, in 1957, the pos-sible usefulness of oculocephalic and caloric responses in comatose patients and included patients who had complete absence of the oculocephalic reflex and caloric stimulation when treated with barbiturates. The clinical-pathological correlation was illustrated by massive brainstem lesions from basilar artery occlusion or swollen glioblastoma with brainstem hematoma. In these patients, disconjugate ocular movements were found; however, the presence or absence of cornea reflexes and pupillary light reaction did not correlate with the findings on oculocephalic and caloric tests. Patients who had a tonic ocular deviation had return of consciousness, while the absence of caloric stimulation and oculocephalic reflexes correlated with no recovery. Thus, oculocephalic and caloric tests were considered indicators of depth of coma and, when absent, indicative of a poor prognosis.43 Furthermore, Ethelberg and Vaernet22 demonstrated the abnormality of conjugate eye movements similar to internuclear ophthalmoplegia in three cases of

FIGURE 1-14 Klingon’s paper on the usefulness of caloric testing.43


supratentorial space-occupying lesions. These earlier studies pioneered the use of clinical tests to assess brainstem function.

Breathing Patterns

The discovery of the morphology of the respiratory center in the medullar oblongata can be attributed to Legallois, in his rabbit experiments in 1812.48 This was followed by a series of studies linking brain injury to abnormalities of the rhythm of breathing.66 Abnormal breathing patterns had been recognized as indicative of a primary brain lesion, and the most commonly known were periodic breathing patterns. The best recognized is the Cheyne-Stokes respiration (CSR), characterized by repeated periods of hyper-pnea that alternate with apnea, with cycles that are not random but stereotypical. Each cycle may last approximately one to three minutes. In 1818, Cheyne16 described a patient with a stroke with a peculiar breathing pattern (Fig. 1-15). “For several days his breath-ing was irregular. It would cease for 1/4 of a minute and then it would become percep-tive; although very low; and then by degrees it became heaving and quick and then it would gradually seize again.” Stokes described a similar pattern, of which he stated as fol-lows: “the symptom in question was observed by Dr Cheyne, although he did not connect it with a special lesion of the heart.”52,64 Studies that connected CSR with autopsy-proven structural lesions of the brain were subsequently reported.

Another classic central breathing pattern is Biot breathing.90 Biot noted that this breathing pattern is different from CSR (Fig. 1-16). He distinguished this breathing pat-tern from Cheyne-Stokes breathing and, because he noted it in a patient with tuberculous meningitis, named it rhythme méningitique. The breathing pattern is irregular and rapid, with rhythmical pauses lasting 10 to 30 seconds, but sometimes with alternating periods of apnea and tachypnea. This breathing pattern lacked the crescendo–decrescendo cycles attributed to Cheyne-Stokes breathing and was completely irregular, with varying peri-ods of apnea.10,11

Central neurogenic hyperventilation was first described by Plum and Swanson68 in 1959. Central neurogenic hyperventilation results in alkalosis due to a very high respira-tory rate (60 to 100 per minute). In this study, the lesions that correlated with central neurogenic hyperventilation were mostly in the pons. Nine patients were described who developed “severe hyperventilation during the course of acute central nervous system disease.” In all of these patients, medial pontine damage was responsible for hyperventila-tion. In their hypothesis, “central neurogenic hyperventilation in man results from the uninhibited stimulation of both inspiratory and expiratory centers in the medulla by a lateral pontile reticular formation and bilateral located descending neuro pathways.” In all


FIGURE 1-15 Cheyne’s original description.16 The patient with a “peculiarity . . . in the state of

breathing” died of apoplexy.

PLANCHE IV. – Tracés pnéumographiques dans la méningite tuberculeuse.

FIGURE 1-16 Biot’s original tracing.10


patients, there was profound hypocapnia with respiratory alkalosis but no hypoxemia.68 Since this original description, many reports linked central neurogenic hyperventilation due to brainstem lymphomas.

Lower brainstem lesions can produce ataxia of respiration characterized by irregular breathing, prolonged inspiratory gasps, and apneustic breathing. Many of these observa-tions were seen in patients with acute bulbar poliomyelitis,68 but other cases involved patients with pontine hemorrhage and infarction, in whom irregular respiratory rhythm and apneic failure were reported. Steegmann79 described patients with irregular slow and labored gasping stertorous respiration. Deep inspiratory gasps were described with dia-phragmatic excursions but without intercostal movement. With each gasp, the chest wall retracted. In other cases, respiration was reduced to two respirations per minute or shal-low without a change in rate. He correlated these inspiratory gasps to apneustic respira-tions in experimental animals. The experimental studies referred to in his paper were by Marckwald, who located a regulatory center at the inferior colliculus and found that long, powerful inspiratory cramps were interrupted by intervals with short expiratory pauses. Apneusis could be produced by severing the vagus nerve, transecting at the pons just posterior to the inferior colliculus.54

Another neurogenic breathing type is cluster breathing. Clusters of regular breath-ing (including tachypneic periods) are interrupted by regular or irregular pauses. Although, allegedly, it has been associated with brainstem lesions, it may be more likely a variant of Cheyne-Stokes breathing (but missing the crescendo–decrescendo pattern).67 Cluster breathing has been recently described with bihemispheric lesions sparing the brainstem.28

In summary, one can only conclude that the localizing value of certain breathing pat-terns is limited, but its presence or sudden appearance has practical significance. It tells the clinician that the patient is potentially deteriorating neurologically and that oxygenation may become compromised, requiring endotracheal intubation and mechanical ventilation.

UNDERSTANDING THE MECHANISMS OF METABOLIC AND DIFFUSE

ENCEPHALOPATHIES

In the second half of the 19th century, most notably Osler62 noted that coma can be due to intoxications, infections, and organ failure.44 Plum and Posner67 in their 1966 textbook categorized it as metabolic, “caused by diffuse failure of neuronal metabolism,” and dis-tinguished primary and secondary metabolic encephalopathies. Metabolic encephalopa-thy has since become a medical umbrella term and includes all conditions not associated with a new mass or destructive lesion.


Much of the understanding of the so-called metabolic causes of coma came from ani-mal experiments. Experimental studies have consistently produced evidence of “selective vulnerability of the brain” and excessive glutamate in brain in the pathogenesis, among other mechanisms.77 Uremic coma and encephalopathy at the earlier stages of renal fail-ure have been best described by Bright12 (Fig. 1-17). Bright noted multiple cases with headache, lassitude, intermittent confusion, and myoclonus evolving into a more serious state heralded by seizures, stupor, and coma. Osler emphasized “mania, noisy and restless patients with a delusional insanity.” Osler noted that seizures were not obligatory before a lapse into stupor, and noted focal signs. After dialysis became commonplace, severe forms became less noticeable. The uremic neurotoxins have remained elusive.

Initially, very little research has been done in understanding encephalopathy associated with acute metabolic derangements. Most of the laboratory experiments included both rapid lowering of plasma glucose and examination of the effects of hyperglycemia. These studies included exploration of the pathogenesis of hyperglycemia and, most notably, the introduction of the existence of idiogenic osmoles by Arieff and Kleeman.7 In these stud-ies, animals became acutely hyperglycemic, and blood sugar levels were then corrected with insulin, fluids, or peritoneal dialysis without insulin. During hyperglycemia, the

FIGURE 1-17 Bright’s original description of cases of neurologic manifestation of acute renal

disease.12


brain water content fell and equalized osmolality of the brain and the CSF. After several hours, the brain water content returned to normal, with no solutes that could explain this phenomenon. The return of brain water to normal levels was attributed to the formation of “idiogenic osmoles.” This experiment suggested that the diabetic brain accumulates an extra solute that defends against brain dehydration. These molecules have included glutamine, taurine, and myoinositol.

Hepatic encephalopathy and decreased consciousness had been noted in von Frerichs’ work. The emergence of jaundice marked the development of delirium, convulsions, and coma. In 1860, von Frerichs emphasized a transitional phase of “gloomy, irritable temper and restlessness” but also “quiet, harmless wandering.” Convulsions were noted in one third of the patients.85 These symptoms paralleled the appearance of jaundice, a clinical sign that could be without neurologic manifestations until “a train of symptoms beto-kening danger supervened.” A landmark paper by Adams and Foley5 further delineated clinical symptoms and pathological changes of the brain. This clinicopathological study introduced asterixis as a key finding (Fig. 1-18). Adams and Foley documented asterixis with electromyographic recordings, but when coma occurred, prognosis was poor, with most patients dying within two weeks. Progressive hepatic encephalopathy in fulminant hepatic failure has only been recently recognized as a clinical syndrome associated with treatable cerebral edema. Treatment requires measures to reduce ICP and emergent liver transplantation. Other “metabolic encephalopathies” associated with hypothyroidism, Addison’s disease, acute pancreatic disease, and sepsis have remained poorly understood due to the lack of a specific animal model.

Of all the diffuse encephalopathies, anoxic-ischemic injury to the brain after cardiac arrest became of interest to pathologists in the early 1950s.59 With the introduction of cardiopulmonary resuscitation (CPR), cerebral damage became recognized by clini-cians and first by Negovsky, who named it post resuscitation disease. Some of the early hypothesis included cerebral reoxygenation injury and postischemic vasospasm cascad-ing to necrosis.61 Some of the attention was directed to the different vulnerability of gray and white matter, and it became clear that the cerebral and cerebellar cortices were more affected with ischemia than the basal ganglia, with the reverse happening with hypox-emia. Levine reported in his rat experiments that white matter was more resistant to anoxic-ischemic injury than gray matter.49 These observations became even more impor-tant when the clinical landscape changed with the introduction of CPR standards set by the American Heart Association in 1966.2 Clinicians now noted that despite treatment of shock and CPR, the brain could still have irreparable damage.8 In his animal experiments, a good deal more optimistic than observed in practice, Heymans correlated improvement of clinical function with the time needed for revival and found five to 10 minutes for the


cornea and pupil reflex and 15 to 30 minutes for the vasomotor and respiration regulation as the threshold for irreversibility.33

UNDERSTANDING PSYCHOGENIC UNRESPONSIVENESS

Attention to psychogenic unresponsiveness may have started with the major hysterical attacks resulting in prolonged unresponsiveness and have been best described and shown in Charcot and Richer’s Les démoniaques dans l’art (Fig. 1-19). Visual hallucinations of animals (rats, snakes) precede trembling motions or contraction of one arm or leg, fol-lowed by the whole body. A “seizure” may follow with breath-holding pallor followed by redness, neck engorgement and upward eye deviation. Foam can appear on the lips, usually early and not during the resolution phase. The muscles are completely “relaxed.” Often, this phase is followed by “acrobatics” in some patients (see Fig. 1-19). Extreme opisthotonus may result with a patient curved forward with the head and feet touching the bed or may occur with the patient lying on the side. Charcot also described bizarre movements (as if wrestling with an imaginary being) and savage cries. Respiration may be hissing and interrupted by hiccups. The mouth may be open with tongue protrusion.

FIGURE 1-18 First descriptions on encephalopathy from liver disease by Adams and Foley, EMG

of asterixis.5


FIGURE 1-19 Title page of Charcot and Richer monograph.


VARIÉTÉ DÉMONIAQUE DE LA GRANDE ATTAQUE HYSTÉRIQUEContorsions.

PÉRIODE DE CLOWISME DE LA GRANDE ATTAQUE HYSTÉRIQUEContorsion. Arc de cercle.

PÉRIODE DE CLOWISME DE LA GRANDE ATTAQUE HYSTÉRIQUEVariété de I'arc de cercle.

PÉRIODE DE CLOWISME DE LA GRANDE ATTAQUE HYSTÉRIQUEAttitude de cruci ement.

FIGURE 1.19 Continued. Drawings of extreme postures of hysterical unresponsiveness.


Charcot often described these contortions as “being possessed.” His treatment of young afflicted women (but also men) included hypnosis and most memorably the compresseur ovarien (an abdominal vise with a knob applying pressure to the ovary) and both could stop the spells. Psychogenic unresponsiveness found entry in psychiatric and medical texts but remained merely descriptive and less ostentatious as Charcot’s examples, often as an afterthought after exclusion of other causes, and certainly not as a first consider-ation. The condition is very rare, and systematic study in a series of patients has not been reported.

UNDERSTANDING THE SPECTRUM OF PROLONGED COMATOSE STATES

Many astute neurologists noted that patients with prolonged unconsciousness had simi-lar clinical characteristics and a need for further classification emerged. How to best name these conditions did not seem easy. Earlier terms for prolonged unconsciousness were discarded because they failed to capture the essence of this state, namely a totally uncon-scious state with only autonomic function being retained. Kretschmer45 introduced the term Das Apallische Syndrom in 1940 (Fig. 1-20), and the connotation is still used in a few European countries. Kretschmer coined the term to be similar to apraxia and agnosia. Apallia referred to a lesion of the pallium, the mantle of gray matter forming the cortex. Other, now abandoned, terms include coma vigile, la stupeur hypertonique post-comateuse, and vie végétative, and more recently wakeful unconscious state.

The first attempts to clinicopathologically define this syndrome (“neocortical death”) came from the Institute of Neurological Sciences in Glasgow, but this term was applied only to patients after cardiac arrest. Jennett and Plum38 proposed the term persistent vegetative state and described clinical features that drew a distinction from other less severely disabling neurologic states (Fig. 1-21). In their 1972 Lancet com-munication, they wrote

the word vegetative itself is not obscure: vegetate is defined in the Oxford English Dictionary

as “to live a merely physical life, devoid of intellectual activity or social intercourse,” and

vegetative is used to describe “an organic body capable of growth and development but

devoid of sensation and thought.”

Jennett and Plum coined the term to emphasize the “vegetative or noncognitive components of the nervous system.” Plum mentioned that “the term persistent auto-nomic state could have been employed almost equally well,” but the term was “less


(A)

(B)

FIGURE 1-20 (A) Kretschmer’s paper and (B) one of the first photographs of a vegetative state.

Reproduced from Kretschmer.45


flexible” and “would have been less understood by the patient’s family.”70 The term persistent vegetative state became transfixed in the medical vernacular.

Cairns and colleagues14 can be credited for introducing the term akinetic mutism. Patients are unaware and mostly immobile but track objects or fixate on their surround-ings. In the original description of akinetic mutism, the clinical picture is described as follows:

The patient sleeps more than normally, but he is easily roused. In the fully developed

state he makes no sound and lies inert, except that his eyes regard the observer steadily,

or follow the movement of objects, and they may be diverted by sound. Despite his

steady gaze, which seems to give promise of speech, the patient is quite mute, or he

answers only in whispered monosyllables. Oft-repeated commands may be carried out

in a feeble, slow, and incomplete manner; but usually there are no movements of volun-

tary character; no restless movements, struggling, or evidence of negativism.14

FIGURE 1-21 Persistent vegetative state, a syndrome suggested by Jennett and Plum.38


Cairns and colleagues noted fluctuations and episodes where the patient would respond by some speech and purposeful movements.14 The clinical entity is difficult to recognize and may disappear with the introduction of new less precise terms (Chapter 4).

Over the years rehabilitation physicians in recognized that patients in a persistent veg-etative state were or became sometimes more awake, albeit minimally so. These patients at times were responsive and other times completely noncommunicative, and therefore an attempt was made to better define this condition tentatively named Minimally Conscious State and to set it apart from persistent vegetative state. This started a new and ongoing discussion on further classifying prolonged comatose states—and unfortunately further ambiguity (Chapter 4).

At the far end of the spectrum of comatose states is brain death. This clinical condi-tion, characterized by coma with loss of all brainstem function including breathing and blood pressure regulation, became noted only in the early 1950s. Irreversible coma and brain death entered the medical lexicon. The initial descriptions of brain death came from neuropathological and electrophysiological observations. As in so many other conditions, neuropathologists were the first to find remarkable characteristics in comatose patients who were on the ventilator. The term respirator brain was coined quickly after the patho-logical features showed a dusky, congested, discolored appearance with liquefied por-tions and often crumbling cerebellar tonsils.47 This finding was simply a consequence of a very high ICP resulting in pressure coning and global intracranial circulatory arrest. At least several days were needed for the brain to become discolored, showing vasoconges-tion and thrombosis in the venous system. However, outer portions of the cortex could remain intact due to retained extracerebral circulation.47,86 Parallel to this finding was the observation by electroencephalographers of a new electrographic phenomenon called isoelectric or low-voltage electroencephalogram (EEG) in deeply comatose patients with loss of all brainstem reflexes (Fig. 1-22).25

It took several years to clearly define the clinical accompaniment of both these laboratory findings, and the discovery was, therefore, in a somewhat reversed order. Although there were prior mentions of brain death (focused on absent flow by angi-ography, or on isoelectric EEG), two French groups proposed criteria. In 1959, Wertheimer, Jouvet, and Descotes89 were among the first to propose criteria for this new clinical state. This manuscript largely focused, as many before, on the significance of an isoelectric EEG but also documented stopping the ventilator to stimulate the respiratory centers through increasing respiratory acidosis. Medulla oblongata func-tion was further tested by carotid compression or ocular pressure (no change in pulse rate), and intravenous injection of atropine and amphetamine (no bradycardia). Neurosurgeon Wertheimer and neurologist Jouvet were set on defining brain death by


electrophysiological criteria and the authors felt objective criteria were needed. They inserted fine bipolar electrodes into the medial thalamic structures, applied strong elec-trical currents, and found no motor response as proof of no brain function (Fig. 1-23).

Even more important and also in 1959, neurologists Mollaret and Goulon57 published Le coma dépassé (best translated as “irreversible coma”), which described for the first time comprehensive neurologic findings in patients who lost brain function (Fig. 1-24).

FIGURE 1-22 Early study on EEG in comatose states.


Ouverture des yeux

Réaction d,arret

Réaction d,éveil

Bruit

Pincement

RESPIRATION ARTIFICIELLE

Pincement

STADES

I

II

III

IV

RÉACTIVITÉ EEGCORRÉLATIONS CORTICO VÉGÉTATIVES

YEUX TONUSRCM

(EYE LID

REFLEX)

CORNÉEN DÉGLUTITION

FIGURE 1.22 Continued. Early description of isoelectric EEG in brain death.25

This type of coma (dépassé) was now classified as the deepest coma known so far (Fig. 1-25). Mollaret and Goulon reserved judgment on whether this condition meant death of the individual. Their description included immobility of eyeballs in a neutral position, fixed and dilated pupils, absent blinking with stimuli, absence of swallowing reflexes, drooping of the jaw, absence of motor response to any stimuli, muscle hyper-tonia, areflexia of tendon reflexes, and equivocal plantar reflexes. More clinical details included “medullary automatisms,” lack of spontaneous respiration after discontinua-tion of ventilation, immediate cardiovascular collapse as soon as the adrenalin infusion was stopped, and a disturbance of thermoregulation and hypothermia, depending on the environmental temperature (poikilothermia).57 The paper also noted the absence of reactivity of the isoelectric EEG. The original observations of Mollaret and Goulon also included deterioration in these comatose patients with the development of oxygen desaturation, hypercapnia, and appearance of combined respiratory metabolic acidosis, polyuria, hypoglycemia, and glycosuria.57 They also found that the heart rate often slowed to 40 beats per minute with no change in pressure of the eyeballs, or carotid sinus, or use of intravenous atropine.


There has been some historical discussion as to whether neurologists Mollaret and Goulon or neurosurgeon Wertheimer and neurologist Jouvet were the first physicians to describe brain death. Both papers—published months apart—have comparable value. A strong argument can be made that Mollaret and Goulon had a more detailed paper, a larger series of patients, significantly more detail on how the patient’s absence of brain function affected systemic instability, and further characterization of laboratory

(A)

(B) (C)

FIGURE 1-23 (A) Wertheimer and colleagues’89 proposal on brain death criteria. (B) Pierre

Wertheimer. (C) Insertion of needles deep into the thalami (Th1 and Th2) documenting no move-

ment after electrical stimulus.


abnormalities. However, this and other earlier European papers did not generate much interest in the United Kingdom or the United States and very little academic debate ensued in the following decade.

A major development occurred in 1968 when the Harvard Medical School Ad Hoc Committee was formed to examine a definition of brain death and published a guide-line.3,92 This committee, spearheaded by anesthesiologist Beecher, commissioned neu-rologists Schwab and Adams to write the initial drafts. The committee worked diligently and in four months produced an important document that was published in JAMA (Fig. 1-26). The document included a definition of brain death, a legal commentary, and a supportive address by the Holy Father Pope Pius XII. No public opinion was voiced and little is known about the implementation at that time.

(A) (B)

FIGURE 1-24 (A, B) Mollaret and Goulon57 and their paper on clinical brain death.


FIGURE 1-25 Proposal of coma classifications (see text).

In the United Kingdom, eight years later, the Conference of Royal College of Physicians—with a major contribution by Pallis—published their document on “Diagnosis of brain death” in 1976.63 Their clinical diagnosis was called brainstem death, and their position was that if the brainstem is dead, the brain is dead; and if the brain is dead, the person is dead. This also implied that confirmatory tests were


(A)

(B)

FIGURE 1-26 (A) Cover page of Harvard brain death paper published in JAMA.3,92 (B) The commit-

tee, chaired by Dr. Beecher (left), included multiple scholars and clinicians with two neurologists

middle and right (Drs. Schwab and Adams).

not required to document absence of brain function.3 The document was important because it more clearly delineated confounding factors, a flexible period of observa-tion, and a technique for apnea testing.


The centrality of the brainstem in death determination has been recognized by many and even Charcot (“le bulbe c’est ultimum moriens des centres nerveux”). Still there was a major focus of U.S. neurologists on cortical injury and the need to document a “flat EEG” when diagnosing brain death. The emphasis on cortical function may have been the reason that during this time, a confusing discussion appeared with new terminology. Brain death was now classified by some bioethicists as whole brain death (hemispheres and brainstem irreversibly damaged) but also higher brain death (hemispheres irreversibly damaged), brainstem death (brainstem irreversibly damaged), and even a super locked-in syndrome (brainstem irreversibly damaged but hemispheres functioning), dividing the death of the brain into segments. This discussion largely was helpful in distinguishing persistent vegeta-tive state (higher brain death) from brain death (whole brain death). It became clear that the dividing line between these positions was the tentorium—brain versus brainstem.

In a series of papers published in the British Medical Journal, Pallis described the diagno-sis of brainstem death and the pitfalls and preconditions.63 His position was that these two different concepts could be reconciled by accepting the loss of all brainstem reflexes as the point of no return (Fig. 1-27). The mere fact that most patients with a catastrophic neuro-logic injury do not lose all brainstem reflexes points to its natural resilience. The UK posi-tion was that the brainstem was the defining part of the brain. However, the UK position also stressed that the patient had to pass through two filters, those of previous conditions and exclusions. Although prior criteria mentioned mimicking factors, this approach was novel in suggesting that no patients should be examined unless this issue was addressed. In addition, testing for apnea was described in more detail using preoxygenation and diffusion oxygenation. The Conference of Medical and Royal Colleges in the UK later changed “brain death” to “brainstem death,” again emphasizing the importance of the brainstem.

United States

United Kingdom

Whole brain death

Whole brain death Brainstem death

An ending controversy

A starting controversy

Vegetative state

FIGURE 1-27 UK and US positions on brain death (modified from Pallis).63


Another notable development was the National Institutes of Neurologic Disorders and Stroke (NINCDS) Multicenter Collaborative Study on Cerebral Death1 (Fig. 1-28). This prospective study enrolled patients with “cerebral unresponsivity and apnea.” Of 189 patients, 187 died from cardiac arrest and two survived, but these were patients with drug intoxication. Their proposed criteria required one examination at least six hours after the onset of coma and apnea. Problems have been recognized and not all of the patients may have met the criteria of brain death by current standards. This study was followed by a report by the “Medical Consultants on the Diagnosis of Death to the President’s Commission on Ethical Issues in Medicine and Biomedical and Behavioral Research.”4

In 1995, the American Academy of Neurology published its evidence-based guide-lines90 (Fig. 1-29). This document specifically defined clinical testing of brainstem function, described conditions that could mimic brain death, listed observations that are compatible with brain death but suggested otherwise, and gave a clear description of the apnea test

FIGURE 1-28 NINCDS collaborative study on brain death.


procedure. The validity of confirmatory laboratory tests was also critically reviewed. An update of the guideline, incorporating new literature and a checklist, followed in 2010. The document also concluded that in adults one full examination would be sufficient and that ancillary tests had little place in the diagnosis of brain death93 (Chapter 5).

CLASSIFICATION OF COMA AND MAJOR WORKS

It was not until the 1960s, with the publication of several noteworthy works, that the evaluation and approach to the comatose patient were described. One of the first books dedicated to coma was by the neurologists Fazekas and Alman. Their book focused on the physiology of acute metabolic disturbances but lacked insight into the mechanisms of coma caused by mass effect (Fig. 1-30). As alluded to earlier, after O’Neilly and Plum published their observations of clinically deteriorating patients and outlined two brain herniation syndromes in 1962, a full textbook followed in 1966 (The Diagnosis of Stupor and Coma) (Fig. 1-31).67 Subsequent editions (1972, 1982) expanded on outcome pre-diction and the use of CT scanning, followed by a fourth rewritten edition in 2007. After the publication of this now-classic work written with Posner, Plum became the primus inter pares of those studying comatose patients. The clinical material came from King

FIGURE 1-29 The American Academy of Neurology guideline on brain death published in 1995.


FIGURE 1-30 First published book on coma in the US (cover and content).


County Hospital and the University of Washington Hospital in Seattle between 1953 and 1963. This book put the emphasis on patients with destructive lesions, supratento-rial mass lesions, infratentorial mass lesions, and metabolic brain disorders. The devel-opment of clinical signs over time—the rostrocaudal patterns—characterized this book. The book broadly classified the metabolic causes and included meningitis, subarachnoid hemorrhage, and cerebral vasculitis as a metabolic encephalopathy. It cemented the dis-tinction between “structural” and “toxic-metabolic” causes of coma and has remained a clinical guide for neurologists. The book was novel in producing a table of toxic and metabolic coma based on changes in respiration (hypoventilation or hyperventilation) and linking types of breathing abnormalities to certain locations in the brain and brain-stem. The book also carefully details bedside methods of neurologic examination.

FIGURE 1-31 Plum and Posner’s book on stupor and coma, first edition.


Soon thereafter, C. M. Fisher published an extraordinarily detailed paper, Neurological Examination of the Comatose Patient27 (Fig. 1-32). Fisher emphasized that ocular signs are “the most important of the entire examination” in a comatose patient. After seeing 10 cases with clinical-pathological correlation, Fisher described ocular bobbing (an intermittent down and up conjugate movement of the eyes), which he correlated with pontine pathology. Other ocular signs were described for the first time, including “wrong-way eyes,” pontine miosis, ocular agitation, doll’s eyes, eye closure and blink-ing in coma, and reflex blepharospasm. Fisher pointed out that the eyelid tone or the length of time the eyes remain open after they are opened by the examiner are both findings that give an indication of the depth of the coma. New observations about the motor examination included bilateral decerebrate posturing resulting from acute lesions involving the supratentorial motor system. In a time before CT scans, Fisher classified coma by CSF abnormalities. The three major categories were normal cellular content in the CSF, gross or microscopic blood in the CSF, and leukocytosis, followed

FIGURE 1-32 Fisher’s landmark paper on examination of coma.


by a subdivision in the presence of symmetric or asymmetric signs. He noted that “examination of the cerebrospinal fluid is the key stone of neurologic diagnosis. The electroencephalogram is rarely of crucial help, clinically.”27 The manuscript is chock-full with clinical pearls and many observations not described before. He summarized these new findings as follows:

The use of head tilting in assessing upper brainstem function, the use of combined head

rotation and caloric stimulation, unilateral decerebrate posture, decerebrate posture of

supratentorial origin, the “ventral midbrain syndrome” (decerebrate posture with full

extraocular movements and fixed pupils in tentorial brainstem compression), ptosis with

mass supratentorial lesions, recurrent unconsciousness in ruptured saccular aneurysm,

athetoid restlessness, the convulsions of double hemiplegia, the recoverability of seizure

tissue, the relative silence of cerebellar pressure cone, doll’s eyelids, hemiplegia-in-flexion,

ocular agitation, the 1½ syndrome, ipsilateral seizures in cerebral hemorrhage and a large

number of adventitious movements.27

In addition, Fisher questioned many extrapolations from experimental studies to humans (particular Sherrington’s cat experiments), the concept of uncal herniation (mid-brain involvement rather than herniating tissue compressing the oculomotor nerve), and even the use of tendon reflexes in coma (“not of great value in assessing the state of the nervous system”).27

Other important works on prolonged comatose states and brain death appeared. Two major works appeared on brain death (Fig. 1-33). One book was a bundle of papers published by Pallis (as mentioned above) and provided not only the UK posi-tion but also other positions around the world. Another work, edited by Korein, included presentations at a symposium in New York and provided the U.S. position and therefore was heavy on ancillary tests. These books not only have historical value but also explain the diversity of opinion when it concerned brain death determina-tion—the pragmatic UK position (clinical examination of the brainstem) versus the more safe guarding position in the United States (confirmatory tests). Surprisingly, to this day there remain differences worldwide in how to best approach the clinical assess-ment of brain death.

The book on persistent vegetative syndrome by Bryan Jennett published in 2002 was a culmination of his major interest but was also remarkable for its discussion of eth-ical and legal issues when dealing with permanently unconscious patients (Fig. 1-34). The monograph reviews the evolution of the nomenclature up to the designation of vegetative state coined by Jennett and Plum. The book carefully discusses topics that

FIGURE 1-33 First comprehensive collection of articles on brain death.


have remained urgent even today, such as “perception of pain” and “awareness without behavioral evidence.” Surveys in the early 1990s found that a considerable proportion of neurologists thought that patients did suffer pain, and a large proportion of neurolo-gists even medicated the patient. Jennett concluded in one of his chapters that “the question of what vegetative patients actually experience is likely a matter of debate for some time.”

PROGNOSTICATION OF COMA

Triage may have prompted outcome studies because the number of beds—particularly in Europe and the UK—became insufficient for the increasing demand. Outcome studies,

FIGURE 1-34 Jennett’s book on the vegetative state.


therefore, were often seen as a way to determine appropriate care of a patient but also as a way to refuse ICU care if “nothing could be done.” Such an assessment of outcome studies led to concerns that the findings could be used as a prioritization tool—a concern that still rings true today.

Judging outcome after a brain injury resulted in coma became a major topic of inter-est in the mid-1970s. Outcome assessment has always been part of the clinical assess-ment, but there was a good reason to identify comatose patients who had a “fighting chance,” so to speak, and patients who might not survive the injury. Parallel to this development was the interest in building databanks30,38,39 that could provide data col-lected in a standardized way. Outcomes that had been described previously included categories such as “permanent invalid,” “slight sequelae,” “partially reintegrated,” and “mental restitution,” and all were insufficient interpretations of a patient’s functional well-being or handicap.

The approach to the long-term care of persistently comatose patients became an important issue, and there was a need for prospective data to guide neurologists in estimating the prognosis of comatose patients. These early seminal studies shaped the prediction models and implied that clinical information alone could assist physicians in making a prediction. Most previous studies focused on patients comatose from trau-matic brain injury, but there had been small studies about prognosis in comatose patients following CPR.

It became clear that neurologic examination could predict the outcome, but the type of cardiac arrest (asystole or ventricular fibrillation) and advanced age were also recog-nized as predictors for outcome.9 The study by Willoughby and Leach95 already corre-lated motor responses to outcome and was followed by a series of studies prognosticating morbidity and mortality, most notably by Levy and associates.15,50,78 The impetus for this study was the result of Plum and Jennett’s collaboration. In 1981, for the first time, com-plex statistics were used to improve the accuracy of prognosis, and this became known as the “Levy algorithms” (Fig. 1-35). This study—using complex statistics—formed the basis of a more systematic approach to predicting outcome in comatose survivors of ischemic-hypoxic brain injury. It was shown that the clinical assessment of brainstem injury—by the testing of pupil, corneal, and oculocephalic reflexes—was crucial in esti-mating a prognosis in these patients. The algorithms in the paper became well accepted by neurologists over the years, and several of the basic principles of prognostication in comatose patients are still used today.

As early as the 1970s, studies claimed to have identified clinical features that would portend a poor outcome in traumatic brain injury. The Glasgow Group, in collaboration with Dutch centers and Los Angeles County USC Medical Center, created an international


head injury databank and carried it through to a large dataset. The first dataset included 700 patients and showed a mortality of 50% and a degree of morbidity conspicuously similar among the three centers. The data also found that outcome was determined by the severity of injury—particularly when associated with anoxic injury from hypoxemia and hypotension—and age, and not so much with type of treatment and despite admission to specialized ICUs.37 The paper was the first to use mathematical calculations for predicting outcome. The authors were also quick to point out that these predictions could only assist physicians and emphasized that hospital administrators should not use the data to guide the use of resources.

Many other studies on outcome in catastrophic neurologic injury appeared. The early studies on prognostication are discussed in detail elsewhere.91,94 Many patients awaken—albeit with a disability—but some are beyond any medical or neurosurgi-cal help. How to assess outcome with great certainty remains very difficult, and the outcome of a patient seems determined by complexity of care and the decision to de-escalate care.

FIGURE 1-35 Levy and colleagues’ study on coma prognostication (see text).50


CONCLUSIONS

The past century witnessed an impressive transformation in the understanding of the mechanisms of coma, the role of increased ICP, patterns of brain tissue shift, and its clinical correlates. Different categories of coma—persistent vegetative state and brain death—emerged. In contrast, it is noteworthy that our understanding of brain herniation has remained incomplete. In some areas, the explanation was one-dimensional, focused on pathology, and extrapolated from slow-growing brain tumors. Nonetheless, clinicians have accepted the familiar refrains of “herniation” such as fixed pupils, posturing, agonal breathing patterns, and rostrocaudal deterioration. One reason why some of these signs have such a resonance is that they offer a possible explanation where no definitive one exists. No recent comprehensive study, it must be admitted, has unraveled the enigma of how and when brain tissue shift damages the thalamus and upper brainstem, and obser-vation of the comatose patient at the bedside has taught us that clinical deterioration rarely follows characteristic patterns.

Clinicians use a set of brainstem reflexes that localizes where the most destruction can be anticipated. However, MRI in recent years has shown the changes with brain-stem shift, thalamic compression, and destruction, and all these changes correlate with a decrease of consciousness. Better understanding of the mechanisms of coma in acute circumstances is warranted, and future work will likely focus on the boundaries of irreversibility of hemispheric or brainstem injury.

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60

The workings of human consciousness as a whole translate into a person being attentive and thinking, and purports to be a state with reasoning faculties. As a term, consciousness is an abstract concept for which theories abound. As a bio-logical phenomenon, neuronal circuits and networks operate using neurotransmitters, but a clearly configured “vital organ of consciousness” is neither possible nor likely. As a clinical observation, consciousness implies the presence of multiple modules that sense the environment. It involves attributes from conceptual pathways such as the limbic sys-tem (emotion and motivation), the temporal lobes and hippocampal systems (memory), the prefrontal cortex (execution), and other association cortices (processing). We do not know a great deal about consciousness. A venture into an account of the philosophi-cal and phenomenal aspects of consciousness—a knowledge of what is going on in our minds—would be predictably formulaic and outside the purview of this chapter. Those of us managing comatose patients can resort to two fundamental questions, and this remains the focus of this chapter: Which anatomical structures control conscious states, and how much must be disconnected, perturbed, or lost to change its main function?

Pathways that rouse us to become awake have been postulated in humans, and these structures may become interrupted by lesions, pharmacologically altered, or disrupted by a physiological derangement or toxin. The three main structures needed to keep a person alert and primed to respond are the ascending reticular activating system (ARAS) in the midbrain and pons, the thalamus, and the cortex. This chapter examines the key studies that led to the discovery of the main structures and projections producing what neurolo-gists considered consciousness and reviews the current understanding on the neurophys-iological correlates of consciousness.

The neuroscience of the Awake state

/ / / 2 / / /

The neuroscience of the Awake state / / 61

EARLY STUDIES

Research into sleep and wake mechanisms became active in the 1930s. It may have been influenced by von Economo’s publication on encephalitis lethargica in 1923 (pointing toward hypothalamic lesions). but more likely discoveries in the laboratories were sepa-rate observations and perhaps occurred even by chance when researchers sectioned dif-ferent parts of the brainstem looking for neural control of muscular tone.22,48

Bremer pioneered this research with his cerveau isolé and encéphale isolé experiments, and similar observations were made by others.3,4,6,10 “Acute isolation” of the cat’s forebrain from the upper brainstem through complete transection (cerveau isolé) would produce persistent sleep and a continuous pattern of spindles and slow waves on EEG. Alternating sleep and awake states occurred in the encéphale isolé preparation (transaction through the lower brainstem; Fig. 2-1). Chronic preparations would demonstrate sleep–wake pat-terns with running movements and crude walking.4 This led to the postulate that neural interconnections in the brain involved in wakefulness would need a spur from a brain-stem center.

Decades later, an activating network was discovered that signaled the thalamus and cortex and caused wakefulness. The experiments showed that electrical excitation of the reticular formation of the brainstem—and not so much the sensory tracts—caused changes in the EEG that were identical to EEG changes when a person awakens from sleep. Replacement of high-voltage slow waves with low-voltage waves and desynchroni-zation was interpreted as activation.28

One of the earliest attempts at defining the thalamocortical pathway was by Morison and Dempsey27 of the Department of Anatomy and Physiology of Harvard Medical School. Their topographical studies found that cortical responses occur with thalamic stimulation. A wide cortical distribution of the recruited responses was found, but they mostly converged in the gyrus proreus, the middle suprasylvian, and a triangular area at the lower margin of the posterior suprasylvian gyrus (Fig. 2-2). The authors concluded not only that the projection fibers of the thalamus radiate to the association cortex but also that the medial or interlaminar portions of the thalamus were likely responsible.27

Moruzzi and Magoun,28 from the Department of Anatomy of Northwestern Medical School, concluded from their experiments in cats that stimulation of parts of the reticular formation (medial bulbar reticular formation, pontine, and mesencephalic tegmentum) of the brainstem, and also the dorsal hypothalamus and subthalamus, abolished synchro-nization and caused low-voltage fast activity of the EEG. Its effects were further mediated by a diffuse thalamic projection system to the cortex. The distribution of the ARAS was illustrated in a figure that became an example for future drawings by others (Fig. 2-3).


(a) (b) (c)

(d) (e)

S S

(A)

(B)

FIGURE 2-1 (A) Portrait of Belgian Neurologist Frédéric Bremer.10 (B) Original experiment by

Bremer, also known as “Bremer’s cats”6: (a) Cat eyes with slit miosis after transection between

the pons and mesencephalon caudal to the third nerve nuclei in cerveau isolé; (b) sleeping cat;

(c) alert and attentive cat (b and c showing alternating states in encéphale isolé); (d) transection

through the pontomesencephalic function, producing cat in (a); and (e) transection through the

bulbar brainstem, producing cat in b and c.


Parallel with the search for the “seat of consciousness”—considered present in humans with a better-developed neopallium than lower creatures—came the search for lesions associated with prolonged unconsciousness. What was then the clinicians’ view on impaired consciousness? Notably, neurosurgeons repeatedly observing patients with localized tumors speculated that the responsible sites were in the frontal lobes, thalamus, or hypothalamus. Cairns pointed out that many areas of the cortex could be removed without an effect on consciousness but that mechanical interference or hemorrhage in the brainstem or surrounding the third ventricle may induce immediate coma or a sleep-like

FIGURE 2-2 Original drawing from Morison and Dempsey’s classic work of distribution of cor-

tical responses, with thalamic stimulation. Reproduced from Morison and Dempsey,27 with

permission.

MI

SC IC

A

P

PY

CER

IVIII

OC

FIGURE 2-3 Original drawing from Moruzzi and Magoun. Reconstruction of the ascending reticu-

lar activating system after stimulation experiments in the cat. A = aqueduct; CER = cerebellum;

IC = interior colliculus; MI = massa intermedia; OC = optic chiasma; P = pons; PY = pyramidal

crossing; SC = superior colliculus; III = third ventricle; IV = fourth ventricle. Reproduced from

Moruzzi and Magoun,28 with permission.


state.8 Cairns, analyzing his neurosurgical cases, localized these abnormalities at any level of either the brainstem or thalamus.

However, further understanding of the neural correlates of consciousness came with animal studies by neurophysiologist Lindsley23 and neurosurgeon French at UCLA.14 Lindsley coagulated the reticular formation in the mesencephalon or posterior hypo-thalamus that resulted in coma.23 Earlier cat studies were replicated in monkeys, and by using animals with higher encephalization the investigators linked the findings closer to humans. Again, changes occurred on the electrocorticogram of the monkey after stimu-lating the brainstem reticular formation. Reemergence of EEG synchrony was also seen after stimulation stopped and was most prominent in the anterior part of the hemispheres. Stimulation of the reticular formation and tegmentum of the lower brainstem, dienceph-alon, subthalamus, dorsal hypothalamus, and ventral medial thalamus could all produce such an EEG arousal. This experiment was followed by actually producing lesions in these locations. Central brainstem injury caused hypersynchronous EEG, no longer affected by peripheral stimuli, and in a monkey it resulted in an unresponsive state. The monkeys were stuporous and akinetic, some with short periods of arousal but helpless and with no purposeful adaptive movements. Most interestingly, these experiments also showed that barbiturates could produce similar findings, including absence of arousal reaction to afferent stimulation but with a reversible reduction of EEG activity. These landmark stud-ies concluded that transection of the upper brainstem would leave the rest of the cerebral hemisphere in a “state of sleep” (Figs. 2-4, 2-5, and 2-6).

THE ANATOMY OF THE AWAKE STATE

Cortical activation requires several structures. The four major structures are the thala-mus, basal forebrain, posterior hypothalamus, and brainstem monoaminergic nuclei in the ascending reticular formation. All these structures are active during the awake state, and hypofunction may be due to normal circadian rhythm, disease, or hypnotic drugs that produce drowsiness.7,13

The ARAS is stimulated by spinal and cranial nerves carrying proprioceptive, visual, and auditory information. These interconnecting cells located in the dorsal part of the lower pons ascend with some individual bundles to the thalamus and become active during the awake state and also during rapid eye movement (REM) sleep, play-ing a major role in the sleep–wake cycle. Two anatomical pathways have been located. The dorsal pathway projects to the thalamus and connects to the cortex with multi-ple loops and circuits. The ventral pathway synapses and ends in the posterior hypo-thalamus, subthalamus, and basal forebrain connecting to the cortex but bypassing


AC

OC OC

MI PCO

III SC

ICA

CER

PIV

AC

STIMULATING & RECORDING EXPERIMENTS

MI PCO

SC

IC

CER

P

Activation of EEG

Evoked potentials

LESION EXPERIMENTS

Not ComatoseMonkeys 2–4

ComatoseMonkeys 6–7–8

SuccumbedMonkeys 1–5–9–10

CommonLesion

Monkey 7

Monkey 2

Monkey 4

Monkey 8

CommonLesion

IndividualVariation

III

FIGURE 2-4 Experimental lesion studies. Electrodes were passed through the burr hole using

stereotaxic instruments. Reproduced from French and Magoun,14 with permission.


L SEN-MOT.

I 100-VI SEC

R SEN-MOT.

L-R CRU.

L-R PRO.

B

4 DAYSLA

RA

LP

RP

A

M

P

4 DAYSLA

RA

LP

RP

A

M

P

10 DAYS

WHISTLE

CLICKS

CLAP HANDS

LA

Chronic Monkey No. 7

RA

LP

RP

A

M

P

I 50 mv

I SEC

I 50 mv

I SEC

(A)

(B)

FIGURE 2-5 (A) Stimulation of the brainstem reticular formation (note line); high-voltage waves

are replaced by low-voltage fast activity. (B) Unresponsive EEG (clicks, whistle, clap hands)

in comatose monkeys. These EEG abnormalities were not found in animals in which the teg-

mentum was spared or incompletely destroyed. (A) and (B) are reproduced from French and

Magoun,14 with permission.


the thalamus (Fig. 2-7). The reticular formation consists of neurochemically defined nuclei that extend throughout the brainstem tegmentum and posterior hypothalamus. Now high-angular-resolution diffusion imaging is able to visualize these complex net-works, and a recent study of normal brain from autopsy documented additional fiber bundles connecting the cuneiform/subcuneiform nucleus in the rostral midbrain to the

FIGURE 2-6 Stuporous and akinetic monkeys after lesions of the brainstem. Reproduced from

French and Magoun,14 with permission.

FIGURE 2-7 Anatomical structures and dorsal and ventral pathways involved with the awake

state (see text).


thalamus, hypothalamus, and basal forebrain and these images reemphasize the redun-dancy in connectivity between the key structures (Fig. 2-8).11,12

Within the thalamus, the medial and intralaminar nuclei relay input from the reticular formation and limbic system structures before spreading out throughout the cortex. The tha-lamic reticular nucleus is considered important in “gating” signals and control of the activity of other thalamic nuclei. The thalamic reticular nucleus participates in cortico-thalamo-cortical interactions involved in synchronization of cortical activity during non-REM sleep. Another important structure is the anterior cingulate cortex. Its key role is the orchestration of atten-tional mechanisms and motivation. Other inputs include nociception (pain) pathways. It is targeted by projections from the ventral tegmental area and it specifically functions when persons are aroused to make executive decisions with precision. In many instances abulia and mutism result from its dysfunction, but awareness is markedly impaired.

Wakefulness is alternated by sleep. Some insight in neurobiology of sleep is neces-sary.25 Normal human sleep has been studied previously using EEG recordings. The EEG correlate of awake state is an alpha rhythm on the posterior leads. During slow-wave sleep, spindles and delta rhythms appear. The major change with slow-wave sleep is a progressive decrease of neuronal activity in cholinergic and monoaminergic groups. This reflects inhibition of these neurons by input from the sleep-promoting ventrolateral pre-optic (VLPO) area and is further discussed in the section on neurotransmitters. Sleep generation could therefore be hypothesized as a decrease of the activity of the mesen-cephalic reticular formation and cholinergic reticular nuclei which in turn do not facili-tate the thalami nuclei. Some investigators argue that the sleep–wake rhythm is caused by basal ganglia activity.5 Basal ganglia modulate cortical arousal after receiving signals from the reticular core via the intralaminar thalamus. Depression of the cerebellar hemi-spheres is also seen during slow-wave sleep and facilitates decreased muscle tone and proprioception. In REM sleep, however, a significant increase in regional blood flow is seen and interpreted as generalized activation of the arousal systems.5 In the awakening process there is establishment of functional circuits that are necessary to become alert.2 The connection between caudate, prefrontal cortex, and thalamus seen only 20 minutes after awakening is an indication of re-establishment of the function of the prefrontal cor-ticostriatal thalamocortical circuit, typically uncoupled during sleep. An interesting new finding is that the precuneus located on the medial aspect of the parietal lobe is very active during wakefulness, but much different in different stages of sleep and is hypoac-tive in pharmaceutical sedation and in a persistent vegetative state.24

Neuroimaging studies have contributed to our understanding of wakefulness. The anatomical boundaries of the brainstem tegmentum in which specific nuclei could be involved in the maintenance of consciousness in humans have been revisited recently.32


(A)

(B) (C)

FIGURE 2-8 High angular resolution diffusion imaging (HARDI) tractography of the midbrain

reticular formation (MRF) and pontis oralis (PO) pathways in the human brain. (A) Dorsal view of

MRF fiber tracts (red) and PO fiber tracts (blue) connecting with thalamic nuclei: reticular nucleus

(Ret, purple), central lateral nucleus (CL, light blue), and centromedian/parafascicular nucleus

(CEM/Pf, pink). Fiber tracts are superimposed on an axial non-diffusion-weighted (b = 0 sec/mm2)

image (b0) at the level of the inferior colliculi and a coronal b0 image at the mid-thalamus. (B)

Right lateral view and (C) ventral view of MRF and PO fiber tracts connecting with the hypothala-

mus (HyTh) ventrally and the thalamus rostrally. Fiber tracts in (B) are superimposed on an axial

b0 image at the level of the mid-pons and a sagittal b0 image at the midline. Fiber tracts in (C)

are superimposed on an axial b0 image at the level of the red nuclei and a coronal b0 image

at the mid-thalamus. The b0 images in (A) and (C) are semitransparent so that the fiber tract

trajectories can be seen as they cross the coronal plane. Of note, the red fiber tracts emanating

from the MRF extend both rostrally and caudally, likely representing ascending and descending

pathways of the ascending reticular activating system. For additional details regarding HARDI

tractography methods, see Edlow et al. JNEN 2012;71:531–546.12 See color plate.


Patients with brainstem stroke were examined using a retrospective study of MRI map-ping, and the maximal area involved was in the upper pontine tegmentum. The territories of the lesions in this study that were most affected were the rostral raphe complex, locus coeruleus, lateral dorsal tegmental nucleus, nucleus pontis oralis, parabrachial nucleus, and white matter in between these nuclei.32

Proton-emission tomography (PET) has been used to indirectly study neuronal activity of the brain. In these studies, cerebral blood flow is used as an indicator of neuro-nal activity. It is assumed that increased neuronal activity induces an increase in metab-olism, which then facilitates a vasodilatory hemodynamic response. In addition, there is a coupling between the metabolic rate for oxygen and regional cerebral blood flow. Propofol-induced loss of consciousness has been studied using PET studies. Anesthetic drugs depress thalamic function, again confirming the role of the thalamus.

PET scanning also showed that these changes are not accompanied by changes in oxygen consumption, which increased the interest in using functional MRI scanning (MRI signals are sensitive to oxygenation of blood).33,34 Functional MRI has recently been used to study wakefulness, sleep, and minimally conscious and persistent vegetative states. Using functional MRI, it has been proposed that the posterior cingulate, retrosple-nial, and all associative cortices are important in the processing of cortical information. The connections observed involve the ARAS, mesiofrontal cortex, thalamus, and cuneus and precuneus. (The cuneus is a structure with high metabolic demand, but there has not been a clinical description of an isolated lesion.) This concept of a “disconnection syn-drome” in consciousness was supported by reduced glucose metabolism as measured by PET, and the glucose metabolism increased with improvement of consciousness.

THE CHEMISTRY OF THE AWAKE STATE

Neurotransmitters are needed to amplify the firing of these neurons and to regulate wake-fulness, and are located in several monoaminergic neuronal cell groups in the brainstem and hypothalamus.19–21 The main neurotransmitters are norepinephrine (originates in locus coeruleus and lateral tegmental area), dopamine (originates in ventral tegmental area, known as A10 neurons), serotonin (dorsal and medial raphe nuclei), acetylcholine (basal forebrain and brainstem), histamine (located in posterior hypothalamus), and orexin-hypocretin (presumably located in the perifornical region of the lateral hypo-thalamus).19–21 All the pathways project diffusely to the cortex, some with more specific targets. Norepinephrine is very active during awake states and silent during REM sleep. Dopamine neurons may have a more specific role in maintaining wakefulness, and this has been indirectly demonstrated in studies using amphetamines. (Amphetamines work


by enhancing the release and simultaneously inhibiting the reuptake of dopamine and thereby enhancing arousal.) Histamine seems to inhibit the “sleep-promoting” preoptic region, and antihistamines thus reactivate this region, resulting in sleep.

The four major neurotransmitter pathways are depicted in Figure 2-9. The reticu-lar formation is largely active through the neurotransmitter glutamate.45 In addition, the reticular formation contains neurons that use gamma-amino butyric acid (GABA),

FIGURE 2-9 Neurotransmitter pathways involved with the awake state.


FIGURE 2.9 Continued


which has inhibitory control. It has been suggested that these two systems may pro-mote or dampen cortical activation. Ketamine and virtually all volatile anesthetic agents block glutaminergic transmission. On the other hand, barbiturates enhance GABAergic transmission through GABA receptors.39,49,50 More specifically, ketamine blocks the N-methyl-d-aspartate (NMDA) receptors on inhibitory GABA interneurons. Propofol enhances GABAergic inhibition but also counteracts excitatory pyramidal input. Networks, including the thalamus and brainstem, seem to disconnect on functional MRI studies when propofol is used.18

The neurons in the pontomesencephalic portion and nucleus basalis contain acetyl-choline. These cholinergic neurons ascend parallel to the reticular formation and extend to the thalamus and to the hypothalamus and basal forebrain. These cholinergic cells apparently are active in wakefulness and during REM sleep. Use of inhibitors of acetyl-choline esterase increases cortical activation and awakening; however, specific destruc-tion of the cholinergic neurons does not influence cortical activation but does cause a loss of REM sleep.

The noradrenergic neurons are located in the locus coeruleus (floor of the fourth ven-tricle), with primary projection sites throughout the entire cortex; they also relay input to the thalamus, hypothalamus, and basal forebrain. There is evidence that the noradren-ergic locus coeruleus mostly discharges in situations with high arousal, including stress. Norepinephrine is also found in the ventral medulla and mediates autonomic responses



and arousal. Modafinil interferes with noradrenaline reuptake, and this probable mecha-nism (together with dopamine reuptake blockade) makes it a useful agent for narcolepsy.

The substantia nigra and ventral tegmental area and retrorubral field all contain dopa-minergic neurons. They ascend from the brainstem and descend to the forebrain, and relay in the dorsal striatum and cerebral cortex. Dopamine release is expected during aroused and rewarding waking situations, and again depletion of catecholamines also results in hypersomnia, akinesia, and aphagia.

The serotonergic raphe neurons use serotonin, and from the midbrain raphe nucleus they ascend to the forebrain and cortex. Depletion of serotonin leads to insomnia and also an aroused waking state with increased eating and sexual behavior. An inhibitor of serotonin-synthesizing enzyme, para-chlorpheniramine, can cause complete insomnia. Serotonin reuptake inhibitors (SSRI) increase wakefulness, and serotonin blockers may become drugs used for insomnia. Serotonin syndrome (response to serotonin reuptake inhibitors) causes agitation followed by stupor.

The posterior hypothalamus has a plethora of neurotransmitters or neuroactive sub-stances that include GABAergic and glutaminergic neurons, dopaminergic neurons, the neuropeptide orexin-hypocretin, and histaminergic cell bodies in the tuberomammillary nucleus. The posterior hypothalamus receives descending tracts from the preoptic anterior hypothalamus and forebrain and ascending input from the brainstem. The posterior hypo-thalamus has also been called the “waking center” and remains an important structure in the reticular ascending activating system complex. Studies have identified lesions in cer-tain areas that produce insomnia, thus pointing toward a role in promoting sleep. These areas have been identified as the preoptic area of the hypothalamus.1,16,26,29 Rat studies doc-umented sleepiness with bilateral lesions of the preoptic area of the hypothalamus. The cell group designated as the VLPO projects to monoaminergic cell groups and inhibits through galanin and GABA, resulting in sleep. However, the relationship between VLPO and the monoaminergic systems is reciprocal. Thus, during wakefulness, the monoaminer-gic nuclei inhibit VLPO and vice versa during sleep. A sleep switch has been postulated.35–37 These neurons are typically inhibited by acetylcholine, nonadrenaline, and histamine.16 Other substances with somnogenic properties are adenosine, cytokines, prostaglandin P2 delta sleep-inducing peptides, and opiate peptides, among many others.

It remains important to recognize that lesions that are in the thalamocortical activat-ing system or in the hypothalamic arousal system do not always produce longstanding difficulties with waking. A recent study found that destruction of the thalamic neurons did not result in loss of cortical activation.47 Similarly, destruction of the neurons in the posterior hypothalamus did not result in waking difficulties. The posterior hypothala-mus, when stimulated, creates not only cortical activation but also arousal responses


that include pupillary dilatation, increased respiratory rate, increased heart rate, and increased blood pressure. Moreover, there is some evidence that pharmacological manipulation is possible. Dexmedetomidine—an alpha-2 adrenergic agonist—is a use-ful sedative agent in the intensive care unit and during neurologic procedures and may modulate the VLPO.30,43

Of considerable interest are the histaminergic neurons using histamine as a neu-rotransmitter located in the ventral lateral posterior hypothalamus (tuberomammillary nucleus), lateral to the mammillary nuclei. It has an important role in waking because antihistaminic drugs cause drowsiness and rats that have no histamine are less easily awakened.31 Histaminergic cells are also involved in cortical activation of waking and improving attention. The histaminergic neurons have been found to send widespread ascending and descending tracts through areas of the brain that are known to control sleep–wake states. In some animal species, increased histamine release in the posterior hypothalamus occurs on awaking. Some experiments have found that the intraperitoneal injection of an inhibitor of the histamine synthesis enzyme causes a significant decrease in waking and patterns associated with deep slow-wave sleep on EEG.16 H3 antagonists such as ciproxifan improve daytime sleepiness when it is part of narcolepsy complex.13

THE PHYSIOLOGY OF THE AWAKE STATE

Steriade and colleagues’ work has improved the comprehension of the electrical underpinnings of awakening and sleep.44 Depolarization of the thalamic neurons, in turn activated by the pedunculopontine tegmental nucleus, results in EEG desyn-chronizing and suppression of sleep spindles and delta waves. With this depolariz-ing effect comes single-spike firing rather than bursts. High-frequency oscillations of 40 cycles per second highly synchronized across the brain have been recorded using magnetoencephalography and were also present during REM sleep, but its significance is not clear beyond the fact that loss of this 40-Hz pacemaker causes coma. Thalamic reticular neurons (GABAergic) are bordered by the anterior and ventral surface of the dorsal thalamus.15 During the awake state, there is spontaneous tonic firing but no spike bursts. The role of the central thalamus is under investigation. High-frequency stimu-lation (100 Hz) of the thalamus generates cortical activation and, in rats, changes in exploration and grooming behaviors.41

In 2007 a study found that deep brain stimulation improved arousal and motor activ-ities in a patient disabled by traumatic brain injury, suggesting that electrical manipu-lation of central thalamic function may be effective.38 It has been postulated that deep brain stimulation could work through (1) depolarization of cortical and striatal neurons,


(2) inhibition of pallidothalamic projections due to depolarization of striatal neurons, (3) facilitation of cortico-cortical connections, and (4) facilitation of synaptic plasticity.40

Ineffective in prolonged coma, the role of deep brain stimulation in the treatment of patients with diminished arousal after brain injury is yet undefined but holds out an expectation. This surgical procedure may improve severely disabled patients, but cri-teria for selection of patients are not yet known and no new data on the magnitude of improvement—if any—has been reported since 2007.17

TRANSLATION INTO CLINICAL PRACTICE

Alertness is mostly a function of the thalamus and reticular formation, and awareness is in the cortex with an important contributing role of the precuneus and anterior cingulate gyrus. With such an abundance of projections, connections, and multiple involved neu-rotransmitters, abnormal consciousness and coma can only be a result of a widespread dysfunction of the brain and brainstem. Functionality can be impaired by factors that reduce energy metabolism, mostly through a decrease in synthesis of acetylcholine, glu-tamate, or GABA (e.g., hypoxia, hypoglycemia, hyperammonemia, or anesthetic drugs). However, when control structures such as the ARAS, thalamus, anterior cingulate cortex, and association cortex (precuneus and cuneus) become structurally damaged, the frame-work collapses (Fig. 2-10).

FIGURE 2-10 Key structures in maintaining an awake state and awareness.


How can these concepts of wakefulness and awareness be translated to the clinical examination of comatose patients? First, it is necessary to say that while these ideas of the awake state and arousal were worked out, clinicians had already described certain patterns in coma (Chapter 1). The above-mentioned concepts and structures could not have been considered in the clinical descriptions of coma and herniation and thus were later incorporated. Second, most destructive lesions involve the cortex or thalamus or connecting fibers in the white matter and are the major mechanisms of coma. This doctrine remains valid and has been corroborated by MR studies intra vitam and neu-ropathology postmortem. The thalamus and ARAS can also be damaged from shift or distortion of the brainstem or due to direct destruction. The impact of lesions on these structures can be substantial, leaving some patients in a permanent state of uncon-sciousness. More selective lesions or those involving only unilateral lesions of the thal-amus and upper brainstem will not impair consciousness or will affect consciousness only transiently when lesions are small. Involvement of the thalamus alone may lead to fluctuation of consciousness, but persistent coma is usually seen if the lesion—whether compressive or directly destructive—extends into the mesencephalon. Involvement of the anterior cingulate gyrus is seldom seen in isolation, and the same is true for lesions in the association cortex involving the precuneus and cuneus. Akinetic mut-ism is the most common clinical correlate of lesions of the anterior cingulate cortex. Most of the dorsal brainstem injury is due to shift, torsion, compaction, and second-ary vascular lesions from damage to the penetrating arteries. Sudden enlargement of the aqueduct in obstructive hydrocephalus may be another mechanism of localized brainstem injury. Structural injury may also occur as a rapid succession of events. Typical examples are apnea and cardiac arrest with acute brainstem lesions leading to additional anoxic-ischemic cortical injury. Traumatic head injury is commonly asso-ciated with anoxic-ischemic injury, and this dual mechanism is underrecognized. In some patients traumatic brain injury may lead to carotid artery dissection, resulting in a swollen hemispheric infarct with brain tissue shift. Thus, to a certain extent, the multiplicity of lesions found in comatose patients does not always fit neatly into this logical anatomical structure.

At the other end of the spectrum is hypersomnia (roughly defined as excessive day-time sleepiness and marked difficulty waking up), which is often due to lesions in the hypothalamus, paramedian thalamus, or tegmental pons. It involves orexin-hypocretin, a peptide that also has a role in energy regulation, promotes eating, and enhances car-diovascular responses.42,46 Examples abound not only of an ischemic stroke, tumor, or removal of adjacent tumors such as craniopharyngioma, causing damage to surrounding structures, but also rare disorders such as sarcoidosis and Whipple disease.


CONCLUSIONS

When the reticular formation is stimulated electrically, it creates cortical activation. The ascending neuronal networks that project to the cortex and stimulate cortical acti-vation can be recapitulated. The ARAS includes cholinergic neurons of the mesopon-tine tegmentum projecting to the thalamus and monoaminergic groups that project to the thalamus, hypothalamus, basal forebrain, and cortex. These monoaminergic groups include noradrenergic neurons of the locus coeruleus, serotonergic neurons of the dorsal raphe, dopaminergic neurons of the ventral tegmental area and periaqueductal gray, and histaminergic neurons of the tuberomammillary nucleus of the posterior hypothalamus. These groups receive excitatory input from the posterior lateral hypothalamus (through orexin-hypocretin) and receive inhibitory inputs from neurons of the VLPO.

All in all, the thalamus, through its intralaminar nuclei, plays an important role; it maintains arousal and relays sensory, motor, and critical cortical circuits. Functionally it may be just as important as the entire cortex to maintain consciousness, and therefore it is understandable that there are multiple projections in the thalamocortical activating system. The gist of it is that each has its own function, but there is evidence that they are redundant, set to work when one system is down or destroyed. In addition, there is a hypothalamic arousal system and a basal forebrain wake- and sleep-promoting system. Therefore, we can expect that any change in level of arousal correlates with abnormality in the midbrain, pons, thalamus, or cortex. Sometimes one strategically structural lesion causes the entire system to break down, but most of the time there is diffuse and multi-focal injury. We have now come to understand that certain cortical structures, namely the anterior cingulate cortex, precuneus, and cuneus, are important.9 Transitions from a minimally conscious state or akinetic mutism to better vigilance may be related to func-tional improvement in these locations.

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81

Physicians find it taxing to approach a comatose patient. Perhaps it is, but the techniques of the neurologic examination have evolved greatly and have matured into a comprehensive clinical assessment for everyone to master. What is needed first is an initial understanding of the degree of coma and the stage of progression. Coma scales can be useful for that.40,43 Further clinical tests may predict the location of the responsible lesion and cause. However, it follows a thorough history and an accurate interpretation of events leading up to its presentation. The ability to do all that is shaped by clinical experience and includes pattern recognition, knowing what is likely, and the ability to weigh the significance of each finding.26

In all fairness, the examination of the comatose patient may not be all that revealing. In fact, many comatose patients present in an undistinguished way and have their eyes closed, do not respond to forceful prodding or to a noxious stimulus (except for some withdrawal), have normal pupils and all other brainstem reflexes intact, and thus defy any attempt at localization.

The neurologic examination of the comatose patient is a fundamental clinical skill that physicians of many disciplines may need to acquire. This chapter describes the clini-cal tools to identify the abnormalities in acute comatose patients and to amass certain signs into a recognizable pattern. The examination of prolonged comatose states and brain death are described in Chapters 4 and 5. Diagnosis leads to clinical decisions, and Chapter 7 discusses practice.

neurologic Examination of the Comatose Patient and Localization Principles

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DEFINITIONS

Unconsciousness has been classified into different states of reduced wakefulness and self-awareness. The boundaries of each of these states are recognizable clinically, but these divisions are necessarily artificial with overlap between the designations. A disturbance of wakefulness is a disturbance of arousal (mostly due to lesions of the ascending reticular acti-vating system and thalamus) and an inability to integrate perceived events in the inner and external world (mostly the cortex). Usually both components of consciousness are impaired simultaneously, but patients can be awake but not aware. The following conditions have been defined, ranging from a locked-in syndrome, mimicking unresponsiveness, to com-plete unawareness. Strictly speaking, acute confusional state, or delirium, may not belong in the category of decreased consciousness but is included for comparison, and it may be a premonitory sign in patients deteriorating from acute derangements of metabolism.

Locked-in Syndrome

This condition can be misinterpreted as a state of unawareness and is therefore discussed here. However, many patients have their eyes spontaneously open and blink, setting it apart from any other comatose state except vegetative state, with which it can be con-fused. Locked-in syndrome is a neurologic condition in which the patient is alert but is unable to communicate except for blinking and vertical eye movements. The experience to the patient must be absolutely frightening, although many are less alert than presumed (VC 3-1). In locked-in syndrome, the mesencephalic structures remain intact, but all vol-untary motor activity below the level of the third nerve nuclei due to a ventral pontine lesion is lost. The patient is able to hear all conversation and feel noxious stimuli. The condition typically occurs with acute occlusion of the basilar artery or a destructive hem-orrhage into the pons. When the basilar artery is occluded at the top the thalami may be involved reducing alertness. Some patients with a locked-in syndrome have some addi-tional residual motor control of fingers, mouth, and lips; that is clinically relevant because patients with an incomplete locked-in syndrome may improve further and often signifi-cantly (VC 3-2). Neuromuscular causes of a locked-in syndrome have been recognized (e.g., botulism, Guillain-Barré syndrome, and most notoriously, use of neuromuscular blocking agents and inadequate sedation during surgical procedures under general anes-thesia). This involves loss of all motor activity, and thus also blinking and vertical gaze.

Hypersomnia

The term hypersomnia usually applies to patients who sleep mostly throughout the day and may not be easily awakened. When left alone and unstimulated, the patient will

neurologic Examination of the Comatose Patient and Localization Principles / / 83

easily lose vigilance and fritter away time. Patients may assume comfortable sleep posi-tions not found in stuporous patients. Neurologic examination in these patients should generally be normal, although some patients may be disoriented in time due to pro-longed sleeping. Attention span is shortened markedly. This condition can be seen in individuals using sedative drugs, in patients with acute or chronic hepatic or renal fail-ure, or in the setting of hypercapnia. It may be due to thalamic, hypothalamic or dorsal pontine lesions.

Acute Confusional State and Delirium

The major disorder here is abnormal attention. The patient is unable to retain experi-ences in chronological order, and thought processes are fragmented. Many of these patients are unable to repeat a series of numbers, know heads of state, or synthesize simple daily events. Neurologic examination will reveal normal findings, except for the inability to recall information and disorientation in time and place. Localizing signs such as apraxia or aphasia are absent. Delirium is the next stage, mostly marked by profound agitation. There are two different types of delirium: a quiet delirium in which the patient withdraws without any dysautonomic features or a more typical agi-tated delirium with overt dysautonomia characterized by hypertension, tachycardia, and profuse sweating. Many of these patients are bewildered and restless, misperceive the environment, and may have vivid visual hallucinations. When seen in a setting of alcohol withdrawal, patients may see insects or other small animals whisking through the room.

Stupor and Coma

These degrees of coma are difficult to define, and a series of less precise terms have been introduced in the medical literature. There is a spectrum from brisk localization of pain with eye opening to an immobile state with eyes closed and flaccid tone. The term “stu-por” has been used to identify a state in which patients have their eyes closed and open them only after a vigorous pain stimulus such as nail bed compression and prodding, and localize a pain stimulus by making purposeful movements toward it. These patients lapse into an unresponsive state when not stimulated.

Coma is most simply defined as a state in which an unaware patient does not awaken, speak, or open the eyes, and has motor responses that are withdrawal or reflexive and not purposeful. Another operational definition is by Plum and Posner: “Coma is defined as a condition in which the patient is unarousable, unresponsive, and lies with the eyes


closed. These patients do not have a response to any external stimulus or inner need and do not communicate appropriately.”29 Fisher emphasized that “Coma is a continuum rather than a single state.”5 Fisher defined drowsiness as follows: command that elicits motor response, question elicits speech, pain elicits speech or groan, voice elicits open-ing of eyes or stirring, and threat with examiner’s arm elicits blink or greater response. Stupor was defined as pain eliciting a voluntary response, grimacing, and opening of eyes and blinking. A patient was considered comatose when pain elicits elementary reflex responses or no reaction and eyes were often unblinking.5 Because currently used coma scales are able to more accurately describe the depth of coma, there is no use in describ-ing coma as deep (e.g., pain elicits elementary reflex responses or no reaction), moderate (e.g., pain elicits a voluntary response or grimacing), or light (e.g., question elicits speech or groan and opening of eyes). The Glasgow Coma Scale has been the ubiquitous coma scale used for decades—simply defined coma as not obeying commands, not uttering words, and not opening eyes. Jennett and Teasdale15 noted that sum scores of seven or less on the Glasgow Coma Sum Scale (GCS) included all comatose patients. In this mono-graph we use a different coma scale, the FOUR score.

Perhaps the best definition of coma approximates the following description: a com-pletely unaware patient with, at best, only eye opening with pain or eyes open with no tracking or fixation, the presence of withdrawal to a noxious stimulus, at best, and mostly worse with the presence of reflex motor movements. Brainstem reflexes can be partly absent or absent.

THE CLINICAL EXAMINATION OF A COMATOSE PATIENT

Neurologic examination of a patient in coma requires three key components: observa-tion and inspection; testing of responses evoked by the examiner; and, most importantly, abstraction of the findings which are then consolidated into a localization followed by consideration of causes (Chapter 7). The first premise is that a general physical examina-tion may help in the evaluation of comatose patients. Some combination of changes in vital signs may point to a toxidrome (a combination of toxic and syndrome). Extremes in temperature and blood pressure, sweating or dryness, cardiac arrhythmias or EKG abnor-malities may point to certain causes and may require specific laboratory tests. The second premise is that, although the neurologic examination of the comatose patient approxi-mates the lesion in both hemispheres, thalamus, or dorsal brainstem, it is often not pos-sible to clinically differentiate between a diffuse structural lesion and acute physiologic brain dysfunction. Neuroimaging, notably CT and MRI, can narrow the differential diag-nosis by demonstrating structural injury.


Fundamentals of Functional Anatomy

Readers may find it helpful to first see a summary of the functional anatomy. The neuro-anatomical correlates of arousal and awareness state have been discussed in Chapter 2. The implication of this organizational structure is that coma is caused by an interrup-tion in any of these circuits. Clinicopathological correlations have been published, and there is an agreement among clinicians that certain locations can cause unconsciousness and that combinations of these locations can cause permanent unconsciousness. These anatomical locations are shown in Figure 3-1.12 Bihemispheric cortical injury must be diffuse in order to cause coma. Destructive damage involving the entire cortical mantle can occur after anoxic-ischemic injury, although the parieto-occipital regions are most severely affected. The white matter core can be damaged mostly from acute demyelinat-ing disorders or from acute hydrocephalus, and this will interrupt the thalamocortical circuits. The thalamus can be preferentially affected, at times due to ischemic injury both from arterial and venous occlusions, but in most instances function is impaired due to compression and distortion from a new mass. Thalamic injury leads to disconnection from the cortex and the reticular formation. Involvement of the dorsal parts of the mes-encephalon, pons, and pontomedullary border interrupts arousal by disconnecting with the thalamus, hypothalamus, and cortex.

The hemispheres in comatose patients can only be examined by gross assessment of responses to sound, touch, and noxious stimuli. The thalamus and upper brainstem may produce more localizable signs. Therefore, before detailed features of the neurologic

Whitematter

Thalamus

Cortex

Dorsalbrainstem

FIGURE 3-1 Anatomical locations causing coma.


examination are described, it is useful to revisit the important reflex circuits. When any of these reflexes are absent, it is helpful in localization of the lesion.

The pupillary light reflex involves the optic tract (cranial nerve II), and the sig-nal leaves to enter the midbrain into the pretectal area, synapsing to Edinger-Westphal nucleus and farther on to fibers in the oculomotor nerve (cranial nerve III) connecting with constrictor pupillae. A lesion in the tectum or pretectum with involvement of the posterior commissure fixes the pupil to a light swung in front of the pupil. When the third nerve nucleus (Edinger-Westphal) is involved, the pupil fixes in a midposition. Stretching or compression of the oculomotor nerve or compression of the midbrain ocu-lomotor complex results in a dilated pupil due to an intact, unopposed sympathetic path-way (Fig. 3-2A). Conversely, pinpoint pupils are seen in pontine lesions from damage to descending sympathetic fibers, but light reflex is intact.

The blink reflex arc is complex, depending on the stimulus (Fig. 3-2B,C). This stimu-lus is usually sound (acoustic nerve is the afferent part) or a rapid hand approach (optic nerve is the afferent part). The efferent parts are the orbicularis oculi muscles innervated by the facial nerve. The acoustic arc is through the brainstem, and blinking does not need cortical input after a loud sound. An intact visual system including a functioning visual cortex is needed to cause blinking after a visual stimulus. This difference is useful when examining patients with severe hemispheric injury and intact brainstem function such as in a persistent vegetative state (Chapter 4). Visual tracking requires cortical input from the primary visual cortex and frontal eye fields (Fig. 3-2D). Horizontal visual tracking is a coordinated response using the lateral gaze center or pontine paramedian reticular formation. It activates the oculomotor nucleus in the mesencephalon and the abducens nucleus in the pons. The ascending pathway from the lateral gaze center to the oculo-motor center is known as the medial longitudinal fasciculus. Vertical visual tracking is coordinated through the vertical gaze center present in the periaqueductal gray matter of the mesencephalon. It projects to the oculomotor and trochlear nuclei. The cornea reflex is elicited after touching the cornea. The ophthalmic (I) division of the trigeminal nerve (nasociliary branch) synapses with the motor division of the facial nerve that contracts the orbicularis oculi muscles (Fig. 3-2E).

An oculovestibular reflex can be elicited in comatose patients. It requires introduction of cold (iced) water into the ear canal, detection of cold water by the semicircular canals, signaling through the eighth cranial nerve to the vestibular nuclei, and projecting to the third, fourth, and sixth nuclei via the gaze centers. In comatose patients, this results in a gradual movement of the eyes toward the cold stimulus (Fig. 3-2F). Internuclear oph-thalmoplegia involves a lesion of the medial longitudinal fasciculus in the upper pons and can be documented with caloric irrigation testing. Its presence reveals a pontine lesion


PosteriorcommissurePretectalarea

II

IIIEdinger-Westphalnucleus

Light reex(A)

Facialnucleus

VII VIII

Blinkreex

(B)

Facialnucleus

VII

Blinkreex

(C)

Vertical gazecenterOculomotornucleusLateral gazecenterAbducensnucleus

VI

III

Visualtracking

(D)

VI

VII

Facialnucleus

Corneareex

(E)

Vertical gazecenterOculomotornucleusAbducensnucleusLateral gazecenterVestibularnuclei

VI VIII

III

Oculovestibularreex

(F)

Vertical gazecenterOculomotornucleus

AbducensnucleusLateral gazecenterVestibularnucleiAbduction

Noadduction

VI VIII

III

Oculovestibularreex

(G)Coughreex

(H)

IXX

FIGURE 3-2 Functional anatomy pathways (see text for explanation). Roman numbers indicate

cranial nerves II–X.


(Fig. 3-2G). The cough reflex is usually best elicited with tracheal suctioning. It consists of a pathway from the sensory laryngeal nerve to the efferent vagal nerve (Fig. 3-2H).

Physical Examination

It is imperative to evaluate vital clinical signs such as breathing frequency and depth, pulse, and blood pressure, and also body and breath odor, skin color and texture, and lac-erations.42 These clinical signs should be systematically examined, and all can be telltale signs of certain systemic disorders. The most important physical signs are summarized in Table 3-1. More details are found in the clinical vignettes (Part II, Chapters 12–112).

Fever at the onset of coma is significant. Infections of the central nervous system of any sort produce fever, and this is a key pointer to its diagnosis. It is also a common pre-senting sign in destructive midbrain or pontine hemorrhages, but temperature may sway to hypothermia when all brainstem function is lost. Multiple medical conditions can cause coma with fever such as endocarditis with embolic infarcts, sepsis, agonal uremic coma, and, perhaps best known, typhoid fever. Marked spikes in temperature may occur as a manifestation of malignant catatonia neuroleptic malignant syndrome or serotonin syndrome, but rigidity is usually present.58 Early fever in combination with tachycardia, sweating, and shivers may indicate paroxysmal sympathetic hyperactivity syndrome. The emergence of fever later during the clinical course is most often due to an infectious cause, and this may be of much less practical value in determining the degree of neuro-logic injury. Hypothermia may be due to environmental triggers but can also point to myxedema coma or certain drug ingestions.

Hypertension should not always be equated with increased intracranial pressure but can be the cause of coma in the setting of posterior reversible encephalopathy syn-drome (PRES), and it is also a feature of amphetamine or cocaine use. Hypotension in a comatose patient mostly points to a marked hypovolemic state or may, in appropriate circumstances, indicate that the patient has progressed to brain death. The pulse may be indicative of certain causes of coma, but its diagnostic precision is very questionable. Earlier observations have noted certain characteristics, such as a hard and unyielding pulse with hypertension in uremic coma and a thready pulse in diabetic hyperglyce-mic coma. Cardiac arrhythmias are commonly seen with toxins, including tricyclic antidepressants.

The general skin appearance may indicate other clues, and the most easily recogniz-able are cold, malar flushed, yellow tinged, puffy face (myxedema), dark pigmentation (Addison’s disease), butterfly eruption on the face (lupus erythematosus encephalopa-thy), and purpura (thrombocytopenic purpura, vasculitis, aspirin intoxication, and


disseminated intravascular coagulation). Any skin rash or erythema may indicate the presence of a bacterial meningitis or arthropod-borne viral encephalitis and rickettsia. An important diagnostic sign is tache cérébrale or tache méningéale. Drawing a finger over the forehead or abdomen will leave a red patch seconds later. It is an urticarial rash mostly associated with meningitis but also seen with hyperparathyroidism. Dry skin, particularly when the feet and axillae are without any sweat droplets, points to an overdose of tricyclic antidepressants. Profuse sweating, on the other hand, could point to a severe traumatic brain injury with excessive sympathetic outbursts, severe hypoglycemia, or more spec-tacular pesticide (organophosphate) poisoning.

Neurologic Examination: Coma Scales and the FOUR Score

The major components of a neurologic examination are assessment of eye opening, eye tracking, motor responses (spontaneous and to noxious stimuli), and assessment of brain-stem reflexes. It includes assessment of tendon stretch reflex patterns (asymmetries, clo-nus, or Babinski sign) and assessment of tone (flaccid or rigid). A noxious stimulus may involve sternal rubbing on the chest; pressure on the supraorbital nerve (easily found as a

TABLE 3-1 Physical signs in Comatose Patients Indicating a systemic Illness or Drug Toxicity

Sign Consideration

Hyperthermia Endocarditis, sepsis, drug ingestion (cocaine, amphetamines, cyclic

antidepressants, phencyclidine, salicylates), malignant catatonia, neuroleptic

malignant syndromeHypothermia Hypothyroidism, drug ingestion (barbiturates, opioids, sedatives, phenothiazine)

Hypertension Pheochromocytoma, eclampsia, calcineurin inhibitor toxicity, drug overdose

(phencyclidine, cocaine, amphetamine)

Hypotension Beta blockers, calcium channel blockers, Addison’s disease, sepsis

Tachycardia Alcohol, amphetamine, ethylene glycol

Bradycardia Uremic coma, myxedema coma

Hyperventilation Ethylene glycol, salicylate, diabetic ketoacidosis

Hypoventilation Alcohol, sedative drugs, heroin

Sweating Thyroid storm, hypoglycemia, organophosphate exposure

Dry skin Hypothyroidism, drug overdose (tricyclic antidepressant, barbiturates, anticholinergic

agents)

Odor Dirty toilet (uremia), fruity sweet (ketoacidosis), musty (acute hepatic failure), garlic

(organophosphates)


groove located on the medial orbital rim), deep pressure on the nail bed (except in antico-agulated patients),50 or preferably on both condyles at the level of the temporomandibu-lar joint45 (Fig. 3-3). The key findings of the neurologic examination can be entered into a practical scale that would then allow physicians to communicate with each other and with other health care staff. Ideally, a coma scale encapsulates the most important features of the unconscious state and allows grading these patients over time, which could point toward changes in clinical condition. An instrument that measures different depths of coma should fulfill certain criteria. An ideal coma scale should be reliable, valid, easy to use, easy to remember, and an indicator of patient outcome.

FIGURE 3-3 Type of noxious stimuli used in comatose patients.


A coma scale should not be limited in its use in daily practice, but any scale will be affected by sedative drugs and neuromuscular blockers, periorbital edema preventing eye opening, hearing loss, inability to comprehend speech (language foreign to the exam-iner, dementia, psychiatric disorder, or major developmental delay), tracheostomy, spinal cord injury, or limb fractures. Moreover, if components of the scale cannot be tested, one should resist the practice of “pseudo scoring” (adding the average value of the motor and eye score to the sum in place of the missing verbal score in assessment of the GCS)34 and should avoid “educated guessing” (to rate an expected response).

How much of the clinical neurologic examination should be abstracted into a coma scale remains arbitrary. Surely, a complicated scale with multiple testable components would provide great detail, but such scales cannot be practical and would be abandoned quickly. Too simple and too little information would not provide enough detail to capture changes in consciousness. Any scale will have to trade off sensitivity against specificity. No question, a coma scale is a better tool for communication than terms such as “non-communicative,” “out of it,” or “arousable but unresponsive.”

Earlier coma scales (e.g., Ommaya)43 recognized that the motor response to command and pain could identify different levels of coma. However, the grading of coma was impor-tantly improved, if not radically changed, with the introduction of the GCS (Table 3-2). The GCS has been celebrated as the de facto standard scale. It has been incorporated into intensive care and trauma scoring systems that assess the risk of in-hospital mortality.26 It has strongly positioned itself since its introduction in 1974.40 Prior attempts at modifica-tion of the GCS or development of entirely new scales have not come to fruition, and this is understandable because the GCS is an example of admirable simplicity. The GCS was rapidly adopted by physicians other than neurologists and neurosurgeons. The GCS sum score became a marker for prognosis.

However, there are limitations to the GCS. First, it has difficulty detecting more sub-tle abnormalities of arousal, and it does not assess brainstem function and respiration pat-terns. A major emphasis was on the verbal response and the distinction between expletive language, confused conversation, and normal orientation.40 However, the verbal response cannot be graded in endotracheally intubated patients.25,34 In clinical practice, most physi-cians substitute verbal rating for a T for tube, but how sum scores are calculated remains unclear, and practices may vary: a GCS score of 2T provides little information. If the patient has swollen eyelids from trauma or an extensive craniotomy, the GCS is reduced to a motor response only, and if a polytrauma patient has additional cervical spinal cord injury, the scale is completely useless as a neurologic assessment.

There have been attempts to modify the GCS over the years, and these are indicative of dissatisfaction with its use in patients with severe brain injury. Most of the alternative


coma scales were more complicated and were not used outside the country of origin.2,37 Moreover, detailed knowledge by physicians of the GCS—when tested—is lacking.30

This monograph makes use of the FOUR score currently operational in our neuro-sciences intensive care unit and many other places. It has been translated in several languages.9,13,23,41 The FOUR (Full Outline of UnResponsiveness) score is shown in Fig. 3-4. The FOUR score has four testable components.46 The number of components and the maximal grade in each of the categories is four; this makes it easy to remember and is reinforced by the acronym. These four components are eye responses (eye open-ing and eye movements), motor responses (following complex commands and response to pain stimuli), brainstem reflexes (pupil, corneal, and cough reflexes), and respira-tion (spontaneous respiratory rhythm or presence of respiratory drive on a mechanical ventilator). The FOUR score can be obtained in a few minutes.

The FOUR score not only measures eye opening but also makes an assessment of voluntary horizontal and vertical eye movements. It therefore detects a locked-in syn-drome in a patient with the lowest possible GCS score of 3. It detects the presence of a vegetative state where the eyes can be spontaneously open but do not track the exam-iner’s finger. The motor category includes the presence of myoclonus status epilepticus (persistent multisegmental arrhythmic, jerky movements), a known poor prognostic sign after cardiac resuscitation.48 The motor component combines decorticate and with-drawal responses because this difference between the two are often difficult to discern.

TABLE 3-2 Glasgow Coma scale

EYE RESPONSE4 = Eyes open spontaneously3 = Eye opening to verbal command2 = Eye opening to pain1 = No eye openingMOTOR RESPONSE6 = Obeys commands5 = Localizing pain4 = Withdrawal from pain3 = Flexion response to pain2 = Extension response to pain1 = No motor responseVERBAL RESPONSE5 = Oriented4 = Confused3 = Inappropriate words2 = Incomprehensible sounds1 = No verbal response

FIGURE 3-4 The FOUR score. (See color insert.)

Eye response4 = eyelids open or opened, tracking, or blinking

to command3 = eyelids open but not tracking2 = eyelids closed but open to loud voice1 = eyelids closed but open to pain0 = eyelids remain closed with pain

Motor response4 = thumbs-up, fist, or peace sign3 = localizing to pain2 = flexion response to pain1 = extension response to pain0 = no response to pain or generalized

myoclonus status

Brainstem reflexes4 = pupil and corneal reflexes present3 = one pupil wide and fixed2 = pupil or corneal reflexes absent1 = pupil and corneal reflexes absent0 = absent pupil, corneal, and cough reflex

Respiration4 = not intubated, regular breathing pattern3 = not intubated, Cheyne-Stokes breathing

pattern2 = not intubated, irregular breathing1 = breathes above ventilatory rate0 = breathes at ventilator rate or apnea


The hand position tests (thumbs-up, fist, and peace sign) can further assess alertness, and the validity has been tested.47 Three brainstem reflexes testing mesencephalon, pons, and medulla oblongata functions are used in different combinations. Breathing patterns are graded. Cheyne-Stokes respiration and irregular breathing can represent bihemispheric or lower brainstem dysfunction of respiratory control. In intubated patients, overbreath-ing of the mechanical ventilator or spontaneous breaths supported by the ventilator represent functioning respiratory centers. The FOUR score, unlike the GCS, does not include a verbal response; it thus is more valuable in intensive care practices that typically have a large number of intubated patients, and it may be more useful in young children.

FOUR score assessment in our validation studies was good to excellent, and the FOUR score predicted outcome.8,14,19,38,49 The patterns of breathing can be easily mastered by physicians and interpreted satisfactorily by intensive care nurses.46,54 The FOUR score has also been validated in the emergency department, and this suggests that it can be used by emergency physicians at any level of training and by the nursing staff.38 The FOUR score validity has been tested in several countries around the world and with different physicians and nursing specialties.1,3,4,23,35,41 A recent prospective study on nearly 2,000 critically ill patients found that the FOUR score was a better prognostic tool for mortality than the GCS, because it incorporates brainstem reflexes and respiration.52

Using the FOUR score, the examiner is forced to describe these important, if not essential, clinical features. With all categories graded 0, the examiner is alerted to con-sider a brain death examination. The FOUR score has not been tested outside the realm of acute disorders of consciousness but may also be useful in patients in a minimally con-scious state and in persistent vegetative state, notwithstanding other valid coma recovery scales.36,51 (Instruction of the FOUR score is shown in VC 3-3.)

Neurological Examination: Clinical Observations

After an initial assessment using a coma scale, a more detailed examination follows. These clinical signs may eventually lead to further localization of the lesion or lesions causing coma, and they are further described in the following section.

Breathing Patterns

The assessment of airway and ventilation should ideally coincide with an observation of respiratory rhythm, and it remains an underappreciated “neurologic” sign (Chapter 1). Endotracheal intubation is indicated when breathing becomes irregular, the oxygen requirement increases, or hypoxemia occurs, and thus the clinical observation of breath-ing patterns is often too short to appreciate. Breathing patterns fluctuate with change in


alertness. In any patient with progressive acute neurologic hemispheric injury, there is possibly a gradual deterioration from initial emergence of periodic breathing (cluster or Cheyne-Stokes) to tachypnea and finally irregular breathing to gasping with long, irreg-ular apneic periods. Moreover, ataxic breathing may be more often due to intermittent upper airway obstruction in a comatose patient with reduced protective laryngeal reflexes.

Cluster breathing is characterized by short, regular bursts of breaths followed by apneic periods of variable duration, possibly caused by pontomedullary lesions.26 Other reports of cluster breathing include a cerebellar hemorrhage with brainstem compres-sion56 and anoxic-ischemic encephalopathy.7,18 Cheyne-Stokes breathing has a typical crescendo–decrescendo (spindle) breathing pattern but is nonspecific. It is common in stuporous patients and patients deteriorating from brain tissue displacement, but it can also accompany congestive heart failure and can occur in patients with prior sleep apnea. Central periodic breathing patterns are more common in large hemispheric infarcts with mass effect and are correlated with poor outcome.33

Another periodic breathing pattern is apneustic breathing. This is an agonal breathing pattern marked by inspirational holds followed by gradual expiration. It has been associ-ated with tegmental lesions of the pons, but it can be observed in any patient with upper brainstem destruction after extubation to withdraw life support.

Rapid and shallow breathing in a comatose patient is rarely a primary cause of acute neurologic brain injury. It may be associated with respiratory alkalosis, and the physician should consider severe hypoxemia, sepsis, end-stage hepatic failure, and compensation for metabolic acidosis (e.g., Kussmaul breathing in diabetic ketoacidosis or salicylate or ethylene glycol ingestion). Central neurogenic hyperventilation can be associated with both midbrain lesions (traumatic injury and, most often, lymphoma) and bihemispheric lesions.39 Diagnostic criteria for central neurogenic hyperventilation include hyperven-tilation with marked respiratory alkalosis (increased arterial pH, decreased arterial Pco2, and increased Po2).28,39 The sudden appearance of marked tachypnea (frequencies in the range of 50 to 60 breaths per minute) without hypoxemia or increasing oxygen require-ment or PEEP often points to a “central” cause. The abnormality may persist even after awakening. Patients often cannot hold their breath.20

The major breathing patterns are summarized in Table 3-3. (The most common breathing patterns are further demonstrated in VC 3-4.)

Cranial Nerve Examination

Neuro-ophthalmological examination is very valuable in the comatose patient. Before the eyes are examined, the globes are inspected and palpated. After traumatic injury, exoph-thalmos and ocular movement impairment could indicate an orbital fracture that requires


immediate attention by a craniofacial surgeon. Funduscopy is an essential part of the exami-nation, but papilledema or retinal hemorrhages are uncommonly seen. The presence of retinal hemorrhages confirms an aneurysmal subarachnoid hemorrhage, but it may also be seen with traumatic brain injury and battered child syndrome. Papilledema can be difficult to detect; it is rarely present in acutely comatose patients and could be mistaken for the far more benign drusen optic disk. Acutely increased intracranial pressure or cerebral venous occlusion increases retinal venous pressure, dampens venous pulsations, and blurs the mar-gins. Acute papilledema associated with flame-like hemorrhages in a patient with progressive decline in consciousness and acute hypertension may indicate PRES. Massive intravitreal hemorrhages may occur blurring the optic disk.11

Pupil abnormality (size and light response), if present, is one of the hallmark clinical signs in comatose patients. The causes of pupil abnormalities are shown in Figure 3-5. Pupils can become small or pinhole (pons), midsized (midbrain tectum), or asymmetric or maximally dilated (third nerve nuclei in mesencephalon or peripheral fibers). The pres-ence of a unilaterally fixed pupil is due to an oculomotor lesion. It can be from compres-sion or ischemia of the midbrain oculomotor complex (pupil changes only) or traction of the oculomotor nerve (ptosis and downward position). Pressure of the nerve against the clivus has also been suggested as a mechanism. As alluded to in Chapter 1, the more traditional explanation is that it can be from herniation of the uncal hippocampus directly compressing the third nerve at the edge of the tentorium. The shape of the pupil may also change and become irregular, football-shaped or oval, or pear-shaped. An oval pupil is most frequently seen ipsilateral to the mass but is transitory, quickly becoming round, midsized, or dilated and fixed to light. Increased intracranial pressure has mostly been associated with an oval pupil6,24,32 (Fig. 3-6). These changes in shape may be explained by

TABLE 3-3 Breathing Abnormalities

Breathing Abnormality Description of Breathing Localization

Cheyne-Stokes Crescendo-decrescendo breathing pattern

followed by apnea or hypopnea, persists

in sleep

Bihemispheric (unilateral or

bilateral) or brainstem

Cluster Irregular clusters of breaths followed by

apneic periods of variable duration

Bihemispheric or pons

Ataxic or irregular Irregular respiratory rate, rhythm, and

amplitudes interrupted by apnea

Nonlocalizing or dorsomedial medulla

Apneustic Prolonged inspiration with a 2- to 3-second

pause, then expiration

Lateral tegmentum of lower pons

Central neurogenic

hyperventilation

Sustained hyperventilation, exceeding

40 breaths per minute

Bihemispheric, pons, midbrain


Normal pupil size

Oculomotor palsy from acuteintracranial mass, contusion ofbulbus oculi (late phenomenon)

Normal pupil size

Oval pupil (often transitory appearanceof pupils in brain death)

Normal pupil size

Mydriasis (anxiety, delirium, pain,seizures, botulism, atropine, amylnitrite,magnesium excess, norepinephrine,dopamine)

Normal pupil size

Midposition pupils (brain death,mesencephalon lesion)

Normal pupil size

Horner‘s syndrome (carotid dissection,medulla oblongata infarct fromvertebrobasilar artery occlusion, traumaticsympathetic chain lesion due to catheterplacement in jugular vein)

Normal pupil size

Miosis (opioids, acute pontinelesion, nonketotic hyperglycemia,hypercapnia)

FIGURE 3-5 Spectrum of pupil abnormalities and causes.


differences in parasympathetic tone in various iris segments or involvement of different parts of the mesencephalic nuclei.

Coma can affect eye movements in a substantial manner. Eyes do not track due to loss of fixation. Roving (slow horizontal to and fro) eye movements become apparent, are often dysconjugate, and are mostly initially seen in stuporous patients who can be briefly aroused with prodding. Roving eyes may disappear in deeper stages of coma. In other patients, the eyes may be immobile or deviated to one side horizontally or vertically. The position of the eyes may be minimally skewed and of no importance and may be due to inhibition of a fusional mechanism that is operative with arousal. However, when skew deviation is prominent, any of the ocular nerves (trochlear, abducens, or oculomotor) can be dysfunctional, either peripherally or at its brainstem nucleus site. Conjugate gaze deviation is due to a lesion of one hemisphere and is directed toward the abnormality and contralateral to the hemiparesis. When eyes deviate to the opposite direction and toward the site of the hemiparesis (“wrong-way eyes”), a thalamic lesion is inferred. This may be an important clinical sign of thalamic compression that can be used to monitor the pro-gression of mass effect and brain tissue shift. Persistent downward movement of both eyes also is indicative of a thalamic lesion. It is common in postresuscitation anoxic-ischemic encephalopathy. Brief horizontal eye deviation with eyelid opening and with subtle eyelid flutter in a comatose patient may be a sign of nonconvulsive status epilepticus. Head turn-ing and eye turning can be seen during a generalized tonic-clonic seizure, and the version is then ipsilateral.55,56

After inspection, examination further requires eliciting of eye movements using oculocephalic responses (“doll’s eye response”) and oculovestibular responses (“caloric testing”). There are two maneuvers. While holding the eyelids open, the doll’s eye maneuver consists of gradually rotating the head to allow both eyes to reach the cor-ner of the orbit, followed by a jerk back to neutral (straight ahead) position. The same maneuver can be done with neck flexion. This horizontal rotation or vertical flexion excites the semicircular canals, and loss of cortical ocular fixation results in rolling eyes with head turning. Another procedure is to turn the head and put the eyes in the most

FIGURE 3-6 Oval and pear-shaped pupil. These are often transitory forms ending up in a

midposition pupil.


eccentric positions in the orbit. This position is produced by a brainstem–cerebellar gaze-holding network and is absent with a brainstem lesion.21 Forced upward or down-ward ocular deviation with rapid oscillation (“head shaking”) is indicative of major neocortical and Purkinje cell damage. In patients with vertical eye deviations after such a stimulus, prominent MRI abnormalities were found in the cortex, lentiform nuclei, and cerebellum (VC 3-5).16,17

Oculovestibular responses are tested next. Positioning the head at 30 degrees will put the horizontal canals in a vertical position. Ice water flushing of the ear slowly moves the eyes toward the stimulus, and warm water moves the eyes upward. The downward motion of endolymph from cooling will eventually stimulate the vestibular centers to produce a movement (VC 3-5). Absent caloric responses indicate a pontine lesion and imply interruption of the vestibulo-ocular pathways, but the reflex is suppressed by drugs in toxic doses (e.g., antiepileptic drugs, barbiturates) and by more ordinary causes such as blood or cerumen in the ear canal. As a general rule, with a normally evoked conju-gate eye movement, the centers of horizontal gaze and medial longitudinal fasciculi are spared, and this indicates a largely intact brainstem. A brainstem lesion in a patient inter-rupts the medial longitudinal fasciculus, resulting in abduction of the eye ipsilateral to the irrigated ear but with a failure of the opposite eye to adduct. Absent oculovestibu-lar responses in coma—not caused by drug intoxications—is a grave prognostic sign in many conditions.10,21,22,27

Several spontaneous eye movement abnormalities have been recognized (Table 3-4). Their presence has some localizing value and points mostly to a diffuse structural hemi-spheric injury. These uncommon eye movements require specific attention because they may be present early at the onset of coma and could disappear quickly. Alternating hori-zontal gaze deviation may occur spontaneously and is also known as periodic alternating gaze. This spontaneous eye movement abnormality is indicative of a bihemispheric lesion and not further localizing. Other spontaneous eye movements are ping-pong gaze and ocular dipping. Ocular bobbing (fast downward and slow upward movement) is due to a lesion in the pons (VC 3-5).

Inspection of the mouth and oropharyngeal function should not be neglected. The mouth can be discolored by corrosives due to a suicide attempt, and tongue biting may have occurred as a result of a seizure. Other brainstem reflexes involve the lower brain-stem and medulla oblongata. Cough reflexes and breathing drive are the key functions to test. The oropharyngeal function can be tested through the gag reflex. However, the pha-ryngeal reflexes are better tested by using suctioning with a catheter in the endotracheal tube. The breathing drive is noted in intubated patients and may require adjustment of the ventilator or brief disconnection at normal arterial Pco2.


Spontaneous Movements

Motor responses evoked by noxious stimuli are graded from localization to no response45 (VC 3-6). Flexion or extension at the arms can be observed and may indicate decorticate responses (stereotyped slow flexion in elbow, wrist, and finger grasping) or decerebrate responses (adduction and internal rotation of shoulder, arm extension, and wrist prona-tion with fist formation), or there may be more-difficult-to-classify arm excursions with alternating formes frustes of pathological flexion and extension.

Other abnormal and definitively unusual movements are extreme opisthotonus or leg walking (stepping) that represents an alternating, exaggerated, spontaneous triple flexion response. Many body movements are spontaneous, periodic, and hard to classify. They may be misinterpreted by the family as purposeful or indicating an intent of the patient to communicate. Some are best described as choreoathetoid fidgets, for lack of a better term. These movements may be due to diffuse cortical disinhibition but also thalamic injury interrupting the pallidothalamic circuits can be implicated (VC 3-6).

Generalized myoclonus can be seen following anoxic-ischemic injury after cardio-pulmonary resuscitation, lithium intoxication, penicillin and cephalosporin intoxication, and pesticides. It consists of brief rapid jerks in all extremities and the face or eyelids and can be quite forceful. It may involve the abdominal muscles, causing difficulty in patient-ventilator synchrony (VC 3-7).

Shivering is not uncommon after awakening from anesthesia, but in patients admitted to the emergency department, it can also indicate hypothermia or early sepsis. Fine shivering may also occur after upper brainstem destruction and may be difficult to differentiate from spontaneous clonus. Shivering is without sweating or piloerection and therefore is due to reticulospinal injury44 (VC 3-8).

LOCALIZATION PRINCIPLES AND BRAIN DISPLACEMENT SYNDROMES

The change in shape and position of the thalamus-brainstem structure when displace-ment occurs is shown in Figure 3-7. This key structure can move in a horizontal plane

TABLE 3-4 Eye movement Abnormalities in Coma

Type Lesion

Periodic alternating gaze (lateral deviation every few minutes, left and right) Bihemispheric, midbrain, vermisPing-pong (lateral deviation every few seconds, left and right) Bihemispheric, vermisConvergence nystagmus (bilateral abduction, slow with rapid jerk back) MesencephalonRetractory nystagmus (retraction orbit) MesencephalonBobbing (rapid down, slow up) PonsDipping (slow down, rapid up) Bihemispheric


at the thalamus and pontine level and vertically at the thalamus-mesencephalon level, or can become compressed from both directions due to a swollen hemisphere. Rotation or an angular vector due to a combined horizontal and vertical force can also displace the thalamus-brainstem structure. The clinical signs of brainstem displacement likely reflect the change in geometry. What is noted clinically is a summation of damage of each involved structure. Brainstem displacement and distortion are often maximal at the onset of an acute, rapidly expanding mass lesion. In more slowly expanding lesions (e.g., hemispheric ischemic edema), clinical signs are due to more compression effects and not necessarily more shift.

The three time-honored questions that need to be asked to elucidate the cause of coma are as follows: (1) Is it a destructive structural lesion or is it due to a global acute physiologic derangement of brain function? (2) Is the structural lesion bihemispheric or in the brainstem? (3) Is the lesion inside the brainstem or due to displacement of the brainstem?

An approximate localization can be made using the components of the FOUR score, assessment of eye position (skewed or forced gaze), and further use of provocative tests (doll’s eye maneuver or oculovestibular responses). It is practically useful to divide these entities into a bihemispheric syndrome, intrinsic brainstem syndrome (including locked-in syndrome), and lateral and central brainstem displacement syndromes. These syndromes are shown in Figure 3-8(A–G).

The bihemispheric syndrome pattern is due to cortical injury, extensive white mat-ter injury, or an acute physiological brain dysfunction (e.g., acute metabolic derange-ments, toxins, ongoing seizures, or postictal phase) and is shown in Figure 3-8A. Patients with a bihemispheric syndrome have few localizing findings. Gaze preference may be seen temporarily. Most patients open their eyes initially to voice, but later to pain stimuli. Spontaneous roving eye movements are seen, but some patients may

FIGURE 3-7 Types of thalamus-brainstem compression and shift.


Normal doll’s eyesphenomenon

E1E2E3

M0M1M2M3

B4

R3R4

Intactoculovestibular

responses

Eye deviation

Bihemispheric syndrome(A)

E0

M1M2

B1

Skewdeviation

INO

Miosis

Anisocoria

Absent doll’s eyesphenomenon

Intrinsic brain stem syndrome(B)

FIGURE 3-8 Major clinical syndromes in coma. (See color insert.)


Bobbing

Skewdeviation

B2B4

R2R1

E4

M1

Locked-in syndrome(C)

E1E2

M2M3

B3


responses

Lateral brain stem displacement syndrome(D)



E0E1

M1M2

B2

R2R1

Absent doll’s eyesphenomenon

Absentoculovestibular

responses

Lateral brain stem displacement syndrome(E)

Central brain stem displacement syndrome(F)


responses

R1

B2

M2M1M0

E1E0

R2



display rapid roving or ping-pong movements (VC 3-9). The full spectrum of motor responses is seen. The brainstem reflexes (cornea, pupil, and oculovestibular) are fully intact. Pupils may be small but not pinpoint, and this may be a result of decreased consciousness alone. Myoclonus status epilepticus may be seen in the most severely affected patients and predominantly in survivors of cardiopulmonary resuscitation. Breathing patterns may be periodic or regular, although intubation may be needed when insufficient tidal volumes are generated.

Brainstem syndromes can be divided into intrinsic brainstem syndromes and brain-stem displacement syndromes. These two syndromes may overlap in terms of clinical signs, but knowledge about the chronology of events usually differentiates the two syn-dromes. Patients with intrinsic brainstem syndromes (Fig. 3-8B) present instantaneously with failure to open their eyes to a noxious stimulus, withdrawal motor response, or extensor posturing, skew deviation, miosis or more often anisocoria, and abnormal ocu-lovestibular responses that may show internuclear ophthalmoplegia. The presentation of signs at onset without much later change (except for loss of all brainstem function) points to this pattern. Intrinsic brainstem injury producing coma should be differentiated from a

E0

M0

B0

R0

Absent doll’seyes

phenomenon

Absentoculovestibular

responses

Brain death(G)

FIGURE 3.8 Continued (See color insert)


locked-in syndrome. In a locked-in syndrome, skew deviation is also present, and ocular bobbing is frequent and may be difficult to distinguish from spontaneous vertical eye movements and blinking (Fig. 3-8C). Spontaneous eye movements may include more elaborate movements such as ocular seesaw (VC 3-10). Cornea reflexes and pupil reflexes (although small in size) may be present, or cornea reflexes may be absent. Patients may have extensor posturing. All these clinical signs may suggest to the untaught that the patient is comatose, while in fact the patient is fully alert.

Brainstem displacement syndromes may be central or lateral and due to a mass in the hemispheres or cerebellum. These syndromes present with different combinations of signs, but some progression is often noted (Fig. 3-8D,E).

Lateral brainstem displacement syndrome distorts the thalamus and mesencephalon and, less severely, the pons (Fig. 3-8D). These patients present with a decline in conscious-ness (thalamus-mesencephalon). A unilateral fixed, dilated (varying from 2- to 5-mm dif-ference) pupil is seen early and can be followed by bilateral fixed pupils. Dilatation of the pupil opposite to the mass as a presenting sign may occur but is uncommon. Possible explanation for this discrepancy is axial rotation of the brainstem (the pull is more at the contralateral oculomotor nerve and less at the ipsilateral oculomotor nerve when the ventral part turns counterclockwise); or the mechanism is ischemia from compromise of the displaced mesencephalic branch of the posterior cerebral artery; or there is traction over the clivus31 (Fig. 3-9). The pontine reflexes remain intact. This clinical presentation of acute coma and unilateral fixed pupil, however, can be mimicked by acute lesions in the thalamus that suddenly extend asymmetrically to the mesencephalon (e.g., a thalamic hemorrhage). Lateral brainstem displacement may also occur from acute lesions in the cerebellum, (Fig. 3-8E) which may produce compression of the brainstem but more at the pontine level. Most notable is a predominance of pontine signs, with bilateral miosis, loss of both cornea reflexes, and oculocephalic reflexes. However, sparing of the mesen-cephalon may result in normal pupil size and retained pupil reflexes.

Central brainstem displacement syndrome distorts the thalamus and mesencepha-lon in a vertical plane, causing fixed midposition (4–6 mm) pupils initially. Asymmetric compression of the mesencephalon with large pupil, or an oval pupil at the site of the lesion may be seen. Motor responses vary from decorticate to extensor responses, some-times with variation throughout the day, and no evidence of other signs of deterioration. In patients with a gaze preference toward the expanding mass, the gaze may reverse due to thalamic compression. Brief periods of periodic lateral gaze may occur (Fig. 3-8F). Central brainstem displacement syndrome may occur with bilateral thalamic compres-sion from diffuse brain edema. If compression is confined to the thalamus, the clinical symptoms may strongly mimic a bihemispheric syndrome, but progression can be often


documented. Further vertical displacement of the entire thalamus- mesencephalon pontine structure may occur, but only after the upper brainstem has been destroyed directly from compression. Retained medulla oblongata function may occur frequently. Patients who lose all brainstem reflexes usually lose pontomesencephalic reflexes at onset and medulla oblongata function later. Motor responses do vary in each of these brainstem displacement syndromes, and they often do not correlate with changes in brainstem reflexes. A more common progression is appearance of flaccidity, and no motor response with loss of pontomesencephalic reflexes, and finally, failure to trigger the ventilator, indicating brain death (Fig. 3-8G). A complete brain death examination is discussed in Chapter 5.

CONCLUSIONS

A detailed neurologic examination in comatose patients serves an important purpose in the practice of medicine and is mostly focused on motor responses, eye position and movements, brainstem reflexes, and presence of spontaneous limb movements. These abnormalities also enable differentiation between comatose states. Scales have been used to assess comatose patients. They provide an initial useful and comprehensive evaluation of the level of consciousness. Further neurologic tests are needed to complete a more

FIGURE 3-9 Wrong-side dilated pupil on the right (acute subdural hematoma on the left with

brainstem tilting to the opposite side). With permission of Neurology.53


detailed examination. These findings can then be consolidated in syndromes that could point to the cause of coma. It is clinically useful to try to fit comatose patients into a bihemispheric syndrome, lateral or central brainstem displacement syndrome, intrinsic brainstem syndrome, or at its extreme, brain death.

It makes better sense to summarize the major findings into several syndromes of brainstem displacement. In clinical practice, these brain tissue shifts are often called “her-niation” or the more common saying, “the patient is herniating” or “coning,” and they are very familiar designations in medical language. However, using the term displacement or intrinsic for brainstem injury provides a more specific explanation. The clinical distinc-tion between compression of the brainstem and intrinsic brainstem lesions may remain difficult, and both syndromes may merge into a neurologic state with loss of all ponto-mesencephalic reflexes or even loss of all brain function.

Neurologic examination of the comatose patient will provide an initial localization that then will be verified by neuroimaging studies, resulting in a likely cause. Unfortunately, localizing findings are uncommon in comatose patients. Typically, patients do not open their eyes to pain, withdraw to pain, or have reflexive motor responses; need ventilatory support due to irregular breathing; and have intact brainstem reflexes. This poses a chal-lenge to clinicians searching for a cause.

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111

With time, most comatose patients improve. Awakening from coma can be instantaneously quick, as in treated hypoglycemia, or endlessly slow, as in brain damage from major structural injury. When awakening does not occur and neurologic findings remain much the same within the first four weeks, this condition is referred to as a persistent vegetative state (PVS).44 The transition from coma to PVS is punctuated by eye opening first. Eye contact is absent and this vacant stare can be eerie. Sleep and wake cycles follow and yawning may occur. Very few other responses are noted, and routine nursing procedures may exaggerate vegetative functions such as heart rate or breathing frequency—hence its name.

Prolonged comatose states remain hard to categorize. How do we name a nonre-sponsive state in which the patient spontaneously opens their eyes, does not blink to threat, is not moving the extremities, fails to communicate, grunts to pain (if not made impossible from a tracheostomy), and shows vegetative responses (such as changes in pulse, frequency of breathing, and blood pressure)? The search for a proper name for this condition was described in Chapter 1. Some feel that PVS is an “unfortunate” term, and in Europe “unresponsive wakefulness syndrome” has been proposed as an alternative term.48 Such an indistinctive term, however, leaving out lack of awareness in the description, could potentially trivialize this unfortunate condition and may blur the lines with minimally conscious state, locked-in syndrome, or other levels of severe disability.76 Short of a better alternative, PVS remains a deeply ingrained term and due to its specific association with vegetative symptoms has resonated well. The adjectives

The Clinical Diagnosis of Prolonged Impaired Consciousness

/ / / 4 / / /

112 / / The ComaTose PaTIenT

“persistent” and “permanent” have been used, but it is confusing for clinicians and researchers (and certainly the family). This situation is not easily remediated, but it is advised that PVS be used when the outcome—no recovery—is certain.44

It is a misunderstood notion that PVS is common. States of impaired consciousness are usually much less severe than PVS. This has been further corroborated by a recent study that surveyed the reliability of the diagnosis of PVS in the United Kingdom. Traces of awareness were found in a considerable proportion of patients deemed to be in PVS. Plausible explanations for this finding have been suggested, such as improvement since admission to a nursing home, discontinuation of drugs depressing consciousness, or, more worrisome and perhaps more likely, insufficient observation time by an inexperi-enced examining physician.4,19,72

The assessment of prolonged impaired consciousness remains a purely clinical judgment, and this chapter provides a clinical guide to assessing these patients. The management of prolonged impaired consciousness not only involves supportive medi-cal care but also includes physiotherapy measures,75 and which is further discussed in Chapter 9.

CATEGORIES OF OUTCOME

To keep a better perspective, it is useful to revisit the categories of outcome in a patient whose coma is due to a structural destructive injury. The major categories of outcome are summarized in Figure 4-1.77 Generally speaking, coma due to widespread structural damage (e.g., anoxia-ischemia, trauma, brainstem stroke, or meningoencephalitis) is associated with poor outcome when patients show no improvement in consciousness within the first few weeks. Patients may never regain consciousness and may die if further brain swelling, brain herniation, or medical complications occur. Death from withdrawal of medical support is most common in comatose patients, but primarily in those most severely affected and those who fail to recover neurologically.

It is unlikely that survivors of a prolonged coma will make a full recovery. Full recov-ery refers to the near-complete return to baseline function without physical or cognitive impediments, or the inability to be productive, whether it is a simple or complex task. As shown in Figure 4-1, few patients reach a state with minimal deficit and can return to gainful employment. Patients who awaken often struggle with a disability, usually residual cognitive or motor deficit that prevents them from functioning independently, and many display little effective communication. New in this nosology is the category of minimally conscious state (MCS), the most severe form of neurologic disability in a

The Clinical Diagnosis of Prolonged Impaired Consciousness / / 113

conscious patient. Age may determine the final outcome; for example, traumatic injury to the brain in young individuals may, after a protracted period, lead to a satisfactory outcome, whereas anoxic-ischemic injury after cardiopulmonary resuscitation in elderly persons is associated with few survivors.

PERSISTENT VEGETATIVE STATE

A multisociety task force has defined the main features of PVS.1 These criteria, adopted by the American Academy of Neurology,2 are listed in Table 4-1. As alluded to earlier, it has been suggested that a diagnostic neurologic examination to establish a definitive diagnosis of PVS should be postponed until at least one month has passed since the onset of coma. However, a presumptive diagnosis can be made earlier. Neurologic examination cannot be reliably performed if the patient had recent evidence of bacteremia or early sepsis since these situations can significantly confound assessment of consciousness. Diagnosis also requires exclusion of sedating drugs—a staple of modern intensive care units—which have an effect that is commonly overlooked.72

Systemiccomplications

Death

Braindeath

Withdrawalof support

PVS

MCS

Severedisability

Conscious

Survival

Disability

Structuralcoma

Unconscious

Milddisability

Goodrecovery

FIGURE 4-1 Major categories of outcome in comatose patients due to a structural lesion (the

size of the boxes estimates the frequency of occurrence of each category). The dotted arrows

represent possible transitions.77 PVS: persistent vegetative state, MCS: minimally conscious

state.


A routine neurologic examination may not capture the salient features of PVS, and a clinical methodical guide is provided in Table 4-2. Careful examination of the eye move-ments has a high priority. Eyes may open wide when the patient is touched, but visual pursuit—smoothly following an object—is absent or momentary and not reproduc-ible. Visual fixation is absent, although it can appear later and mostly at random without other signs of improvement.42 A visual orienting reflex may occur with head turning when family members or nursing staff move in the room. Large objects or persons suddenly approaching the patient may result in the patient briefly turning their eyes and suggests target focusing, but the response extinguishes quickly. Placing the front page of a news-paper or an optokinetic tape before the patient and moving it sideways, or tilting a large mirror held in front of the patient, does not consistently elicit visual scanning, optoki-netic nystagmus, or tracking. Eyes are often disconjugate, and they typically rove back and forth, interrupted by nystagmoid jerks.

Response to sound is complex and may be present in some rudimentary form, and many patients may show a startle myoclonus. A sudden, loud hand clap may briefly, but only partly, open the eyes and move the patient’s head toward the stimulus. Characteristically, it occurs only the very first time, and the response is not found with a salvo of hand claps. Consistently looking toward the origin of sound is not compatible with the diagnosis of PVS. Blinking to threat does not occur, because these responses require cortical feedback loops (Chapter 3). Spontaneous blinking or blinking after the area between the eyebrows (glabella) is tapped can be seen because that sign only requires brainstem circuits.

A noxious stimulus could, but inconsistently does, produce some “grimacing,” but usually a response is entirely absent. Spontaneous grimacing with chewing, yawning,

TABLE 4-1 Criteria for the Diagnosis of PVs

• No evidence of awareness of themselves or their environment; incapable of interacting• No evidence of sustained, reproducible, purposeful, or voluntary behavioral responses to visual, auditory,

tactile, or noxious stimuli• Roving, nystagmoid eye movements• No evidence of language comprehension or expression• Evidence of severe bihemispheric injury (marked rigidity, spontaneous clonus, snout reflex)• Mostly preserved cranial nerve (pupillary, oculocephalic, corneal, vestibulo-ocular, gag, and cough) reflexes• The presence of sleep–wake cycles (and often eyes open during the day)• Unsupported blood pressure, intact respiratory drive, and fluctuating heart rate• Bowel and bladder incontinence

Data adapted and modified from Multi-Society Task Force on PVS.1


TABLE 4-2 examination of a Patient in a PVs

INSPECTION• Breathing regular (with tracheostomy in place)• Blood pressure stable• Immobile• Flexion–extension contractures• Eyes closed or open• No evidence of focus or holding attention• No eye movements (except when suddenly entering) to examiner• Eyes roving, nystagmoid, gaze preference changing, no eye contact for more than a few seconds• Spontaneous teeth grinding• Choreiform fidgets, spontaneous clonus, or shiveringPALPATION• Increased tone with flexion or rotation of the head• Increased tone with movements of lower limbsPROVOCATIVE TESTS• Call patient name No response• Ask to lift head, turn head No response• Ask to blink twice, look up No response• Loud hand clap May startle

Myoclonic jitter

No tracking of eyes to sound

No reproducible head turning to sound• Imitate gesture (thumbs up) No response• Move newspaper front page up and down or tilt large

mirror

No fixation

• Rapid head shaking or noxious stimulus (supraorbital

nerve compression)

Eyes move upward or downward or assume

lateral gaze for 1–2 min• Threat reflex No eye blinking• Glabellar reflex No extinction• Snout reflex Present• Palmomental reflex Present (very vivid with extension to upper arms

or even chest)• Corneomandibular reflex Present or absent• Noxious stimuli (temporomandibular joint compression) No grimacing (may increase blood pressure, heart

rate, and respiratory rate)• Grasp reflexes Present• Tendon reflexes Hyperreflexia• Plantar reflexes Equivocal• Pin prick Flexion, extension of limbs


and bruxism may be observed, and these may remain as primitive brainstem reflexes. Grimacing may persist after the stimulus has stopped, but it has an uncertain significance (earlier studies have hinted that this sign may indicate a better prognosis).10 The snout reflex and glabella, palmomental, and corneomandibular reflexes are all easily elicited. The jaw reflex is brisk. In other patients, a tongue depressor may cause forceful biting with the ability to lift the head up (called the “bulldog reflex” by Bricolo).10 Nontracheostomized patients do not talk, but may make sounds with different vowels. They may moan, groan, or squeal. Spontaneous episodic screaming has been reported but is highly unusual.66 More often, patients may express a muffled cry, often painful to hear for the family. An involuntary swallowing gag reflex may remain. Swallowing movements of saliva do occur, but the coordinated stages of oropharyngeal passage are impaired. When an ice chip is placed inside the mouth, a few primitive chewing movements may be observed. It is likely that any food placed in the mouth will be inhaled with the next breath.

Motor response to nail bed or temporomandibular compression is absent or noth-ing more than pathological flexion or extensor responses. Motor responses are muted due to the overriding spasticity and contractures. Thumbs may be buried in balled fists or may wedge through the index and middle finger. Nail bed compression results in an increasing pulse rate and tachypnea, with some limb flexion or extension. Reflexes are difficult to elicit because of these contractures, including an equinovarus, but often clo-nus is present in all extremities (VC 4-1). Spontaneous nondirected choreiform fidgets of the limbs or extreme opisthotonus (arc-de-cercle) may occur in patients in a PVS; these movements are unresponsive to neuroleptic agents, benzodiazepines, or dopa-minergic drugs and could persist for weeks. Manifestations of dysautonomia include increased bronchial secretions, hypertensive surges, tachycardia, and tachypnea. The “vegetative” manifestations may be pronounced within the first week but then settle down to stable blood pressure, regular breathing, regular pulse, normal sweating, and skin temperature. Sleep–wake cycles are preserved in PVS, possibly due to retained ton-ically active mesencephalon synapsing through sympathetic tracts to the pineal gland.78 Circadian sleep–wake cycles may be absent, with the eyes of the patient mostly closed with only brief episodes of opening, and are more often observed when brainstem lesions are found.41

MINIMALLY CONSCIOUS STATE AND AKINETIC MUTISM

The Aspen Consensus Conference Working Group has suggested recognizing a condi-tion of severe disability with minimal awareness. When patients do not fulfill the criteria


of PVS, they suggest the term MCS.35 An estimate reports that MCS could be 10 times more common than PVS.50 However, the definition (or boundaries) of this disabled state has not been based on prospective data, nor is much known about the chances of improvement. The Working Group emphasized that the distinction between MCS and PVS is mostly a partial presence of awareness.35 In the working group’s opinion, this characteristic has implications for medicolegal judgments and use of resources. Rather than waiting for a fuller definition, the acceptance of this condition has been exception-ally rapid. This may have been influenced by attorneys seeking alternative explanations in the recent Wendland and Schiavo cases (Chapter 10). Patients in an MCS are aware, but recognizing and demonstrating awareness is difficult if the patient does not follow a command. A simple motor task does not imply full awareness, and a gesture or verbal-ization is a more useful sign. To the physician observing these patients’ behaviors, the responses are purposeful, slow, sluggish, and intermittently complying. Emotions may be present in MCS—as is pain perception—but it is very difficult to appreciate their true nature. But in all patients the level of awareness is markedly diminished, and is not at a level to express requests for care or to communicate consent for medical procedures6,34 (VC 4-2).

The Working Group acknowledged that the incidence and prevalence of MCS, the ability to be diagnosed accurately, the course of recovery, and the potential for treatment remain largely unknown. MCS is a most useful term for patients without certain neuro-logic characteristics, but it likely is a mixed bag of neurologic conditions. The transition to a full conscious state with severe disability is also undefined. The proposed criteria for MCS are shown in Table 4-3.35

TABLE 4-3 Criteria for mCs

• Clearly discernible evidence of self or environmental awareness• Following simple commands• Gestural or verbal yes–no responses• Intelligible verbalization• Purposeful behaviors Pursuit eye movement of sustained fixation occurring in direct response to moving stimuli Appropriate smiling or crying Vocalizations or gestures occurring in direct response to questions Reaching for objects Touching or holding objects


The differentiating clinical features with PVS are shown in Table 4-4. Akinetic mut-ism is another impaired conscious state, with fairly recognizable characteristics, but there is a continuum and overlap with MCS.12,16,46,53–56 Akinetic mutism is uncommon and pos-sibly underrecognized (VC 4-3). The descriptive term is problematic for several reasons. First, most patients with akinetic mutism are not akinetic, and many may move spontane-ously or to pain stimulus. Second, few patients in a response to a pain stimulus are totally mute, with many uttering a single word. The main clinical features of akinetic mutism are an abulic emotionless state, but with the eyes tracking movement. The ability of the patient to follow the examiner throughout the room or suddenly be prompted by a per-son entering the room has been compared with hypermetamorphosis (a phenomenon observed in monkeys that seem to respond to movement rather than objects after the temporal lobes have been removed). Pain stimuli may provoke no response or decorticate posture. Facial grimacing and blinking to threat is often present (VC 4-3).

There is reasonable consensus among neuroscientists that akinetic mutism can be caused by lesions of the anterior cingulate gyri. The anterior cingulate cortex is involved in executive functions but also affects vocalization, and, due to the connections between the cingulate cortex and supplementary motor area, affects initiation of movement.24 Other lesions have been described and are predominately in the diencephalic struc-tures such as the thalamus, basal ganglia, or even mesencephalic structures.12

Akinetic mutism has been described in patients with aneurysmal subarachnoid hemorrhage and bifrontal lesions16,18 and in the setting of hypothalamic lesions and obstructive hydrocephalus,60 and been associated with an infiltrative astrocytoma in the fornix13,16,53,56 (Table 4-5). Akinetic mutism could be considered a subset of an

TABLE 4-4 signs Present in mCs but absent in PVs

• Eyes hold attention momentarily• Looks at person briefly• Makes eye contact• Turns head when talking• Mouths words after pain• Eyes follow moving person• Localizes to pain, fends off• Some intelligible verbalization• Tracks source of sound• Shrugs shoulders on command• Looks at object or picture when asked• May hold object or use object when asked• Imitates gesture or performs movement on verbal request (e.g., lift head, turn head)


MCS, but there are unique characteristics.13,16,53,56 Moreover, the response to therapeu-tic interventions may differ.

LABORATORY INVESTIGATIONS

Knowing that none of the laboratory abnormalities is sufficiently specific, clinicians have recognized that clinical diagnosis trumps any test. The EEG in PVS shows a spectrum of abnormalities that also changes when a wake–sleep cycle emerges.45 All phases of physi-ological sleep are present on EEG in PVS. During sleep a rapid eye movement (REM) phase remains but is hours shorter than normal.58 Presence of REM sleep is expected because the subceruleus region, involved in generating REM sleep, is located in the pons, which is typically spared in patients in a PVS. EEG patterns have included delta and theta activity, spindle and alpha-like rhythms—more diffusely distributed than in the typical posterior regions—and are not reactive to sound, light, or noxious stimuli.15,40 In patients with more thalamic than cortical damage, the EEG may show diffuse theta and low-voltage fast beta activity. A markedly suppressed EEG has been noted in comatose survivors, often after cardiac arrest, and persists for weeks or months.9,30 Changing or improving EEG patterns, such as a return of reactivity and reduction in delta activity, do not correlate with clinical improvement and should be interpreted cautiously. Some studies have suggested that increasing power in the alpha and theta bands may predict survival, but the results are inconclusive.22 The appearance of an alpha rhythm with a simultaneous increase in background rhythm frequency may appear early, but its predic-tive value for recovery has also been questioned. Therefore, the role of standard EEG in predicting long-term outcome, or recovery for that matter, is very limited. There may be an exception in patients with diffuse and persistently suppressed EEG activity, which

TABLE 4-5 Causes of akinetic mutism

Lesion Disorder

Anterior cingulate gyrus • Rupture of anterior cerebral artery aneurysm complicated by

cerebral infarction

• Brain tumor

• Ischemic strokeDiencephalon • Hypothalamic tumor

• Carbon monoxide intoxication or cyanide poisoningMesencephalon–Pons • Compression by giant basilar artery aneurysm

• Fourth ventricle plexus papilloma


bodes poorly for any meaningful recovery. Continuous EEG may have better predictive value but this has been studied in only very selective populations (Chapter 6).

Neuroimaging reflects the cause of brain injury that led to prolonged impaired con-sciousness. On CT scan, diffuse atrophy and bilateral thalamic lesions are common in both conditions.43 Regardless of the underlying cause, patients who survive in PVS show pronounced reduction in white matter volume, with concomitant enlargement of the ven-tricular system.1 Secondary axotomy and transneuronal degeneration are possible mech-anisms for this progressive loss of brain tissue (Fig. 4-2). Similar, but far more impressive, findings can be found on MRI (Fig. 4-3). Anoxic-ischemic and traumatic injuries are pre-dominant lesions in the brain. Diffuse cortical laminar necrosis and traumatic lesions in corpus callosum and dorsal brainstem from impacting rotational forces are commonly demonstrated on MRI. Diffusion-weighted imaging may have better predictive value in traumatic brain injury with diffuse axonal injury. Concomitant lesions in the brainstem, gray matter, and corpus callosum could increase the probability of PVS.79

Understandably, cerebral angiography has been rarely performed in PVS. In the earlier days, a typical pattern had been recognized with thinning of the arteries and dis-appearance of branches.11 This “tree in the winter” pattern may have had diagnostic or prognostic value but has not been sufficiently studied.

The value that static neuroimaging brings largely pertains to documentation of perma-nent thalamus–brainstem injury or progressive atrophy from a more diffuse injury. There

FIGURE 4-2 Nonenhanced CT scan of the brain in a 45-year-old man showing profound cerebral

atrophy with ventricular dilatation. (The CT has the look of a 90-year-old.) By the time the CT scan

was obtained, the patient had been in a posttraumatic PVS for 15 years.


have been some studies of brain physiology in patients in a PVS. Arguably the most inter-esting are positron emission tomography (PET) studies; however, only preliminary stud-ies in selected patients have been published. One study of five patients in a PVS quantified cerebral metabolism and found that the resting rates are less than 50%. (This decline has been tentatively compared with an anesthetized brain.66) Topographical differences have been found in patients with near-normal cortical metabolism but also profoundly abnor-mal thalamic and mesencephalic function, again confirming its major role in arousal. PET studies in patients in a PVS have also documented that the most severe abnormalities are in the frontal and temporoparietal regions, disconnecting it from the thalamus.17,47,64,65

In an attempt to further investigate brain activation and to separate PVS from an MCS, functional MRI (fMRI) studies have been used, but mostly for research purposes.67 All

FIGURE 4-3 MRI of a 21-year-old man in a PVS. Marked cortical thinning and dilated ventricles

are due to tissue atrophy. Note the large third ventricle and more typical massive enlargement

of the aqueduct.


fMRI studies in PVS and MCS were based on highly selected patients, and selection cri-teria for studies are not known—perhaps because the family “saw something” that doc-tors categorically denied.36,73

In fMRI, increased activity of a stimulated brain region leads to upregulation of the cerebral metabolic rate and changes in the oxygen concentration (also known as blood oxygen level dependent [BOLD] signal). This signal is a result of the change in the mag-netic field of red blood cells and is dependent on the oxygenated state of hemoglobin. It is also susceptible to signal dropout as a result of a sluggish hemodynamic response, head movements, noise, strong response in primary sensory centers, and other artifacts.37,57 The optimal testing conditions in research centers experienced in the study of these patients may not be reproduced in other centers. Acknowledged by researchers in the field, fMRI is of course a surrogate signal for neuronal activity and a BOLD signal is not neuronal spiking.49 Spontaneous BOLD signal variations could mimic chance occurrence and could be artifactual in nature. (The dead salmon positive brain activation example—even though banal—illustrates some of the potential problems.)8

fMRI has demonstrated interacting networks or so-called resting-state networks (i.e., brain activity in the absence of an explicit task—“resting”69). There are several interacting networks, and the best known is the default mode network (DMN).23,32,36 There is also a dorsal attention network consisting of superior parietal and frontal regions. The DMN connects the posterior precuneus cortex (PCC) to the inferior parietal lobe and mesial prefrontal cortex. Still unclear is the connection of DMN to other structures that have been identified with consciousness including the upper brainstem, bilateral orbitofrontal cortex, medical thalamus, and other parietal association cortices.

The posterior cingulate/precuneus has assumed a critical role in maintaining con-sciousness due to its specific abnormality in MCS and its virtually absent activity in PVS (Fig. 4-4). The demonstration of such a resting fMRI also allows researchers to inves-tigate its response (or lack thereof) to a task, either sensory or cognitive. Reduction in DMN activity may be a result of a task and also may be dependent on “cognitive engage-ment.”32 The DMN is also markedly decreased in patients with convulsive or nonconvul-sive seizures.52,70

fMRI responds to a sensory stimulus, and it may activate the primary cortex (in PVS or MCS, in disabled neurologic patients without a decrease in alertness). In MCS, a much more vigorous stimulus is needed to produce activation. Also, so-called “motor imag-ery” tasks are used in fMRI. Motor imagery has been defined as an ability to simulate or emulate movement without actual physical movement (e.g., imagine finger tapping, image playing tennis, imagine walking through the rooms in your house). Activation dur-ing these imagery tests on fMRI has been interpreted as awareness (or some degree of it)


because stimulation results can be reliably produced in normal controls. These motor imagery tasks may not be generated in at least one of four healthy volunteers, and there-fore the specificity and sensitivity of this response are not known and could be low. Falsely negative fMRI studies have been reported in patients with clearly present bedside communication but no activation with fMRI.7

In recent studies communication could be established in some patients linking “yes” and “no” to these imagery tests. However, none of these studies in patients with MCS has yet established a reproducible way of communicating with the environment and pro-vided a sense of overall well-being. Whether a consistent response can be generated that would allow a brain–computer interface remains to be seen (Chapter 9).

An important recent finding is an association between f MRI DMN and tractogra-phy in different degrees of impaired consciousness. Abnormal pathways included cor-tical regions within the DMN and the posterior cingulate cortex/precuneus with the thalamus.31 Even subdividing MCS into patients with intelligible verbalization, yes/no responses, or command following (designated as MCS plus), or patients with only reflexive localization and tracking or fixating only (designated as MCS minus) showed changes in structural integrity of the DMN, suggesting a continuum of injury and the potential for transitions between these states. Tested patients in MCS had focal neu-rologic findings but were able to identify objects visually, were inconsistently able to follow one-step commands, and occasionally responded with single-word verbaliza-tion. Passive simulation tests were performed and included light touch of both hands and an auditory narrative of family events presented by a family member. f MRI showed evidence of activation of the superior middle temporal gyri to passive listening. Due to activation of the occipital cortical regions, it has been speculated that activation of these regions during listening of patient narrative content might imply an “imaginal representation of the person speaking.” Another study from the same group of inves-tigators of a patient with MCS using diffusion tensor MRI and PET imaging showed

Control

0.0 0.8 0.0 0.8 0.0 0.8

MCS PVS

FIGURE 4-4 fMRI changes in MCS and PVS compared with control. Note gradual increase in

abnormalities in the resting network with worsening level of consciousness (See color insert).


increased activity in the association cortex and precuneus. Diffusion tensor MRI showed evidence of axonal outgrowth that coincided with neurologic improvement and evidence of better arousal.62,74

These recent fMRI studies in patients with prolonged unconsciousness raise impor-tant questions. They potentially bring about concerns about the general accuracy of the clinical assessment of these reported patients.25,59 Some of the studied patients had find-ings on examination that would place them outside the diagnostic category of PVS. Be that as it may, the findings on fMRI may only indicate automatic cortical processing of perceived words and not necessarily awareness.

More recently, EEG—recording from a large number of channels to improve spatial resolution and sampling—has been tested and researchers have found that these types of EEG could repeatedly detect a response after a volitional command in some PVS patients.20,21 This method is far from perfect, since it could not produce these responses in 3 of 12 controls. Moreover, recent evaluation of the data suggested a major concern with the validity of these studies.27,38

Other techniques to demonstrate cortical activity through event-related brain poten-tials (Chapter 6). Several paradigms have been used, including audio with a specified tone, harmonic chords, and spoken word pairs. Transcranial magnetic stimulation com-bined with EEG was able to differentiate PVS responses from MCS responses.

Despite highly relevant results and new insights, there are insufficient data to rec-ommend the use of any of these advanced testing methods in clinical decision making. Whether brain activation can be used for communication in these patients remains very uncertain (Chapter 9). Clinical examination by an expert remains the de facto standard in the examination of patients with impaired consciousness.

PREDICTION OF OUTCOME

Many comatose patients with traumatic brain injury improve after one month (Table 4-6). Improvement after prolonged coma is not stereotypical and most often involves a combination of grimacing, localization, verbal utterances, and target focus-ing and fixation. It is also noted by brief eye opening, improving to turning eyes to look when someone is talked to, tracking for a few seconds, vocalization to express mood or needs, and finally, mouthing, gestures, and further improvement in concentration (attending to simple tasks, watching TV, use of a writing aid). Family members often attract patient’s attention, and they make attempts at communication. Once orienta-tion improves, and patients are able to recognize objects they may start remembering parts of the day.


When the clinical criteria of PVS are still present after three months in nontraumatic coma (mostly anoxic-ischemic injury and hypoglycemia) and after 12 months in trau-matic coma (mostly diffuse axonal brain injury with cerebral edema), hope for recovery is unrealistic. Table 4-6 shows a decreasing probability of recovery over a relatively short period. Mortality from untreated infections or sepsis is very high within the first three years. The task force on medical aspects of PVS noted a 70% mortality in three years and a 84% mortality in five years. However, prolonged outcomes can be achieved with meticulous care and aggressive medical intervention for each complication. There are several examples of patients in PVS kept alive for many decades.

Several instances of late recoveries after PVS have been described,3,5,14,29,39,63,68 with one recovery seven years after anoxic brain injury.26 However, all reported patients remained in a severely disabled state, fully dependent on care, and bed bound or wheelchair bound, and having a permanent gastrostomy and urinary catheter.1,26 Predictive factors for recov-ery from prolonged PVS have not been identified, except perhaps for lack of developing

TABLE 4-6 outcome Prediction of PVs

Age n Dead (%) PVS (%) Conscious* (%) Independent (%)

PROBABILITY OF 1-YEAR OUTCOMES OF THOSE IN PVS AT 1 MONTHTraumatic Adults 434 33 15 52 24 Children 106 9 29 62 27Nontraumatic Adults 169 53 32 15 4 Children 45 22 65 13 6PROBABILITY OF 1-YEAR OUTCOMES OF THOSE IN PVS AT 3 MONTHSTraumatic Adults 218 35 30 35 16 Children 50 14 30 56 32Nontraumatic Adults 77 46 47 7 1 Children 31 3 94 3 0PROBABILITY OF 1-YEAR OUTCOMES OF THOSE IN PVS AT 6 MONTHSTraumatic Adults 123 32 52 16 4 Children 28 14 54 32 11Nontraumatic Adults 50 28 72 0 0 Children 30 0 97 3 0

* Includes independent.

Data adapted from Jennet B. The Vegetative State: Ethical Facts, Legal and Ethical Dilemmas,

Cambridge University Press, 2002.


atrophy on CT scan (Cranford, personal communication). Two more recent studies in patients with PVS found more conflicting results in late recoveries. One study found no functional recovery in both PVS and MCS after five years.51 Another larger study in 50 patients from Italy found a surprisingly high number of “late recoveries,” mostly in younger patients with traumatic brain injury, but also recovery of consciousness in two patients in PVS one year after cardiopulmonary resuscitation, which is well outside the customary threshold of six months.28 Three additional recoveries were described in a follow-up study on postanoxic vegetative state. Nonetheless, all patients remained “extremely severely dis-abled” (scores >20 on Disability Rating Scale).61 These studies indicate that late recoveries of PVS and MCS are possible but rare and invariably are associated with poor outcome. How much rehabilitation potential is possible in MCS is unknown, but some health care professionals in this field believe there are major opportunities.33

CONCLUSIONS

The clinical diagnosis of a prolonged comatose state is largely descriptive. Eye movements need most attention, because the response to approaching objects often distinguishes between PVS (inconsistent or absent), akinetic mutism (no tracking but spontaneous focusing on moving targets), and MCS (always present). It requires a skilled neurologist, who can also carefully interpret neuroimaging and electrophysiological studies before a final diagnosis can be made. When the diagnosis of PVS is made, attending physicians (often neurologists and rehabilitation physicians) have serially followed the patient for clinical improvement have noted a complete lack. Ambiguity toward the clinical diagnosis of a PVS is not expected when criteria are strictly followed, but no diagnosis can be perfect. There are patients with fluctuating neurologic findings who may not fit into any category, particularly when they are assessed weeks after the initial brain injury. Whether the term PVS is disrespectful is not easy to resolve, but many families know exactly what is meant by the term “vegetable” and use the term themselves to indicate a patient “just lying there.” Most families do not object to the term.

Some patients are re-examined for legal purposes; in others, a full re-examination is performed to confirm the findings, to facilitate discussion with the family, and to bring closure. The massive destruction in the cortical layers and thalamus at autopsy, the absence of operational modular networks on fMRI, and the marked reduction in glucose metabolism on PET are all test results that confirm the clinical findings. It reminds us, as if we need reminding, of presence of a very unfortunate being with a hope-lessly injured brain and no awareness of surroundings. fMRI has impressively demon-strated reproducible brain activation in some patients with PVS and in many patients with MCS. fMRI has been used as an axillary test in patients with marked impairment


of consciousness, and there is reason to believe the results have been used to make clinical decisions. There are some important facts, limitations, and outright con-cerns. Using fMRI we cannot measure thoughts, emotions, pain, reasoning, and much more. The lack of this information should be a strong case for caution.

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sciousness. Funct Neurol 2011;26:37–43.70. Song M, Du H, Wu N, et al. Impaired resting-state functional integrations within default mode network

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131

Comatose patients not only may have nonsurvivable neurologic injury but may have irrevocably lost all brain function as well. This condition has been distinguished from other comatose states by the term brain death. The clinical diagnosis of brain death implies that the person has died. This condition cannot be reversed—not even partly—by medical or surgical intervention. Its assessment has also been known as the determination of death by neurologic criteria. When the clinical criteria of brain death are met, it allows organ donation or withdrawal of futile support.

Most patients with a catastrophic brain injury do not become brain dead (<10% of all admissions to a neuro-intensive care unit). There are also some indications that the prevalence of brain death is declining for various reasons, including better care. Therefore, because it is far more likely that a patient is not brain dead, the evaluation of brain death requires careful assessment and a healthy sense of skepticism. Neurologists and neurosurgeons, intensivists, and also neonatologists and pediatricians are most likely to make the declaration of brain death. Brain death can be declared when brain-stem reflexes, motor responses, and respiratory drive are absent in a normothermic, nondrugged comatose patient with a known, irreversible, widespread brain lesion and no contributing metabolic derangements.2,18,68,69,71,72,77,78 In most instances, brain death is a result of traumatic brain injury, aneurysmal subarachnoid hemorrhage, and mas-sive cerebral hemorrhage. It is much less common after hypoxic-ischemic injury from cardiac standstill and subsequent cardiopulmonary resuscitation or encephalitis, con-ditions that often spare the brainstem. Regrettably, brain death in children can be a consequence of battering or asphyxia.77

The Clinical Diagnosis of Brain Death

/ / / 5 / / /


A brief history of the development of brain death criteria has been discussed in Chapter 1. The pathology of brain death will be discussed in Chapter 6. This chapter reviews all clinical aspects of the determination of brain death and includes ways to avoid mistakes.

CODE OF PRACTICE

The key principles in brain death determination are fairly similar. Throughout the world, the declaration of brain death calls upon a detailed examination of the brainstem reflexes, apnea test, and consideration of a confirmatory laboratory test.69 Legal standards for the determination of brain death are known in at least 55 of 192 (29%) United Nations member states. Differences in the technique of the apnea test and requirements of con-firmatory tests do exist69 (Fig. 5-1). Many nations in the world and 8 U.S. states require confirmation by a second physician, and a few countries go beyond two physicians (e.g., four physicians in India). Many hospital practice protocols stipulate two physicians, but it is not always clear if this indicates another physician as an observer or a second full examination. Other differences include time of observation (hours and even days) and qualification of physicians (academic rank, specialty), with some countries requiring sev-eral years of ICU expertise.

A second examination by a different physician may potentially delay final declaration and is most concerning to loss of organs for donation if the waiting period has allowed

Mandatory

Optional

Not known

FIGURE 5-1. Need for confirmatory tests in brain death guidelines throughout the world.

The Clinical Diagnosis of Brain Death / / 133

cardiac arrest.38 How these striking differences in procedural matters in brain death dec-laration have evolved is not known. Task forces assigned to develop criteria may have had different representations of specialties—often electrophysiologists—and even have lacked neurosurgeons and neurologists. Perhaps the additional requirements have resulted from a perceived need to safeguard practice.

In the United States, the Uniform Determination of Death Act (UDDA) mandates the presence of irreversible cessation of all functions of the entire brain and brainstem (Table 5-1). The basis for the UDDA was the report of the medical consultants on the diagnosis of death to the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. The report concluded that “it is not necessary—indeed it would be a mistake—to enshrine any particular medical criteria, or any requirements for procedure or review, as part of the statute.” The major conse-quence of the UDDA in the United States was that wills and insurance proceeds would become activated, and no civil or criminal liability can result from removing the body from intensive care unit support. It has been accepted by 44 states and the District of Colombia.77

Determination by one physician is sufficient in most states, but eight states require independent confirmation by another physician (Fig. 5-2). These states have otherwise very comparable statutes, but there are differences. Virginia specifically calls for a special-ist in the neurosciences.7 Florida mandates two physicians, with one being the treating physician and the other a board-eligible or board-certified neurologist, neurosurgeon, internist, pediatrician, surgeon, or anesthesiologist.3 New York and New Jersey have changed their statutes to accommodate religious exemptions.5,6 These unprecedented amendments require physicians to honor objections by family members and to continue medical care until cardiac arrest, despite evidence of loss of brain function. In Alaska and Georgia, a registered nurse is delegated authority to declare death according to the statu-tory criteria, but with subsequent certification by a physician within 24 hours. In Virginia, there is limited authority given to a registered nurse.

Determination of brain death is standardized in hospital policies, and protocols have been developed. However, a survey of 140 U.S. hospital protocols (limited to rural hospitals with an intensive care unit) showed amendments requiring repeated testing

TABLE 5-1 Uniform Determination of Death act

“An individual who has sustained either (1) irreversible cessation of circulatory and respiratory functions,

or (2) irreversible cessation of all functions of the entire brain, including the brain stem, is dead.

A determination of death must be made in accordance with accepted medical standards.”


(recommended or required in 60% of protocols) and mandatory confirmatory labora-tory tests in 8%, even though it is not stipulated in the American Academy of Neurology (AAN) guidelines.53 A survey of renowned U.S. medical institutions found major discrepancies between institutions when reviewing AAN guideline performance, includ-ing preclinical testing, clinical examination, apnea test, and ancillary tests.27 The AAN recognized the complexity of criteria and revised an earlier guideline.71

The 2010 guideline is the main template for this chapter.

THE CLINICAL EXAMINATION

The clinical examination requires a skillset that takes years of experience but can be trun-cated to a set of 25 tests and verifications. Most of the time should be spent excluding pos-sible confounders, and only after none are found, is it followed by a systematic testing of brainstem function and breathing drive (Figs. 5-3 and 5-4). Clinical neurologic examination is the standard for determination of brain death. An animation of examination is shown in a video clip (VC 5-1).

Prerequisites and Major Confounders

The cause and irreversibility of coma should be established before a neurologic examina-tion is performed. Confounding factors should be excluded, such as the absence of severe

FIGURE 5-2. U.S. states where statutes (black) require confirmation by another physician.


hypothermia (defined as a core temperature of 36°C or less), absence of hypotension (defined as systolic blood pressure of 90 mm Hg or less), the absence of evidence of drug intoxication or poisoning or absence of lingering effects (defined by a careful history and, if needed, a normal drug screen), absence of recent or current administration of neuro-muscular blocking agents (defined by the presence of four twitches with a train-of-four with maximal ulnar nerve stimulation), and absence of electrolyte, acid–base, or endo-crine disturbances (defined by severe acidosis and marked deviation from the norm).

Core temperature (36.5° C); systolic BP (90 mm Hg); uid balance (positive for 6 hours)

Preoxygenate (FIO2 = 1.0 for 10 min); decrease ventilation rate

Disconnect ventilator if PaO2 > 200 mm Hg and PaCO2 40 mm Hg

Oxygen catheter at carina (6 L/min)

Observe chest and abdominal wall for respiration for 8–10 minutes;monitor for change in vital functionsIf PaCO2 > 60 mm Hg or increases more than 20 mm Hg from normal baseline value, apnea is conrmed

FIGURE 5-3. The steps in a clinical examination to assess brain death. In step 1, the physician

determines that there is no motor response, and the eyes do not open when a painful stimulus

is applied to the supraorbital nerve or nail bed. In step 2, a clinical assessment of brainstem

reflexes is undertaken. In step 3, the apnea test is performed. ABP = arterial blood pressure;

HR = heart rate; RESP = respirations; Spo2 = oxygen saturation measured by pulse oximetry.

Roman numbers indicate cranial nerves. From Wijdicks68 with permission of New England Journal of Medicine. (See color insert.)


The CT scan of the brain requires careful inspection, and brain destruction should be found. The abnormalities seen on CT are often impressive with a large mass and brain tissue shift, multiple hemispheric lesions, or diffuse cerebral edema with obliteration of the basal cisterns. Most patients comatose from anoxic-ischemic injury do not fulfill the criteria of brain death, but if there has been such a severe injury damaging hemispheres and brainstem, early brain edema is expected on the CT scan. The CT scan is also initially normal in a patient with fulminant meningitis or encephalitis. Cerebrospinal fluid exami-nation showing a pleocytosis or urgent MRI definitively assists in the diagnosis, particu-larly if a febrile comatose patient presents unexpectedly. It should again be pointed out that even neuroimaging findings of severe brain injury do not exclude the search for a potential confounder. For example, a massive intracranial hematoma can be seen after the use of cocaine, massive subdural hematoma may be seen after a drinking bout, and car-diac resuscitation might be a consequence of poisoning or a suicide attempt. It is prudent to obtain a routine drug screen and additional laboratory tests (arterial blood gas, osmo-lality, and osmolar gap) in every patient who is admitted to the emergency department

FIGURE 5-4. A check card to diagnose brain death.


and, in particular, those found under suspicious circumstances. As a general warning, the clinical diagnosis of brain death should not be made in the emergency department, and observation in an intensive care unit is needed to exclude all possible confounders and often to obtain a more accurate and comprehensive history.

Patients who lost all brain function become hypothermic but rarely with the core temperature less than 35°C. Marked hypothermia (32°C or less) may actually confound neurologic examination and brainstem reflexes become difficult to elicit. Accidental hypothermia is infrequent but mostly involves young survivors of mountaineering acci-dents or rescues from submersion in ice water. Hypothermia can be associated with ingestion of drugs such as opioids, barbiturates, benzodiazepines, phenothiazines, tricy-clic antidepressants, and lithium, although exposure to cold is necessary to reduce core temperature. Hypothermia may markedly influence the metabolism of administered drugs, particularly those with a first-pass hepatic metabolism. Cytochrome P450 is mark-edly different under hypothermic conditions.24 This may become a concern in comatose patients rewarmed after induced hypothermia for cardiac arrest. None of these patients should have a brain death examination until core temperature is normalized and linger-ing effects of recently administered sedative drugs (e.g., fentanyl) have been excluded—which, not knowing the changed pharmacokinetics, is virtually impossible.

Drug screens may be helpful, but these laboratory tests may miss certain types of drugs. Alcohol, barbiturates, antiepileptics, benzodiazepines, antihistamines, antide-pressants, antipsychotics, stimulants such as amphetamines, narcotics, analgesics, and many of the cardiovascular drugs can all be traced in most toxicologic screens. In addi-tion, several drugs induce acid–base abnormalities that should already point to a possible intoxication. Respiratory acidosis is associated with opiates, ethanol, barbiturates, and anesthetics. Metabolic acidosis is common with acetaminophen, ethanol and methanol, ethylene glycol, salicylates, isoniazid, cyanide, cocaine, strychnine, and papaverine.

The absence of drug interference with clinical examination remains difficult to deter-mine, and extreme caution is advised. An arbitrary waiting time (e.g., 12 to 24 hours) may not be sufficient.43 A reasonable guideline is to calculate five to seven times the excretion half-life in hours and allow that time to pass before clinical examination is performed. (This will remove approximately 97% to 99% of the drug, assuming first-order elimina-tion kinetics.) Examples of long elimination half-life are phenobarbital, 100 hours; diaz-epam, 40 hours; amitriptyline, 24 hours; lorazepam, 15 hours; fentanyl, 6 hours; and midazolam, 3 hours. Prior use of therapeutic hypothermia may substantially slow down the metabolism of propofol, fentanyl, or morphine.13 Neuromuscular blocking agents can be monitored with a train-of-four twitch monitor. However, a train-of-four of three twitches corresponds with 80% blockade, and a train-of-four of four twitches may still


be associated with some blockade.10 Finally, alcohol is another common confounder and has an elimination rate of 10 mL/h, but it is highly variable. Naïve or occasional alco-hol drinkers can become comatose with a blood alcohol content of 0.2%, with 0.4% or more usually measured in a fatal ingestion. The legal alcohol limit for driving (blood alco-hol content in most U.S. states of 0.08%) is a practical threshold, and below this level it should be allowed to determine brain death.

The Bedside Examination

After all confounding factors have been excluded, the clinical examination can start if there are no motor responses to pain, the patient fails to grimace or buck the ventila-tor, pupils are fixed, eyes are immobile, hypotension has occurred, and vasopressors have been started. Conversely, not examining the patient because the patient is still trigger-ing the ventilator would unnecessarily delay examination if the cause (often ventilator auto-cycling) is not identified. Physicians who perform this examination may ask a col-league to be present or have fellows, residents, or nursing staff present. The presence of family members is not uniformly seen as an advantage.35

Coma

With complete loss of consciousness, patients should lack all evidence of responsiveness. The depth of coma is further examined by using standard noxious stimuli, compression of the supraorbital nerve (localized on the medial part of the eyebrow ridge), forceful nail bed pressure, or bilateral temporomandibular joint compression. Any other stimulus may be insufficient and can lead to different interpretations. One should resist the use of stimuli such as sternal rubbing, twisting of the forearm or nipples, or simply applying pinpricks on several parts of the extremities. Eye opening to noxious stimuli or sponta-neous eye movements (horizontal and vertical) should be absent. No motor response is observed in the arms after a noxious stimulus. However, occasionally, a stimulus may gen-erate a brief response in the extremities. These responses may also occur during periods of extreme hypoxemia. Most often, these movements are observed during the transition to brain death or shortly after brain death has been established.55,58,74 These rudimentary spontaneous or reflex movements are generated from pathways inside the spinal cord. Corticoreticular disconnection may leave disorganized fragments of unisegmental (plan-tar flexion) or polysegmental (triple flexion) spinal reflexes. In addition, they are seen in the arms and may involve brief flexion in the fingers (video clip VC 5-2) or very slow rising of one or two arms. Other unusual movements are undulating or wiggling toes after flexion of the big toe, repetitive triple flexion response, myoclonus, fasciculations and dystonic


posturing with bilateral arm flexion and shoulder, finger, and thumb flexion abduction, and slow head turning. Forceful neck flexion may cause brief leg movements (video clip VC 5-3). Babinski signs were absent in a study of 144 patients, but some response closely resembling an upgoing toe can be observed (video clip VC 5-4).17,44 The clinical differen-tiation of spinal responses from motor responses associated with brain activity requires expertise, but usually there is absence of a stereotypical coordinated pathologic flexion or extension response, and many of these movements disappear after repeated stimula-tion.40,68 The differentiation between decerebrate or decorticate responses and “spinal reflexes or responses” are based on five aspects: (1) the response does not resemble the synchronized decorticate or decerebrate response; (2) spinal responses are mostly slow and short, but some extremity responses are quick jerks; (3) most movements are pro-voked and not spontaneous, often extinguishing or becoming more muted down after diagnosis; (4) spinal responses are not seen with pressure on the supraorbital ridge or temporomandibular joints; and (5) the most common spinal reflex is triple flexion response (flexion in foot, knee, hip) or foot wiggles with pricking the sole.

Absence of Brainstem Reflexes

First the pupils are examined. No response to a bright light source such as a flashlight is documented in both eyes, and when any uncertainty remains, a magnifying glass should be used. In brain death, the pupils are fixed in a midsize position (4 to 6 mm). One should consider the possibility that topical ocular instillation of drugs and trauma to the bulbus oculi may have caused pupil abnormalities, and some patients do have pre-existing abnormalities or have had prior cataract surgery distorting the pupil. Absence of the ocular movements is best documented using oculovestibular reflex testing. Fast turning of the head to both sides should not produce any eye movement. However, when there is extreme conjunctival swelling, absence of excursions may be difficult to interpret. Moreover, neck movements should be avoided in patients with a traumatic brain injury. It is more convenient to test the oculovestibular responses using ice water flushed alterna-tively into left and right ear. The results of caloric testing can be confounded when blood or cerumen is present in the auditory canal, and therefore direct inspection is necessary before the test is performed. The head is elevated to 30 degrees to allow the horizontal semicircular canal to become vertical. Approximately 50 cc of ice water is injected, and no movement of the eyes toward the side of the stimulus should be present. Waiting for 2 minutes should suffice to confidently determine its absence.

This test is followed by examination of facial sensation and facial motor response. An absent corneal reflex is demonstrated using a piece of cotton or by squirting water on the cornea, and no blinking should be seen. Absence of grimacing to a noxious stimulus


is confirmed with deep pressure on the condyles at the level of the temporomandibular joints. Then the examiner proceeds with testing the function of the medulla oblongata. Gag reflex is absent, but this remains an unreliable test and is difficult to assess in an intu-bated patient. The best way to assess it is to put a gloved finger deep into the mouth, moving the uvula.

Oropharyngeal function is also most reliably tested by examining a cough response to tracheobronchial suctioning. Simply moving the endotracheal tube to and fro is not an adequate stimulus to obtain a cough response. A catheter should be inserted into the trachea and advanced to the level of the carina, followed by two suctioning passes and close observation of the patient for chest or abdomen movement. Absence of vagal nerve function is demonstrated by the presence of an invariant heart rate. If atropine (0.5 mg) is administered, no acceleration is noted because of lack of output from the dorsal nucleus of the vagal nerve in the medulla. Conversely, a sympathicomimetic drug such as isopro-terenol will accelerate the heart rate through intact cervical thoracic sympathetic path-ways. However, these tests are rarely performed. Next, the absence of respiratory drive is documented with a CO2 challenge.

No Breathing Drive

Oxygen diffusion is the most commonly used method for the apnea test in brain death determination. At atmospheric pressure, the driving force is the partial pressure gradi-ent across the alveolar membrane that diffuses oxygen. This method is simple and only involves disconnection from the mechanical ventilator while providing an adequate source of oxygen. The CO2 challenge results in respiratory acidosis and concomitant cere-brospinal fluid acidosis that stimulates the respiratory centers.12,23,36,39 The arterial Pco2 rise is, on average, 3 mm per minute.56,73 In some patients, arterial Pco2 rise can be pro-tracted beyond 10 minutes and even breathing may occur after such a long interval. With adequate preoxygenation, the apnea test, using the oxygen-diffusion method, is very safe and infrequently has to be aborted.26 Monitoring the arterial Pco2 rise is necessary. Blood gas determination can be done at the bedside, and current handheld devices take about 2 minutes to give reliable readings (Fig. 5-5).

A useful practice is to obtain a second sample at 8 minutes and await the result while keeping the ventilator disconnected, but only if the patient is hemodynamically stable and oxygenates well. If the arterial Pco2 has not reached the target level, a second sample is taken at approximately 10 to 12 minutes, and the ventilator is reconnected. The apnea test is considered positive (supporting the diagnosis of brain death) if posttest arterial Pco2 is more than 60 mm Hg (or has increased more than 20 mm Hg from a normal pre-test level) and there are no observable effective respiratory movements.


Transcutaneous Pco2 monitoring correlates very well with Paco2. Continuous monitor-ing, therefore, could shorten the apnea test, and this could be useful in patients with poor oxygenation during the test.65 However, the apnea test should be aborted if oxygen desat-uration occurs, cardiac arrhythmias intervene, or blood pressure decreases. Mostly this occurs within the first minutes of disconnection. Prior evidence of pulmonary disease or an increased alveolar–arterial gradient due to pulmonary edema and requirements of high levels of positive end-expiratory pressure (PEEP) before disconnection predict an apnea test with potential complications. In some instances, a T-piece with a continuous positive airway pressure (CPAP) valve could be used and may reduce deoxygenation. It consists of a 10- to 15-cm H2O CPAP valve attached to one of the tubes of the T-piece providing 12 L/min flow of 100% oxygen.37 In addition, recruitment maneuvers can be used before proceeding. One way is to change the pressure control mode and increase pressure levels every 30 seconds, incrementally increasing to 35, 40, and 45 cm H2O peak inspiratory pressures.31 Simply providing high PEEP (25 cm H2O) and using a CPAP valve of 20 cm H2O may also be just sufficient for the patient (Fig. 5-6). Our recent experience with

FIGURE 5-5. Bedside blood gas monitor (I-STAT).


apnea testing using the diffusion–oxygenation method is very good with few complica-tions, and the number of aborted apnea tests has declined to less than 1%.16

Confirmatory Tests

Traditionally, laboratory testing can be used to confirm the clinical diagnosis. These tests should not be used to diagnose brain death.4,21 In adults, the diagnosis is based on a sin-gle clinical examination, and confirmatory tests are not required in the United States. Confirmatory tests are advised when the apnea test has been aborted due to hemody-namic instability and hypoxemia, but also when the patient is a known CO2 retainer and when certain elements of the clinical examination are not reliable owing to facial trauma. Confirmatory tests are mandatory in children.

There is a preference to use transcranial Doppler or electroencephalography (EEG), because both are noninvasive bedside tests.1,4,14,21,32,45,51 Traumatic cranial soft tissue swell-ing, intravenous pumps, and electrocardiogram may result in artifacts that may make the assessment of an isoelectric EEG very difficult. Flow studies (nuclear scan or cerebral angiogram) are more complicated to perform. None of the currently available laboratory tests can conclusively prove loss of all brain function, and major discrepancies have been reported (e.g., retained EEG with no cerebral blood flow).28 It is possible to have traces of cerebral blood flow, fragments of EEG activity,11 or isotope uptake in the cerebellum while the patient fulfills the clinical criteria of brain death.46

FIGURE 5-6. CPAP valve directly connected to the endotracheal tube with self-inflating bag. The

small catheter inserted in the tube is an oxygen insufflation catheter to provide oxygen to the

level of the carina at 6 L/min. The ventilator is disconnected from the patient.


Cerebral angiography has been considered the gold standard of confirmatory tests; however, results depend on the technique used. Some radiologists prefer an arch injec-tion. Others perform a cerebral angiogram with selective vessel injections and a manual injection rather than a power injection. This may produce different results, varying from no filling to slow filling of the carotid siphon. This may lead to uncertainty as to what con-stitutes an “absent flow study.” These concerns also pertain to less invasive flow studies, such as CT angiograms.15 In other words, all flow study results are closely related to intra-cranial pressure—high ICP, no flow; not-so-high ICP, some flow—and may not perfectly correlate with clinical examination.

Why confirmatory tests gained such prominence in brain death determination in adults is unclear, and the need for such tests is questionable.15 Complicating the diagno-sis with additional laboratory tests must have been driven by a concern that inaccurate assessment of these fatally injured patients may occur. However, more physicians and more confirmatory tests cannot solve that. What remains needed is appropriate education of staff, introduction of checklists in intensive care units, and brain death examination by designated neurologists who have documented proficiency in brain death examination. The pitfalls of each of these tests are shown in Table 5-2. Results of these laboratory tests confirming brain death are shown in Table 5-3 and in Figures 5-7 and 5-8.

TABLE 5-2 Pitfalls of Confirmatory Tests

Cerebral angiography• Image variability with injection of arch or selective arteries• Image variability with injection vs. push technique• No guidelines for interpretationTranscranial Doppler ultrasonography• Technical difficulties and skill-dependent• Normal in anoxic-ischemic injuryEEG• Artifacts in intensive care settings• Information primarily from cortex onlySomatosensory evoked potentials• Absent in patients without brain deathCT angiography• Interpretation difficulties• Retained blood flow in 20% of cases• Possibility of missing slow flow states because of rapid acquisition of imagesNuclear brain scan• Areas of perfusion in thalamus in patients with anoxic injury or skull defect

From Wijdicks70 used with permission.


Documentation

The time of brain death is documented in the medical records. Time of death in a patient determined brain dead is the time the arterial Pco2 reached the target value. In patients determined brain dead with an aborted apnea test, the time of death is the time the confirmatory laboratory test has been completed. Documentation of a comprehensive brain death examination is easily prone to negligence, in particular in the documen-tation of absence of confounders and examination of cranial nerve reflexes.67 When audited, the examination of cranial nerves was incompletely documented in two thirds of the surveyed protocols.53 This confirms an earlier study where cranial nerve reflexes were not documented in more than 10% of patients, with a trend toward less accurate

TABLE 5-3 Confirmatory Testing for a Determination of Brain Death

Cerebral angiographyThe contrast medium should be injected under high pressure in both anterior and posterior circulation.No intracerebral filling of both hemispheres should be detected at the level of entry of the carotid or vertebral

artery to the skull.The external carotid circulation should be patent.EEGA minimum of eight scalp electrodes should be used.Interelectrode impedance should be between 100 and 10,000 Ω.The integrity of the entire recording system should be tested.The distance between electrodes should be at least 10 cm.The sensitivity should be increased to at least 2 µV for 30 min with inclusion of appropriate calibrations.The high-frequency filter setting should not be set below 30 Hz, and the low-frequency setting should not be

above 1 Hz.EEG should demonstrate a lack of reactivity to intense somatosensory or audiovisual stimuli.Transcranial Doppler ultrasonographyThere should be bilateral insonation. The probe should be placed at the temporal bone above the zygomatic

arch or the vertebrobasilar arteries through the suboccipital transcranial window.The abnormalities should include either reverberating flow or small systolic peaks in early systole.A finding of a complete absence of flow may not be reliable owing to inadequate transtemporal windows for

insonation.Cerebral scintigraphyThe isotope should be injected within 30 min after its reconstitution.A static image of 500,000 counts can be obtained at several time points.A correct intravenous injection may be confirmed with additional images of the liver demonstrating uptake

(optional).No isotope uptake in middle cerebral artery, anterior cerebral artery, or basilar artery territory (hollow skull

phenomenon)No tracer in superior sagittal sinus (minimal tracer can come from the scalp)


documentation of pharyngeal reflexes.66 A significant improvement in documentation has been noted with the appointment of a pediatric intensivist or neurointensivist.29,33

Gross errors in actual brain death determination leading to erroneous determination of brain death and initiation of organ transplant procedures, followed by discovery of patient responses before retrieval of organs, are exceedingly rare (personal communica-tion with organ procurement professionals).

Over more than two decades only a few instances were put forward to me for review. The following errors were made: failure to appreciate the cumulative effects of adminis-tered drugs, reliance on confirmatory tests alone, primary brainstem injury with failure to assess (retained) medulla function, and failure to appreciate the possible coexistence of self-poisoning and traumatic head injury.

FIGURE 5-7 Cerebral angiogram filling the supraclinoid segment and ophthalmic artery but not

beyond (common carotid injection). The vertebral injection results in filling of the muscular and

extracranial branches and no intradural flow.

Fp1–F3

F3–C3

C3–P3

F4–C4

C4–P4

P4–O2

P3–O1

Fp2–F4

(A)

sec20 mV

(B)

(C)

(D)

FIGURE 5-8 Examples of bedside tests to confirm brain death. (A) An isoelectric EEG in which the only

pulse is artifactual. Shown is a bipolar montage with the electrodes placed according to the 10/20

configuration. (B) Transcranial Doppler ultrasonogram shows reverberating flow and small systolic

peaks, both of which are patterns seen in patients with profoundly increased intracranial pressure that

can also be seen when brain death has occurred. (C) A dynamic nuclear scan shows no intracranial fill-

ing—the so-called hollow-skull sign. (D) CT angiogram showing no intracranial flow. From Wijdicks.68


SPECIAL ISSUES

There are a number of clinical problems with brain death, and they are discussed in detail elsewhere.77,78 In this section, common issues are discussed. This often involves brain death in a child or neonate and occasionally brain death in a pregnant mother.

The diagnosis of brain death in a child incites strong emotions and requires consid-erable experience of the physician to appropriately and compassionately communicate death to family members.61 Guidelines for the determination of brain death in children in the United States have been proposed by a task force consisting of neurologists and pediatricians and endorsed by the American Academy of Pediatrics and Child Neurology Society. Current recommendations continue to include age brackets with different rec-ommendations for time of observation.47 The new pediatric guideline suggests a 24-hour interval between examinations by two physicians in neonates and children from 37 weeks’ gestation to the end of the first year. However, in children aged 1 year or older the pedi-atric guideline still imposes two examinations 12 hours apart by two different attending physicians. The second examination, according to the pediatric guideline, “proves irrevers-ibility.”77 The pediatric guideline recommends that physicians be competent to perform examinations in infants and neonates and additionally recommends that these examina-tions be performed by pediatric intensivists and neonatologists, pediatric neurologists and neurosurgeons, pediatric trauma surgeons, and pediatric anesthesiologists with criti-cal care training. In addition, the pediatric guideline recommends adult specialists should have appropriate neurologic and critical care training to diagnose brain death when caring for a pediatric patient from birth to 18 years of age. These criteria have been strongly criti-cized, First, physiologically children are not much different than adults, and after several months, they are neurologically no different from adults either.76 Pediatricians have been struggling with brain death determination, and part of the problem is lack of recent large detailed series of patients that could provide guidance. In the end, the clinical determi-nation of brain death in young adults and children should not be different from that in adults. Second, time brackets and repeat neurologic examinations may delay death deter-mination and possibly organ donation. It is possible that by the time a second examination is completed, the family wants closure and no organ donation discussion. Third, there is little basis for the specific requirements of examiners, and this could exclude (competent) general pediatric neurologists. Nonetheless, the endorsement by the Child Neurology Society will likely make these recommendations permanent.47

The clinical examination in children is similar to that in adults; however, the exami-nation of brainstem function is less reliable in preterm and term neonates. Several brainstem reflexes develop after the 28th gestational week. For example, the pupillary


response to light is elicited only after 32 weeks, and the grasp response is elicited at 36 weeks. The response to a CO2 challenge during the apnea test can only be elicited at 33 weeks and could be unreliable in neonates. Furthermore, the arterial Pco2 threshold in children may be higher when brain death is associated with hypoxic-ischemic injury. Nonetheless, an acute increase in arterial Pco2 (target of 60 mm Hg) is still considered a sufficient stimulus in children. It may be difficult to perform the neurologic examina-tion in infants who are in an incubator. This applies to examination of the size of pupils and their reactivity, examination of ocular motility using ice water stimulation, and the cough reflex. Finally, infants with anencephaly have been considered for organ dona-tion. A diagnosis of brain death can be performed in anencephalic patients, but it should be noted that many of them do not meet the accepted brain death criteria and have an intact brainstem. The consent rate for donation in children is high but the organ retrieval rate is low due to hemodynamic instability and multiorgan dysfunction, often a result of anoxic injury.64

Another important issue is the determination of brain death in a patient with an acute destructive lesion in the brainstem. Typically, these situations involve a mas-sive pontine hemorrhage, basilar artery occlusion, or a gunshot wound in which the barrel of a gun was placed inside of the mouth. Obstructive hydrocephalus usually ensues and damages both hemispheres from massively increased intracranial pressure that effectively stops intracranial blood flow. These clinical scenarios are very uncom-mon. Patients with primary brainstem lesions such as pontine hemorrhage or patients with advanced brainstem injury from shift often continue to have some of the medulla oblongata function that causes patients to retain their cough response, blood pres-sure, and breathing drive. In the United States, whole-brain death (hemispheres and brainstem) criteria apply. As discussed in Chapter 1, loss of the brainstem function is irreversible and should be considered final. There is no basis to presume patients with absent brainstem function are nothing but permanently comatose and dead. In these circumstances, many practices will extend the time of observation to 24 hours or obtain a confirmatory test.

Another clinical problem is when the patient seems to trigger the ventilator, but the apnea test shows no breathing effort. Modern ventilators have sensitive apnea alarms, and very little change in flow or pressure in the circuit could trigger the ventilator to provide a breath.19,41,75 This phenomenon is known as auto-cycling. It can be triggered by small leaks in the ventilator tube connections, the presence of a chest tube, the cardiac pulse, and water condensation in the ventilator tubes. Changing the ventilator settings will elim-inate this problem. Failure to recognize this phenomenon could result in a delay in brain death determination or unnecessary confirmatory tests.


A disheartening issue is care of a brain-dead pregnant woman. The fetus often aborts spontaneously, but there is a management dilemma when the fetus is viable. This is usually after 22 weeks. (Two fetuses supported at 13 weeks had intrauterine death. The longest reported support of a brain-dead mother was for 107 days in a fetus of 16.5 weeks.22) If requested by the proxy, somatic support could be provided until a gestational age of 32 weeks before birth; however, with mounting intensive care unit costs and increasing nursing staff stressors, delivery below this mark leaves a high probability of a severe disability and postnatal death of the newborn. Several cases have been published, with successful support in approximately 30 “brain-dead” moth-ers. Whether all reported cases truly constituted brain death is not known, and there is evidence that in many the apnea test is not performed for fear of causing hypox-emia in the fetus.22 The true denominator also is not known, and it is likely that many unpublished attempts at somatic support were unsuccessful. The challenges to the fetus include catheter sepsis, vasopressor use, and toxicity of antibiotics and antifun-gal drugs. Many of the premature births had low Apgar scores, but the developmental milestones were normal. However, follow-up was available only for 3 to 18 months after birth, which is too short to judge their intellectual functioning. There has not been a successful neonatal outcome reported in the United States or Europe over the past 15 years. Organ donation in a brain-dead mother with no viable fetus is very com-plicated, with many organ transplant agencies opting out for fear of linking the death of the fetus with organ donation.

An equally problematic question is whether semen retrieval is allowed. Current case law in the United States indicates that posthumous semen procurement is legal, and does occur in order to provide the opportunity for offspring (“special gift”). Semen retrieval is often refused by judges. Courts have looked at written (usually lacking) consent, the intent of the deceased (specifically expressed plans for conception), and the future well-being of a fatherless child. Physicians may want to consider a court order before proceeding.49

Finally, a dilemma in management occurs when the family explicitly refuses to dis-connect the ventilator and requests continuation of full intensive care. This uncom-mon problem is often resolved by a cardiac arrest within the first week. There is no legal authority for families to direct medical interventions in the deceased person. It is good medical judgment to discontinue mechanical ventilation after the clinical diagnosis of brain death, but the physician may potentially be liable if the family continues to ask for mechanical ventilation and this request is ignored. Confirmatory examination by a second physician may be advisable. Expressing reluctance to ventilate a dead body and repeated communication with the family that the patient has passed away is necessary,


and the family could change their position. Consultation with an ethical committee could be helpful, and further legal counseling could be sought.

PATHOPHYSIOLOGICAL RESPONSE TO BRAIN DEATH

When the brain loses its integrative function, changes do occur in multiple organ sys-tems.8,52 The most important first change is deterioration of posterior pituitary function. This is caused by displacement of the diencephalon and compression of the pituitary stalk and results in direct damage to the posterior lobe. Ischemia is not likely a factor because the pituitary gland is supplied through extradural, inferior hypophysial arteries. Diabetes insipidus emerges, which is apparent with polyuria, decreased urinary sodium concen-tration, and rapid development of hypernatremia. The laboratory criteria are plasma osmolality of more than 300 mosmol/kg, hypotonic polyuria, with more than 4 mL/kg per hour, decreased specific gravity of less than 1.005, and urine osmolality of less than 300 mosmol/kg. Diabetes insipidus can also result in hypomagnesemia, hypokalemia, hypophosphatemia, and hypocalcemia.

Whether the anterior lobe of the pituitary gland is hypofunctional is uncertain, but thyroid function may seem to deteriorate in some patients. This has led to the use of T3 infusion, although it is used typically only in hemodynamically unstable patients.62 Myocardial function can be significantly affected, and this has implications for organ donation. The surge in plasma catecholamines may cause a stressed myocardium or con-traction band necrosis, all resulting in a marked decrease in ventricular function. A mosaic of wall-motion abnormalities can be found on echocardiography, with some areas hypo-kinetic and others akinetic or normal. None of these patterns fit a coronary artery dis-tribution. It is possible that these abnormalities are reversible, but currently its presence defers cardiac transplantation.20,30 Pulmonary function may deteriorate after diagnosis of brain death. Hydrostatic pulmonary edema is one mechanism, but there may also be primary neurogenic pulmonary edema. Inflammatory response with upregulation of interleukins, tumor necrosis factor, and interferon is associated with neutrophil infiltra-tion and may damage the lungs. Methylprednisolone may reduce lung injury.9 The most prominent abnormality is the development of coagulopathy from brain thromboplastin entering the vascular system and releasing after necrosis of large portions of the brain. Diffuse intravascular coagulation contributes to acute renal failure and cardiac arrest. This cascade of organ failure is more often seen after traumatic brain injury and less often after asphyxia or anoxic-ischemic insults to the brain. However, terminal cardiac arrhythmias and cardiac arrest occur within the first 2 weeks after clinical diagnosis in the vast majority of patients, even if mechanical ventilation, vasopressors, or vasopressin is administered.


Cardiac arrest occurs due to loss of vagal function, and reduced coronary flow, and may be facilitated by initial stress cardiomyopathy and incremental doses of vasopressors in order to maintain intravascular tone and blood pressure.

ORGAN PROCUREMENT

Throughout the world, the procedures in organ donation have been regulated.63 In the United States, organ procurement organization agencies will obtain permission to retrieve organs from the family after the diagnosis has been established. There is an obligation for physicians to contact these agencies, who will then discuss the benefits of organ dona-tion. These agencies manage the organ donor until surgical retrieval. The contribution of organ procurement organization agencies is important and eliminates any potential influ-ence of the transplant team in brain death diagnosis and obtaining consent. This allows better care of the organ donor and uncouples the prior attending physician from this part of care and, thus, from the potential for conflict of interest.

The organ procurement process is complex and requires close attention and criti-cal care.50 The major problems that emerge are hypotension, diabetes insipidus, hypo-thermia, electrolyte abnormalities, lactic acidosis, coagulopathy, and finally, cardiac arrhythmias.34,48,54,59 Coagulopathy and diabetes insipidus reduce the number of organs retrieved.57 Many patients may have neurogenic pulmonary edema or aspiration pneu-monia that may lead to a significant respiratory acidosis and, sometimes, acute respira-tory distress syndrome. Acute pulmonary edema may respond to the application of PEEP in combination with diuretics and morphine. Bronchospasm can be relieved with bron-chodilator therapy. The Fio2 should be maintained at less than 40% to reduce the possible effect of oxygen toxicity and atelectasis to the lungs, particularly if the lungs are consid-ered for transplantation.

Another major concern is hemodynamic stability due to absence of autonomic reg-ulation. The challenges to preserve intravascular volume and pressure are considerable, often with a need for incremental doses of vasoactive drugs, colloids, or crystalloids. Fluid boluses of 5% albumin may be necessary. Many procurement guidelines stress the importance of the “rule of hundreds.” This pertains to a minimum systolic blood pressure of 100 mm Hg, heart rate less than 100 beats/min, and urine output more than 100 cc/h.25

Management of diabetes insipidus is a major focus in the process of organ procure-ment. Vasopressin 1 U bolus followed by 0.4 to 1 U/h is effective. The hourly urine output should be maintained at approximately 2 to 3 cc/kg. The goals and targets of management of the organ donor are summarized in Table 5-4.


CONCLUSIONS

Brain death is set apart from other comatose states and should be recognized because it allows declaration of death and, if granted, organ donation. The clinical diagnosis of brain death requires skill. The major pitfalls are failure to recognize lingering metabolites from prior use of sedative drugs and failure to perform a complete examination, most notably an apnea test. There has been some reluctance to perform an apnea test—and rightly so in unstable multitrauma patients—but in most instances, the apnea test procedure is safe. In adults, a meticulous clinical examination should suffice to determine the absence of brain function. Confirmatory tests are mandated in some countries. The optimal management of organ donors remains undefined, but new avenues are explored in animal models and clinical trials to improve organ quality (e.g., immunosuppressive drugs, intensive insulin therapy, vasopressors, or inotropes).42,60

TABLE 5-4 organ Procurement Protocol

Goal Treatment

Po2 ≥ 100 mm Hg Increase Fio2Spo2 > 95% Increase PEEPPaco2 35–45 mm Hg Bronchodilator therapy

Change respiratory rate and tidal volume

Bicarbonate with metabolic acidosisArterial blood pressure Dopamine or norepinephrineSABP ≥ 90 mm Hg 5% albuminDABP < 100 mm Hg When CVP increased, use diuretic agentsTemperature ≥ 36.5°C Air heating warm up IV fluidsSodium < 150 mEq/L Use D5W or D5 0.25 normal salinePotassium > 3.6 mEq/L Aqueous vasopressin or DDAVP KCl bolus 10 mEq over 1 hIonized calcium ≥ 1.2 mmol/L CaCl2 500 mg IVMagnesium ≥ 1.5 mEq/L MgSO4: 4 g over 1 hPhosphorus ≥ 2.5 mg/dL 2 packets Nutra-PhosGlucose ≤ 300 mg/dL InsulinUrine output 50–200 cc/h Oliguria

IV fluids

5% albumin

Furosemide; mannitol (high CVP)

Polyuria

Aqueous vasopressin 1–4 units/h

PEEP = positive end expiratory pressure; Spo2 = saturation of peripheral oxygen;

CVP = cerebral venous pressure; SABP = systolic arterial blood pressure; DABP = diastolic

arterial blood pressure; DDAP = desmopressin acetate.


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156

Knowing the particulars of the neurologic examination in the comatose patient, clinicians will seek the cause of the lesion responsible. Neuroimaging may provide that, and it may show a destructive lesion (hemorrhage) or a lesion that involves major structures but is potentially reversible (cerebral edema). When neu-roimaging results are normal in comatose patients, physicians face an uncomfortable dilemma about how to proceed next.

Computed tomography (CT) of the brain is the most frequently used imaging modality and the quickest test to find a possible cause of coma. CT scan of the brain in comatose patients is thus necessary unless the clinical signs are reversing rapidly; for example, as a result of a corrected metabolic derangement. CT scan may docu-ment a new mass, diffuse or multiple hemispheric lesions, edema, hemorrhage, hydro-cephalus, and also brain tissue shift and other indirect signs of increased intracranial pressure (ICP). Magnetic resonance imaging (MRI) is being used more often in the urgent setting. This does not mean that MRI can help resolve the cause of coma in most instances.

The first part of this chapter concentrates on abnormalities on CT scanning and MRI and addresses its usefulness in the evaluation of the comatose patient. In some disorders, the findings on neuroimaging studies portend poor outcome and may even preclude neu-rosurgical or medical intervention. Other modalities (such as single-photon-emission computed tomography or magnetic resonance spectroscopy) are mentioned in the clinical vignettes when it is appropriate to the case.

neuroimaging, neurophysiology, and neuropathology

/ / / 6 / / /

neuroimaging, neurophysiology, and neuropathology / / 157

All things considered, electroencephalogram (EEG) has lost its prominence since the introduction of neuroimaging, but there is renewed interest in its use in comatose patients, perhaps even a revival.6 A major discussion is ongoing as to whether continu-ous EEG monitoring is warranted to detect epileptiform activity. This chapter therefore discusses the current role of electrophysiology in acute evaluation or monitoring of the comatose patient (its potential for use in brain–computer interfaces is discussed briefly in Chapter 4).

It makes intuitive sense to combine neuropathological findings with neuroimag-ing and electrophysiological findings in one chapter because this allows comparisons. Neuropathology not only can provide a description of the architectural alterations in acute catastrophic neurologic disease but also can be more specific in diagnosis using histochemical and immunohistological stains (e.g., to document viral antigens). In some fulminant cases of coma, the diagnosis is only made at autopsy (e.g., bacterial meningi-tis). Brain tissue and meningeal biopsy, or finally autopsy, can be revealing, but the results can also be frustratingly ambiguous. Moreover, as expected, neuropathology findings do not always correlate with the clinical manifestations. For example, certain disease states such as persistent vegetative state (PVS) and brain death may have only subtle patho-logical differences, while the clinical manifestations are vastly different. This chapter is therefore also the place to review the most pertinent clinical pathological syndromes.

NEUROIMAGING IN COMA

Further decisions are made based on the reading of the CT scan of the brain in comatose patients (Chapter 7), so a detailed knowledge of abnormal patterns is needed. Table 6-1 provides such a basic guide. CT of the brain is invaluable for understanding the cause of coma and addressing the severity of mass effect. The artifacts on CT are minimal, except in the posterior fossa, where the compact temporal bone causes streak artifacts.

Hypodensity on CT in comatose patients indicates infarction, edema, or tumor. Very low density indicates air, mostly from penetrating injury. Hyperdensity on CT indicates hemorrhage or calcifications. However, in patients with early diffuse cere-bral edema (e.g., anoxic-ischemic encephalopathy), the arteries in the basal cisterns are more clearly seen against a hypodense background, and this may falsely suggest subarachnoid blood. Contrast CT in the acute setting is rarely performed but could show a ring lesion in a poorly defined hypodense area; this could indicate an abscess or glioma. Epidural empyema is also much better imaged with contrast, but in all those cases uncertainties in interpretation are best resolved with MRI. A normal CT scan is


TABLE 6-1 Reading Guide of CT scan of the Brain in Coma

Structures Findings Causes

Bone windows Skull fractures TraumaSoft tissue swelling Trauma

Sphenoid, mastoid Sinusitis

Skull base Fractures, erosion Trauma; tumor

Globes Reversed cupping optic nerve head Papilledema

Deviated Early hemispheric stroke, acute brainstem

lesion

Ventricles Slit Subdural hematoma, cerebral hematoma

Absent third ventricle Colloid cyst, edema

Absent fourth ventricle Early cerebellar stroke with compression

Bilateral hydrocephalus Obstructive or communicating

Unilateral hydrocephalus Massive horizontal brain tissue shift

Sulci, cisterns, and

fissures

Effaced sulci Edema, early infarction

Absent basal cisterns Diffuse edema

Blood basal cisterns Subarachnoid hemorrhage

Absent sylvian fissure Subacute isodense subarachnoid hemorrhage

Parenchyma lobes Hypodensity Infarction, edema, tumor, abscess

Hyperdensity Hematoma, contrast, calcium, metals,

meningioma, lymphoma

Mixed density Contusions, sinus thrombosis, and venous

infarction

White-gray matter Petechial hemorrhages Shear lesions

Veins and arteries Hyperdense MCA Clot in MCA

Hyperdense basilar artery Clot in basilar artery

Hyperdense transverse sinus Sinus thrombosis

Hypodense MCA Air emboli

MCA = middle cerebral artery.

expected in comatose patients seen immediately after cardiac or respiratory resuscita-tion, asphyxia, near-drowning, most poisonings and intoxications, and acute metabolic disturbance or endocrine crises, and CT scan is not sensitive enough to document abnormalities. CT scan abnormalities may become apparent later when the patient remains deeply comatose.


MRI is far more revealing in demonstrating anoxic-ischemic injury to the brain. MRI is also superior in documenting acute demyelination; the presence of pus or blood; and encephalitis, predominantly herpes simplex or limbic encephalitis; with contrast enhancement it could demonstrate meningitis and ventriculitis. Fat embolism is often clearly seen on early MRI. Sagittal and coronal MR images are particularly important to view brain tissue shift and brainstem displacement. MRI usually includes T1- and T2-weighted images and diffusion-weighted imaging (DWI) and mapping of the apparent diffusion coefficient (ADC). DWI—measuring diffusion of water through tissue—is a new modality with a major discriminatory value. Normally, water diffusion is restricted, and thus the ADC is low. Under pathological circumstances, water accu-mulates and in ischemic lesions the decrease in ADC is shown as a hyperintense region on DWI.

Fluid attenuated inversion recovery (FLAIR) sequences and DWI are the most use-ful MR modalities in patients with unexplained coma. Several studies have found that increased signal intensity on FLAIR in the cerebrospinal fluid (CSF) compartment can indicate subarachnoid hemorrhage or purulent exudate in meningitis.34,43 The hyperin-tensity on FLAIR is explained by the presence of increased protein or pleocytosis and will decrease T1 relaxation time. However, increased signal intensity in the subarachnoid space can also be caused by oxygenation, mostly 100% Fio2, such as in patients under general anesthesia. The oxyhemoglobin concentration increases after administration of oxygen, which causes this additional paramagnetic effect.4

Magnetic resonance angiography is more elaborate but could be important in evalu-ating comatose patients with a pontine infarct due to an acute basilar artery occlusion. Magnetic resonance venography has a role in demonstrating occlusion of the sagittal venous sinus, particularly in patients with multiple hemorrhagic infarcts. Both modalities are potentially valuable, and the decision to proceed with these additional tests depends on the initial MR findings.

MR abnormalities in coma (summarized in Tables 6-2 and 6-3) provide further guid-ance to interpretation. MR spectroscopy creates metabolic maps of the brain and could become a useful additive tool, but there are timing issues and complex processing is involved, limiting its immediate clinical value. It could help define types of white matter diseases and help distinguish tumor necrosis from recurrent tumors. New techniques, such as diffusion tensor imaging, which reconstructs white matter tracts and fiber ori-entation, may provide prognostic information after diffuse axonal injury and stroke, but current experience with this technique pertains to improving motor function or cogni-tion and less recovery of consciousness.17,29


Diagnostic Imaging of Brain Tissue Shift

Mass effect is readily identified on both CT and MRI studies, but only MRI can pro-vide important details and information on its effect on surrounding brain tissue. MRI can quantify the extent of mass effect, indicate the directions of shift, and demonstrate the possible consequences of compression and may document secondary ischemic damage. MRI produces a three-dimensional image of tissue shift that is not always available with neuropathological sections. This would need unconventional brain removal and hand slicing in a different orientation.

CT scan of the brain provides good information, and particularly with serial studies, it can delineate the progression of brain tissue and brainstem shift. When a mass expands, a reproducible sequence of events has been recognized, and examples of mass effect on CT scan are shown in Figures 6-1 and 6-2. The key anatomic changes to observe on CT scan are displacement of the septum pellucidum (a midline structure located between the frontal horns), shift of the calcified pineal gland, obliteration and widening of the ambient cisterns surrounding the brainstem, change in shape of the mesencephalon and pons, and develop-ment of hydrocephalus. Displacement of the septum pellucidum follows the development of compression of the frontal horn, and, when considerable (>1 cm), the pineal gland will start to shift horizontally. However, the position of the displacing mass determines the dis-placement of these two major landmarks. (When the expanding mass is anterior, less shift of the pineal gland is expected.) Indentation of the lateral part of the suprasellar cistern is an early CT sign of tissue filling the tentorial opening, and often the tip of an enlarged temporal horn can be identified (Fig. 6-1). The midbrain and pons will rotate and displace, opening up the ambient cistern at the same side of the mass.

TABLE 6-2 mRI signal Intensity Characteristics of substances on T1-Weighted Imaging (T1WI) and T2-Weighted Imaging (T2WI)

High Intensity on T1WI Low Intensity on T1WI High Intensity on T2WI Low Intensity on T2WI

High protein Water (CSF, edema) Water (CSF, edema) High protein

(deoxyhemoglobin)Subacute hemorrhage

(methemoglobin)

Acute hemorrhage

(deoxyhemoglobin)Gadolinium Chronic hemorrhage

(hemosiderin)

Chronic hemorrhage

(hemosiderin)Other paramagnetics

(manganese, calcium,

melanin)

Diamagnetic effects

(calcification, air)

Early subacute

hemorrhage (intracellular

methemoglobin)Fat Very viscous protein Diamagnetics

(calcification, air)

From Grossman and Yousem.18


On a contrast CT, the posterior cerebral artery displaces medially, and the middle cerebral artery displaces anteriorly at the side of the mass. With further brain tissue shift, the parasellar and interpeduncular cisterns become obliterated, and bilateral compression results in anterior–posterior elongation of the brainstem. The brain-stem may become difficult to recognize when not separated by cisterns, and it may coalesce into swollen brain tissue. When expansion progresses or is suddenly maximal at onset, secondary brainstem hemorrhages can develop and are recognized as a linear or round hyperdensity in the brainstem (Fig. 6-3). They are a consequence of perfora-tion of small arteries or due to congestion from backup pressure at the circle of Willis

TABLE 6-3 Reading Guide of mRI of the Brain in Coma

Hyperintensity (FLAIR) Causes

White matter (including brainstem) Acute disseminated encephalomyelitisImmunosuppression neurotoxicityPosterior reversible encephalopathy syndromeMetabolic leukodystrophiesGliomatosisFulminant multiple sclerosisAutoimmune thyroiditis

Temporal lobes Herpes simplex encephalitis

Limbic encephalitisFulminant multiple sclerosisOsmotic demyelinationWernicke-Korsakoff syndrome

Hemispheres Astrocytoma

LymphomaOpportunistic infectionFulminant multiple sclerosisAbscessMetastasis

Cortex (multiple or diffuse) Anoxic-ischemic injury

Embolic strokesCNS vasculitisMELASThrombotic thrombocytopenic purpura or heparin-induced

thrombocytopeniaAorta dissection

Caudate nucleus globus pallidus Near-hanging

Near-drowningProlonged cardiorespiratory resuscitation

FLAIR = Fluid-attenuated inversion-recovery sequence.


(A) (B)

FIGURE 6-1 CT images of acute brain tissue shift resulting in coma. (A) Typical features of mass

effect on CT: substantial acute subdural hematoma with brainstem displacement, compression

of basal cistern, and development of contralateral hydrocephalus. Note the marked shift of the

septum pellucidum and the pineal gland and right temporal lobe indicative of moving tissue

into the tentorial opening. The right ambient cistern is wide open and the left ambient cistern is

almost obliterated from brainstem displacement. The clinical syndrome was a lateral brainstem

displacement syndrome (Chapter 3). (B) Warfarin-associated thalamic hemorrhage. There is shift

of the septum pellucidum (1 cm) but little shift of the pineal gland (1 mm). The pons has not been

displaced with symmetric ambient cisterns. The mesencephalon appears twisted. The clinical

picture was a central brainstem displacement syndrome (Chapter 3).


(Chapter 1). When an acute mass compresses the ventricular system (fourth ventri-cle) and brainstem in the posterior fossa, it is referred to as a tight posterior fossa. In most instances, it is due to an acute cerebellar hemorrhage, swollen cerebellar infarct, or traumatic epidural hematoma. The structure to note is a twisted or obliterated fourth ventricle, and the prepontine cistern and quadrigeminal cistern are difficult to recognize (Fig. 6-4).

Downward displacement of the brainstem cannot be judged reliably on CT scan. Possible signs are (1) a basilar artery visualized at lower CT scan slices rather than at its usual localization at the dorsum sellae and (2) a calcified pineal gland outside its usual plane together with the calcified choroid plexus. The reliability of both these CT signs has not been validated.19,37 Indirect signs of “downward herniation” or compression of the posterior cerebral artery have been linked to evolution of bithalamic infarcts on CT, but in clinical practice they are rarely, if ever, observed.

(A)

(B)

(C)

FIGURE 6-2 Development of mass effect on CT due to ischemic hemisphere swelling. Note the

displacement of the pineal gland and compression–elongation of the brainstem (see text for

details). (A) Admission. (B) Two days later. (C) Four days later.


MRI in comatose patients has allowed a better view of mass effect in all directions, but obtaining artifact-free images is difficult without additional anesthesia support in agitated or disoriented stuporous patients. MRI is rarely possible in most patients with acute lateral brainstem displacement and a fixed pupil. This should prompt emergency neurosurgical evacuation of the mass, and physicians cannot allow an hour’s delay for image acquisition. The secondary effects of tissue displacement (i.e., ischemic strokes) may have prognostic value. Again, most studies documenting compression of large cere-bral arteries described longstanding compression associated with tumors and not acute brain shifts developing in hours. In fact, neurologic signs and symptoms correlate with displacement and not with the development of secondary infarcts and even secondary brainstem hemorrhage.

(A)

(C)

(B)

FIGURE 6-3 (A) Massive ganglionic hematoma. (B) After evacuation of the hematoma, (C) Duret

brainstem hemorrhages are apparent.


A good MR estimate of brain tissue shift is obtained using line drawings on axial and coronal images. In addition, posterior buckling of the upper brainstem can be seen on a sagittal image and may be due to relative resistance of white matter in the basis pontis to pressure when compared with gray matter in the tegmentum.

To assist in imaging interpretation and to understand anatomical changes with brain tissue shift, orienting lines have been drawn. Coronal landmarks have been proposed by Ropper.41 They include (1) the bottom of the superior sagittal sinus to the pontomesen-cephalic junction (SSS–PMJ), seen as lateral indentation, and (2) the inferior temporal lobe to the pontomesencephalic (temp–PMJ). The sum of both is the height of the brain (SSS–temp). Lateral displacement can be measured using the third ventricle (half the distance of the brain hemispheres) (Fig. 6-5). Sagittal landmarks have been proposed by Reich and colleagues.40 The Twining line is a line from the tuberculum sellae to the

FIGURE 6-4 Cerebellar hematoma with a “tight posterior fossa.” Note acute hydrocephalus and

obliteration of cisterns and fourth ventricle (see text for details).


internal occipital protuberance that determines the position of the fourth ventricle. Reich modified measurements using the incisural line (a line from the anterior tuberculum sel-lae anteriorly to the inferior point of the junction of the straight sinus, great cerebral vein, and inferior sagittal sinus posteriorly). This line approximates the plane of the opening (incisura) of the tentorium of the cerebellum and passes through the proximal opening of the sylvian aqueduct (known as iter) (Fig. 6-5). The foramen magnum line is from the inferior tip of the clivus to the posterior lip of the occiput.40 It is a useful tool to measure tonsillar descent.

There is little experience in MRI of acute brain tissue shift, but several patterns are emerging. It may document subfalcine herniation (Fig. 6-6) or horizontal shift with no vertical shift (Fig. 6-7A). Subtle downward displacement may not be easily recognized.

SSS-PMJ SSS-temp

PMJ-temp

III ventricle

H

V

Incisuralline

Cerebellartonsil

ITER

Foramenmagnum line

(B)

(A)

FIGURE 6-5 (A) Coronal landmarks on MRI and proposed by Ropper41: SSS–PMJ: Bottom of the

superior sagittal sinuses (SSS) to pontomesencephalic junction (PMJ). H, horizontal. Redrawn

with permission. (B) Sagittal landmarks proposed by Reich et al. Redrawn with permission.40


FIGURE 6-6 Displacement of tissue under the falx on MRI.

(A)

(B)

FIGURE 6-7 (A) Two examples of MRI showing horizontal shift but no vertical shift: Clinical find-

ings of drowsiness alone with following commands after prodding of the patient. (B) Patient with

a large territorial hemorrhagic infarct, tilting of the red nuclei, and central brainstem displace-

ment syndrome (Chapter 3). Adapted from Wijdicks.51


We pointed to the potential usefulness of red nuclei displacement.53 The red nuclei are recognizable structures in the midbrain (best visualized by spin echo sequences on coronal MR images), and downward shift would be noticed by tilting of their paired presence52 (Fig. 6-7B). Lateral brainstem displacement may compromise the posterior cerebral artery and damage the mesencephalic branch, leaving a peduncular infarct (Fig. 6-8).52 Profound central displacement and downward shift and brainstem ischemia can be recognized on MRI (Fig. 6-9). MRI may document tonsillar herniation in acute processes in the posterior fossa (Fig. 6-10). Any acute tonsillar herniation may lead to patchy hyperintensity in the cervicomedullary junction and clinically may be associated with quadriplegia and marked involvement of dorsal columns, producing abnormal joint position sense32 (Fig. 6-11).

MRI may show abnormalities in patients who survived the onslaught of tissue dis-placement and increased ICP resulting in additional injury but distant from the original lesion (Fig. 6-12).

However, all these abnormalities require a clinical correlate to be useful in clinical practice. Clinically, the mass effect may develop too fast, and MRI at the very moment of emerging clinical signs may be impossible.

Diagnostic Imaging of Gray and White Matter Disorders

A few generalizations are useful here. More specific abnormalities on neuroimaging in comatose states are provided in the clinical vignettes (Part II, Chapters 12–112).

FIGURE 6-8 MRI (spin-echo sequence) showing lateral displacement of the brainstem in a

patient with a ganglionic cerebral hematoma resulting in compromise of the posterior cere-

bral artery and infarct of the peduncle but no uncal herniation. On ADC mapping, there is

reduced ADC.


Gray matter lesions are often infarctions and due to global ischemia. The characteris-tic abnormalities seen on DWI or FLAIR MR images represent cortical laminar necrosis (Fig. 6-13). MRI detects cortical edema, which is hyperintense on T2 or shows thick-ening of the cortex on T1. Gray matter involvement can be seen with encephalitis and is predominant in all areas. Herpes simplex encephalitis has a proclivity for the uncus, with edema in the medial, temporal, and inferior temporal lobes. There is a low signal in T1-weighted images and an increased signal in T2-weighted images, but the signal abnor-mality often unilateral with mass effect and gyral enhancement. DWI may be useful in detecting cortical neuronal cell loss associated with status epilepticus, but experience in humans is limited.

Several rare metabolic diseases causing progressive stupor can primarily involve the gray matter, and most of these result in an abnormal signal in the basal ganglia on

FIGURE 6-9 MRI showing notable features of downward displacement. MRI was obtained two

days after decompressive surgery for swollen hemisphere after repair of an intracranial aneu-

rysm. MRI corresponded with a FOUR score of E0 M2 B1 R1 and absent caloric testing. Upper

row: On axial image (left), some effacement of sulci is still seen. On sagittal image (middle), com-

pared with a normal sagittal MRI (right), there is downward displacement of the medulla, dented

corpus callosum, and downward displacement of the internal cerebral vein and fourth ventricle,

the pons has moved to the clivus, and the suprasellar cisterns have disappeared. Lower row: On

axial image (left), the substantia nigra and red nuclei are compressed and there is absence of

the prepontine and ambient cisterns. DWI and ADC mapping shows signal changes indicating

pontine infarction (middle and right).


FIGURE 6-10 Marked displacement of the pons in a patient with an acute swollen cerebel-

lar infarct. Tonsillar herniation on sagittal MRI. Note occipital indentation, and compare with

Figure 6-26.

(A) (B) (C)

FIGURE 6-11 MRI: T1-weighted postgadolinium sagittal (A and B) and T2-weighted axial (C)

images 1.5 weeks after the onset of illness show cerebellar tonsillar herniation below the fora-

men magnum with subsequent cervicomedullary compression. Patchy gadolinium enhancement

and T2 signal changes are restricted to the cervicomedullary junction and cerebellar tonsils, as

indicated by the arrows. From Muralidharan et al.32


T2-weighted images. Typical examples are ceroid-lipofuscinosis, an autosomal reces-sive encephalopathy that causes gray matter degeneration. There is marked hypoden-sity on T2-weighted images. Hallervorden-Spatz disease is a metabolic disorder with abnormality of iron metabolism causing deposition in the basal ganglia, with MRI showing a characteristic abnormality in the globus pallidus. Juvenile Huntington’s disease may also present with gray matter involvement. Mitochondrial disorders that present at early adult age are MELAS (myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) with acute episodes of cerebral infarction. Diffuse T2-weighted hyperintensities in the temporal, parietal, and occipital cortical areas are found, and eventually lead to atrophy. However, most metabolic disorders have both gray and white matter abnormalities.

(A) (B) (C)

(D) (E) (F)

FIGURE 6-12 CT scan shows crowding of the basal cisterns (A) due to an acute subdural hema-

toma with displacement of the septum pellucidum and pineal gland (B); a brainstem hemor-

rhage appeared the day after evacuation of the hemorrhage (C). MRI (FLAIR and GRE sequences)

shows hyperintensity in the thalamus (D); hemorrhage in the mid-pons (E); hyperintensity in

the peduncle opposite to the mass, a mixed density in the brainstem, and hyperintensity in the

occipital lobe (F). From Wijdicks.55


Acute diffuse or multifocal lesions involving the white matter may cause coma, and MRI is most helpful here. Demyelination may be strategically placed in the upper brainstem and thalamus when patients present in coma, but it is more likely diffuse and interrupting most connections to the cortex. A typical MR image of acute leu-koencephalopathy is shown in Figure 6-14. Arteritis can involve the white matter, but when present it is more likely with multifocal, cortical infarcts. MRI is very use-ful in documenting white matter involvement in inherited leukodystrophies. Most hereditary metabolic disorders and immune-mediated inflammatory disorders do not enhance. This should be contrasted with disorders such as adrenoleukodystrophy, radiation necrosis, and acute multiple sclerosis plaques that enhance after gadolinium administration.

MRI is better at showing the consequences of deceleration injury to the white matter (Fig. 6-15). White matter lesions in traumatic brain injury (shear lesion) can be imaged by CT scan but are often barely recognizable. MRI is highly sensitive to traumatic brain injury and is the primary modality to assess the severity of impact.

Posterior reversible encephalopathy syndrome has a proclivity for posterior regions of the white matter but may extend throughout the entire white matter, pons, and cerebel-lum. It is a major feature of eclampsia, cyclosporine or tacrolimus toxicity, certain chemo-therapeutic agents (e.g., 5-fluorouracil and levamisole), and many occupational toxins. Disseminated necrotizing leukoencephalopathy following cranial or spinal radiation or in combination with chemotherapeutic agents also has been recognized as a cause for acute leukoencephalopathy. The abnormalities are diffuse and widespread, with enhancement after gadolinium administration.

FIGURE 6-13 MR FLAIR imaging showing increased intensity in bilateral cortices.


FIGURE 6-14 CT and MRI demonstrate an acute diffuse leukoencephalopathy (associated with

Sjögren’s syndrome).


FIGURE 6-15 CT scan with multiple shear lesions. Corresponding MR image (FLAIR) shows dif-

fuse hyperintensities indicating contusional lesions in frontal lobe, temporal lobe, and posterior

splenium.


Neuroimaging in acute metabolic disturbances can be very informative. Acute meta-bolic derangements can damage neuronal tissue from edema or from neuronal dropout when seizures occur. However, concomitant anoxia or ischemia from shock or airway obstruction in acute metabolic derangement may occur and become visible on MRI.

In severe hypoglycemia, restricted diffusion has been reported in the cortex of the temporal and occipital lobes and is clearly visible on DWI or FLAIR images. A study of four patients in PVS after severe hypoglycemia reported laminar necrosis in the insu-lar and parieto-occipital cortices, substantia nigra, bilateral hippocampus, and caudate nuclei and lentiform nuclei.12 Thalamic lesions were conspicuously absent.10 Rapidly overcorrected hyponatremia causes osmotic demyelination, and abnormalities are most impressive in the thalamus, putamen, caudate nuclei, internal capsule, claustrum, amyg-dala, and cerebellum. The pontine lesion is bat- or trident-shaped due to sparing of the descending corticospinal tract.

MRI can be helpful in showing the major effects of organ failure. Liver failure can show characteristics of T1-weighted images with increased signal intensity in the cau-date nucleus, tectum, globus pallidus, putamen, red nucleus, and substantia nigra. These abnormalities have been attributed to manganese, which causes shortening of the relax-ation time. When examined, the concentration of manganese is higher in patients with liver cirrhosis compared to controls, and its effects may be neurotoxic and result in dopa-mine depletion. Renal failure does not appear to permanently damage the brain unless it leads to a posterior reversible encephalopathy syndrome or is seen in the setting of thrombotic thrombocytopenic purpura. In both these conditions, cerebral infarction may occur. Hyperthyroidism can be a cause of rapidly evolving stupor. Thyrotoxic coma can lead to MRI abnormalities that are diffuse and patchy and often involve the white matter.

Finally, toxins can be considered. The most studied is carbon monoxide poisoning, which results in lesions in the globus pallidus; high T1-signal intensity or hyperintensity on T2-weighted images in the putamen and the lentiform nuclei is apparent. There is no involvement of the cerebellum and occipital regions. Necrosis may be found in the paramedian aspects of the frontal lobes. Acute carbon monoxide poisoning may produce predominantly white matter lesions. MR abnormalities from toxins that cause coma are summarized in Table 6-4.

NEUROPHYSIOLOGY OF COMA

A normal EEG shows a well-structured pattern with posterior basic rhythm of more than 8 Hz and less than 13 Hz and amplitude of 30 to 50 µV, with reactivity to eye opening


and no evidence of slow waves or abnormal wave forms.26 For nearly half a century, EEG was the most valuable tool in assessment of “encephalopathies,” stupor, coma, and brain death. Classically, suppression of EEG activity—in its broadest term—correlated with abnormal consciousness. More or less specific EEG patterns for what was later called “metabolic encephalopathies” became recognized such as triphasic waves (most fre-quently seen in acute renal or hepatic failure) or periodic lateral epileptiform discharges (severe hyponatremia), but it was quite clear that EEG patterns progress in a certain direction with transition to slower oscillations (theta and delta) with worsening of the encephalopathy.57 EEG is still used to diagnose (to look for ongoing seizures or seizure focus), to prognosticate (to look for burst suppression or marked background suppres-sion), and to monitor treatment (to look for adequate suppression of EEG in seizures). The value of EEG in the emergency department as a diagnostic tool in a patient with low clinical suspicion is discussed in Chapter 7.

EEG Patterns in Coma

The EEG already changes when patients become slightly drowsy or what might be called encephalopathic. The EEG has been used to “grade” the severity of encephalopathy, usu-ally when seen in the setting of sepsis or multiorgan dysfunction, but the transitions are far more gradual than a simple shift from one category to another (Table 6-5). A decrease in responsiveness leads to major changes in EEG pattern such as (1) dyssynchroniza-tion of fast activity; (2) increase in rhythmicity and voltage and emerging delta activity;

TABLE 6-4 Preferential Locations of mR Lesions Due to Toxins

Methanol Optic nervePutamen

Subcortical white matterEthylene glycol Thalamus

PonsToluene Corpus callosum

Cerebellar vermisCarbon monoxide Globus pallidus

White matterHippocampus

Turpentine Frontotemporal white matterOrganic mercury poisoning Calcarine cortex

CerebellumPostcentral gyri

Trichloroethane Globus pallidus


(3) mixtures of slow with fast frequencies and more frequent delta activity; and finally (4) burst-suppression patterns followed by full suppression or isoelectric EEG.56 Several other early EEG patterns are seen, such as intermittent rhythmic delta activity in the fron-tal regions (FIRDA)—such a pattern is seen both in structural injury and acute metabolic derangements. Triphasic waves may appear; they are characterized by a high-voltage posi-tive wave preceded and followed by a low-amplitude negative wave. Triphasic waves can occur in earlier stages of encephalopathy, but their appearance has been mostly recorded in coma as the result of an acute metabolic derangement or toxin. Triphasic waves, however, are not specific and also seen in acute destructive lesions, although this is much less com-mon.46 In these conditions the EEG may show epileptiform activity, but its classification has remained problematic, with variations in terminology and no standardized terms and definition.21

A number of EEG descriptors and further classifications in comatose patients have been published. All of them identify several key patterns, and one example of a classification is shown in Table 6-6. Several of these EEG patterns are shown in Figure 6-16. The definition of electrographic seizures remains difficult in a group of patients with structural injury and multiple confounding drugs. Usually there is a clear beginning and end, and the wave is sharply contoured, with synchronous atten-uation of background activity.

Some of the most interesting patterns are periodic lateralized epileptiform dis-charges (PLEDs) and generalized periodic epileptiform discharges (GPEDs). PLEDs are morphologically sharp waves, spikes, slow waves, or combinations. They can be seen in any new structural lesion (often central nervous system [CNS] viral infections), but these morphologies should not be considered seizures if they do not progress to low-amplitude rhythmic discharges. Clinically they are not associated with facial myoc-lonus or extremity twitching; but if they are, it may indicate nonconvulsive status epilep-ticus. Many experts have argued for the existence of an ictal–interictal continuum, and therefore these EEG patterns should not be easily dismissed as completely insignificant.2

TABLE 6-5 eeG Changes in encephalopathy

Encephalopathy EEG Recording

Early signs Suppressed α rhythmHigh prevalence of β rhythm

Mild Low-frequency α rhythm (8 Hz)Random waves in theta range

Moderate Background in theta. Random high waves in the delta range.Severe Disorganized asynchronous theta and delta waves with often triphasic waves


GPEDs are periodic discharges, and their relation to seizures is equally unclear. One study in comatose patients with continuous EEG recordings for 10 or more days found that 37% of patients had prolonged GPEDs; they were often treated—rightly or wrongly—with antiepileptic drugs. GPEDs did not predict outcome or recovery from coma. We consider these patterns interictal, particularly when they are consistently at least 2 or 2.5 Hz. GPEDs do indicate a higher susceptibility to seizures. Stimulus-induced rhythmic, periodic, or ictal discharges (SIRPIDs) are often seen after noxious stimuli; these nonepileptic discharges were found in one of three monitored patients. The signifi-cance has not been fully clarified.11,36

As a result of more frequent monitoring, more data on EEG patterns have recently become available in critically ill comatose patients. Nonconvulsive seizures may be detected depending upon the time of recording in up to 48% of patients.27 In a large ICU cohort study, periodic epileptiform activity or seizures were found in 13% of patients using a spot EEG, but all patients had some decline in consciousness.27 There are other marginally more specific EEG patterns, such as α coma and spindle coma pat-terns. Patients with α coma patterns show fast frequency with slow abnormalities, and EEG resembles an “awake” state. It is an EEG pattern that has been mostly recorded in anoxic-ischemic encephalopathy after cardiopulmonary arrest, and the pattern is promi-nent over the anterior region. Reactivity to sensory stimuli is absent. This α coma pat-tern has also been seen with brainstem lesions and drug overdose. In acute brainstem lesions there may be one caveat: alpha rhythm may be a normal finding in an awake

TABLE 6-6 eeG Grading scale in Coma

Mild (grade 1) Moderate (grade 2) Severe (grade 3)

Excess beta Diffuse or focal delta slowing Burst-suppression patternTheta slowing SIRPIDS Low-voltage output pattern (<10 µV)Anesthetic pattern ELAE Alpha/theta coma

Spindle coma Focal or generalized seizuresInterictal epileptiform discharges Nonreactive to stimuliGeneralized triphasic waves GPEDFIRDA, TIRDA, OIRDA Status epilepticusPLED

ELAE = episodic low-amplitude events; FIRDA = frontal intermittent rhythmic delta

activity; GPED = generalized periodic epileptiform discharges; OIRDA = occipital

intermittent rhythmic delta activity; PLED = periodic lateralized epileptiform discharges;

SIRPIDS = stimulation-induced rhythmical, periodic, or ictal discharges; TIRDA = temporal

intermittent rhythmic delta activity.7


(A)

(B)

FIGURE 6-16 Common EEG patterns in comatose patients. (A) Generalized nonconvulsive status

epilepticus. (B) Triphasic waves.


(C)

(D)

FIGURE 6.16 Continued. (C) Periodic lateralized epileptiform discharges (PLEDs). (D) Generalized

periodic epileptiform discharges (GPEDs).


(E)

FIGURE 6.16 Continued. (E) Nonspecific diffuse slowing.

patient with locked-in syndrome, but again this pattern would then be in its typical nor-mal posterior location.

The EEG has an important role in the early diagnosis of encephalitis, particularly her-pes simplex encephalitis. Most patients with a presumed diagnosis of viral encephalitis are admitted to the neurointensive care unit with impaired level of consciousness or coma, are often unable to protect their airway, and need intubation and mechanical ventilation. CT scan is often normal. MRI cannot be performed easily in these patients, and in some patients CSF findings are nondiagnostic or equivocal. Fairly early in the course of herpes simplex encephalitis, the EEG shows polymorphic delta activity over the temporal lobes, which suggests preferential involvement of these regions. Although nonspecific for her-pes simplex encephalitis, focal or lateralized sharp- or slow-wave complexes emerge early and eventually become periodic, usually after one or two days of illness. Sharp waves may occur almost continuously or several seconds apart and may evolve into more distinc-tive seizure discharges, recognized by repetitive sharp and slow waves or bursts of spike waves. Periodic complexes in the acute phase may indicate a poor prognosis.

Many other encephalitides have diffuse slow-wave abnormalities, and the degree of slowing is often directly related to the severity of CNS infection.


The most concerning EEG pattern is burst-suppression with a generalized syn-chronous burst of high voltage alternating with marked suppression of background. Burst-suppression in coma can be due to sedative drugs (often barbiturates),9 anesthetic drugs, hypothermia, or diffuse laminar cortical injury from cardiac arrest.44

Isoelectric EEG is most notorious for a poor outcome, but it may occur in major intox-ications and hypothermia.7 In deep hypothermia, paroxysmal activity and spike-wave complexes may occur,38 making it even more difficult to differentiate it from spike and waves from injury. Hypothermia produces significant EEG abnormalities when the body temperature is at 30°C, the EEG becomes discontinuous at 20°C, and there is electri-cal silence when the temperature drops below 17°C. (The EEG trace fully disappeared at 7°C.) It may also occur in severe refractory shock and can be reversible with better blood pressures.

Isoelectric EEG is often simply a markedly depressed EEG, and higher gain will dem-onstrate activity. Criteria for isoelectric EEG—for example, when used for brain death confirmation—are found in Chapter 5.

Continuous EEG Monitoring

There is a renewed interest in continuous EEG monitoring. Such monitoring may increase early recognition of nonconvulsive status epilepticus not evident on a spot EEG. In these monitored patients with a wide spectrum of acute neurologic disorders, EEG may not necessarily contribute to an already clinically evident situation. Despite the utility of EEG in seizure detection and assessment of prognosis in patients treated with therapeutic hypothermia, it is not known whether continuous EEG provides a measurable clinical benefit over “spot check” (20- to 40-minute routine) duration EEG. No question the procedural charges, which include longer review times for continuous EEG, are substan-tially higher than those for routine-duration EEG.7

Nonetheless, in recent years there has been progress in continuous EEG monitoring. A recent recommendation from the neurointensive care section of the European Society of Intensive Care Medicine was based on a critical review of the literature, but low grades of evidence were found for most indications (seizure detection, ischemia detection, and prognostication). Continuous EEG has been recommended during therapeutic hypothermia to provide prognostic information and to monitor for subclinical seizures. Hypothermia may reduce seizures or EEG abnormalities and in experimental studies has antiepileptic effects. The risk of seizures can increase during rewarming. Therefore— logically—treatment of seizures during and after rewarming could improve the outcomes of resuscitated patients. The presence of an epileptic focus or status epilepticus on EEG


has been associated with poor outcome, although survivors have been reported. Other patterns, such as the presence of diffuse slow-wave activity in the absence of malignant patterns such as burst-suppression or generalized epileptiform discharges (GPEDs), correlate with a better prognosis. Some patients after CPR have diffuse epileptiform dis-charges, also known as PLEDs, BIPLEDs, or GPLEDs. These interictal patterns do not necessarily indicate a poor outcome.

Evoked Potentials

Of the available techniques, somatosensory evoked potentials (SSEPs) are most often used; the additional value of brainstem auditory evoked potentials (BAEPs) and visual evoked potentials in the clinical assessment of patients with acute neurologic illness has been disappointing.8 There is currently little additional value of these tests in prognosti-cation or measurement of secondary injury, but they have not been used systematically and thus may need reconsideration. This may require continuous clinical and continuous evoked potential recording as currently used in the operating room.

SSEPs are most often used to determine prognosis in traumatic brain injury and anoxic-ischemic encephalopathy. SSEPs have been used as an electrophysiological marker of prognosis in many acute neurologic conditions but have been best studied after cardiac arrest. An absent cortical response (N20) but present cervical cord response (N13) after median nerve stimulation is considered indicative of severe cortical or subcortical injury and is mostly associated with very poor outcome. (There have been recoveries in patients with absent N20 responses.3) The accuracy of an absent response can usually be ques-tioned, and one recent study found bilateral loss of N20 cortical responses in one of five patients who made full functional recoveries.22 Other studies found very high specificity of an absent SSEP response. 5,31,39,47

The applications of BAEPs in patients with acute neurologic illness are limited to trau-matic head injury and confirmation of the clinical diagnosis of brain death. BAEPs have recently been explored in patients with brainstem compression from a large supratento-rial mass. Several studies have suggested that BAEPs can be useful in testing brainstem integrity. Patients with rapid deterioration from mass effect, may have wave V abnormali-ties with brainstem compression, abnormalities that reverse after ICP was controlled.8

There is also renewed interest in event-related potentials, and some studies suggested a predictive value for recovery. P300 can be generated by introducing new sounds on top of ambient sounds. N400 can be generated using five-word sentences with constant stimulus duration and intensity. The prevalence of identifying a P300 is very wide and has ranged from 10% to 100%.42,48 Similarly the prevalence of N400 varies from 14% to


39% in patients with PVS or minimally conscious state (MCS). A recent study identi-fied a correlation of N400 with favorable outcome, but P300 was not predictive of good outcome.45

NEUROPATHOLOGY OF COMA

The neuropathology associated with disorders causing acute or prolonged coma has been well characterized. The basic neuropathological descriptions are essential to understand brain damage. At times the neuropathologist is at some disadvantage. First, although expanding lesions produce characteristic neuropathological findings of shift, the degree of herniation may have worsened after decisions not to treat the patient. Second, anoxic-ischemic injury may have been a result of not treating hypotension or hypoxemia at the time of withdrawal of support. Third, ischemic neuronal changes may not have yet occurred, underestimating neuronal loss. Brain biopsy is often performed as a last-resort measure and may skip the lesion or result in nonspecific (“inflammatory changes”) find-ings that do not resolve the cause of coma. The major findings in comatose patients who come to autopsy are discussed here.

SPECIFIC TYPES OF INJURY

Hypoxemia and Ischemia

Neither anemia nor hypoxemia causes necrotic brain damage. In fact, there is sufficient evidence that anemia might have an added protective effect in ischemia, presumably through an increase in cerebral blood flow that produces a hyperdynamic circulation. Pure hypoxemia causes changes in synaptic configuration, but there is no evidence of neuronal cell body necrosis. This laboratory observation has a clinical parallel. A consid-erably better outcome in patients who have pure hypoxemic injury to the brain has been noted, compared with patients with circulatory arrest and global ischemic injury.

The neuropathology of hypoxic-ischemic injury is a result of damage to vulnerable areas. These predilection sites include the first and second frontal gyrus, (which is in a watershed zone), globus pallidus, cornu ammonis, and cerebellar cortex with predomi-nantly the Purkinje cells. The ischemic alterations in the cornu ammonis involve the CA1 and CA4 sectors. The hippocampus becomes ischemic in CA1 areas after several minutes of global ischemia, but necrosis occurs later, and in some areas delayed neuronal death may occur even several days after the global cerebral ischemia. The CA4 region requires only minimal ischemic insult for these cells to become damaged. The globus pallidus is


the most commonly affected area. The dentate gyrus, an area that is far more sensitive for injury in hypoglycemia, is rarely involved in ischemia. (In hypoglycemic injury, the Purkinje cells are spared and necrosis of the cortex, brainstem, or cerebellum is absent. Hypoglycemia selectively injures the CA1 pyramidal neurons.)

The neuropathology of ischemic injury has been well described and involves loss of Nissl bodies, basophilia, shrinking of the perikaryon, and development of triangular neu-rons, eosinophilia, acidophilia, and argentophilia (Fig. 6-17). Eosinophilic degeneration of the Purkinje cells in the cerebellum is a common neuropathological finding in a severe anoxic-ischemic injury (Fig. 6-18). The pathological changes of anoxic-ischemic injury are typically in the watershed zones and therefore also involve the posterior cerebral regions, but with overwhelming ischemia pan-necrosis of the cortex is seen, which then also involves the middle cortical layers. Cavity formation in basal ganglia due to liquefac-tion necrosis may involve multiple areas of the brain. This late manifestation is mostly seen in prolonged comatose survivors.

In most patients, hypoxic-ischemic injury spares the brainstem clinically, but necrosis of brainstem nuclei may affect the inferior colliculi and tegmental nuclei of the brainstem. The pars reticulata of the substantia nigra in the midbrain may also be selectively involved.

For forensic purposes, it is important to summarize the time course of ischemia and the alterations that occur. On light microscopy, no changes can be expected within 12 hours of anoxic-ischemic injury. Vacuolization of the neuropil and pallor occurs 12 to 24 hours after injury. Leukocytes are seen 30 minutes to four days after injury; macro-phages, foam cells, or lipid-laden (“gitter”) cells seven days; aggregated macrophages nine

FIGURE 6-17 Typical examples of ischemic lesions showing (H&E) eosinophilic alterations of the

cytoplasm and nucleus, also known as “red dead neurons.” (See color insert.)


to 40 days; increased liquefaction of necrosis 21 to 70 days; development of cysts 50 days to 15 months; cysts containing a few macrophages 11 months to four years; and cysts containing no macrophages after more than 24 months.35

Infarction and Hemorrhage

Besides occasional mention in case reports, systematic autopsy studies of mas-sive cerebral hemorrhages and cerebral infarcts resulting in coma are quite uncom-mon. The pathological changes with cerebral infarcts are dependent on the time the patient comes to autopsy. Macroscopically there is softening but also hyperemia in a wedge-like shape consistent with the territory involved. However, gross pathological findings of small hemorrhagic infarcts may be associated with far more global isch-emic injury and can be deceptive at first sight (Fig. 6-19). Hemorrhagic conversion is common in cerebral infarcts due to cardiac emboli and can be explained by recanaliza-tion. It may also occur in patients with fixed arterial occlusions and from collaterally directed reperfusion.

One study from Salpêtrière Hospital reviewed 45 patients with fatal edema and isch-emic stroke.24 Major findings were an abnormal circle of Willis on the ipsilateral side and higher prevalence of a common carotid occlusion extending the infarct into other territo-ries. This finding—large territorial involvement of the cerebral infarct with little collateral compensation—is a plausible explanation for the appearance of massive brain swelling after ischemic injury.

FIGURE 6-18 Anoxic-ischemic injury to the cerebellum (H&E). Abnormal Purkinje cells situated at

the interface of the molecular and granular cell layer (asterisk). The characteristic prominent pink

cell body and dendritic tree are not identified. (See color insert.)


FIGURE 6-19 Wedge-shaped hemorrhagic border zone infarct after valvular repair. Microscopy

showed diffuse anoxic-ischemic injury not appreciated on a macroscopic specimen. (See color insert.)

For centuries, patients with large ganglionic or pontine hemorrhages—causing “ sudden unexplained death”—have come to autopsy. The ravaging destruction and mass effect is evident. In patients with large thalamic hemorrhage, blood has tracked deep into the brainstem. In other patients, edema may have caused further deterioration. Perihematoma brain edema peaks after several days in most patients after intracerebral hematoma. Edema is a multiphased event and is caused by clot retraction, movement of serum into ambient tissue followed by activation of the coagulation cascade and thrombus, and finally erythrocyte lysis and toxicity of hemoglobin.55 Edema is facilitated by disruption of the blood–brain barrier (Fig. 6-20). Recent evidence has shown that inflammation occurs with activation of the complement system. Increased production of

FIGURE 6-20 Microscopy (H&E) of cerebral hemorrhage: with perilesional edema. (See color insert.)


matrix metalloproteinase iron may play a role in the development of cerebral edema after cerebral hemorrhage because iron chelators have been shown to reduce brain edema in animal studies.55

Trauma and Abuse

Multiple contusions and subdural hematomas are easily identified at autopsy and are localized on the surface of the cortex and bilateral temporal lobes (Fig. 6-21). Diffuse axonal injury is typically caused by rotational acceleration following an impact to the head. On gross examination, hemorrhages of the corpus callosum and cerebel-lar peduncle region are observed, and there may also be hemorrhages in the deeper structures. The so-called gliding contusions in the parasagittal white matter or small white matter hemispheric shear lesions can be found. These contusions are often linear bloody streaks placed perpendicular through the cortical ribbon. Tissue tear hemor-rhages are mostly concentrated in the midline structures such as the corpus callosum, septum pellucidum, fornix, midbrain, pons, and hippocampus. Traumatic brain injury is often in the medial basal cortical areas of the temporal lobes, in the margins of the base of the cerebellar peduncles due to pressure on the tentorial ridge, and on top of the

FIGURE 6-21 Traumatic head injury, with multiple contusions of the brain and subdural hema-

toma at the vertex. (See color insert.)


corpus callosum due to indentation by the free edge of the falx cerebri. Injury can also be found in the basal cortex of the occipital lobes and the dorsal surface of the cerebel-lar hemispheres. Traumatic brain injury may lead to injury to the cortex, hippocampus, thalamus, and cerebellum and, when present, may point toward additional ischemia. Global cerebral ischemia is likely when comatose patients are slowly extracted from motor vehicle wrecks or are found face-down. Even minutes of major respiratory compromise from no airway protection and hypovolemic shock may further damage the brain.

To demonstrate axonal injury, a systematic approach is needed. Geddes suggested a minimum set of blocks (Table 6-7).15 Axonal injury associated with severe traumatic brain injury has been noted microscopically. In the first weeks, “retraction balls” (sheared-off axons with ends retracting into globoid structures) are found, followed by “microglial stars” (hypertrophied microglia). Wallerian degeneration in the white matter and brain-stem tracts is found after six to eight weeks. Under the microscope on routine H&E stains, many of the axons are dystrophic. These axons can also be made more visible with immunohistochemistry, using beta-amyloid precursor protein (βAPP). Only two hours after the impact, anti-βAPP immunocytochemistry can detect damaged axons. Reactive changes to white matter injury can be documented by the presence of glial fibrillary acidic protein (GFAP) or CD68 antibody. The axons become swollen and varicose before they disconnect. The size of axonal swelling in relation to the time of traumatic injury is an inexact correlation.28

TABLE 6-7 minimum set of Tissue Blocks (Two samples of each area) Recommended for Determining the Distribution and amount of axonal Injury

Corpus callosum and parasagittal posterior frontal white matterSplenium of the corpus callosumDeep gray matter to include posterior limb of the internal capsuleCerebral hemisphereMidbrain (to include decussation of superior cerebellar peduncle)Pons (to include superior or middle cerebellar peduncles)Corpus callosum and parasagittal anterior frontal white matterTemporal lobe (to include hippocampus)Nonaccidental infant head injuryMedullaAll the upper cervical cord segments

From Geddes et al.15


Nonaccidental trauma (child battering) is suspected when multiple brain injuries are seen at different stages of evolution. Bilateral subdural hematomas are most common (Fig. 6-22). Skull fractures and depressed diastatic nonparietal growing fractures are also strong indicators. Neuropathology of inflicted head injury has been systematically stud-ied, but the findings are conflicting. In some studies, axonal injury—determined by βAPP positivity—was not a common finding, but instead there was evidence of prominent abnormalities in the craniocervical junction that could trigger apnea.28 Anoxic-ischemic injury was more common than expected with very few contusions—also arguing for a mechanism other than impact.13,14,23

Infection

The neuropathology of bacterial meningitis is fairly characteristic and immediately appar-ent. At autopsy, purulent meningitis is revealed by pus and yellow and green deposits on the leptomeninges. Generally, the pus follows the distribution of the meningeal blood vessels. Additional stains can document bacteria and bacterial lipopolysaccha-ride (Fig. 6-23). Depending on the time elapsed before death, microscopic features are neutrophils and fibrin in subarachnoid space with macrophages. Arteritis has now been recognized as one of the most important secondary complications leading to ischemic strokes and much worse outcome, including prolonged coma.

Fulminant meningitis may show cerebral edema and little exudate, but there have been no systematic pathology studies in adult bacterial meningitis. Acute bacterial meningitis

FIGURE 6-22 Battered child syndrome with subdural hematomas shining through. (See color

insert.)


may be a surprising finding in patients who died rapidly, when no real opportunity for the physician existed to obtain CSF.

Fulminant encephalitis may cause early demise and can be confirmed at autopsy. The findings are generally nonspecific, showing clusters of inflammatory changes and at places perivascular chronic inflammation with microglial nodules and neuronophagia. Herpes simplex encephalitis, however, is associated with hemorrhagic necrosis, specifically

FIGURE 6-23 Macroscopic view of bacterial meningitis with purulent deposits. On microscopy the

different stains document the presence of bacteria (arrows) and bacterial lipopolysaccharide (LPS).

Microscopy also shows evidence of infarction in the pons due to vasculitis. (See color insert.)


involving the temporal lobes, the insula, and the posterior orbitofrontal cortex. Cowdry A intranuclear inclusions can be found in herpes simplex encephalitis (recognized by eosinophilic cells surrounded by a halo), or neurons with homogenous wine-red nuclei with stained-glass appearances are observed, but generally polymerase chain reaction (PCR) amplification of viral DNA is used (Fig. 6-24). When ultrastructural findings are examined, viral particles with hexagonal features and a central nucleoid are found. Cytomegalovirus encephalitis (CMV) is more commonly seen in patients infected with the AIDS virus. CMV has typical microscopic findings of scattered cytomegalic cells with intracytoplasmic viral inclusions, and the absence of an inflammatory infiltrate in these infections is notable. Fungal encephalitis may be difficult to detect microscopically on routine stains, and the fungus may be difficult to culture. Aspergillus fumigatus infection of the CNS is aggressive and destructive. At autopsy, both infarcts and hemorrhages can be found due to angioinvasion (Fig. 6-25).

FIGURE 6-24 Microscopy of encephalitis. Perivascular inflammation and infiltrative cells (cuffing)

and immunochemistry stained for herpes simplex encephalitis. (See color insert.)

FIGURE 6-25 Vascular invasion by hyphal elements of Aspergillus (left magnification ×40; right

magnification ×200). (See color insert.)


A comprehensive discussion of the neuropathological findings in CNS infection is beyond the framework of this book, but the major findings in infectious causes of the CNS are summarized in Table 6-8.

Demyelination

Axons devoid of myelin are the pathological hallmarks, but axonal injury may occur in active lesions of multiple sclerosis and its presence indicates permanent injury with no prospects for repair.20 Demyelination in acute multiple sclerosis plaques also is associ-ated with perivascular cuffs of infiltrates with lymphocytes and foamy lipid-laden macro-phages. In other areas, there is myelin debris and gliotic plaques with no cellular response. In acute leukoencephalopathies, the acute changes are patches of demyelinated tissue, edema with fibrinoid necrosis of blood vessels, and also neutrophils, mononuclear inflammatory cells, and hemorrhages (particularly in acute hemorrhagic leukoencepha-lopathy). Another inflammatory demyelinating disease is acute disseminated encepha-lomyelitis (ADEM), resulting in symmetric subcortical white matter lesions. Bickerstaff encephalitis is an ADEM variant that may produce coma due to its proclivity for the brainstem, but patients rarely come to autopsy due to its benign course. Multiple sclerosis may present with an acute mass (tumefactive form of Marburg). Next to marked demye-linization, the neuropathology (findings in this variant are characterized by macrophages,

TABLE 6-8 Pathology Characteristics in Fulminant Cns Infections

Disorder Macroscopy Microscopy

Bacterial meningitis Pus at base, sulci

Brain edema

Multiple infarcts

Vasculitis

Neutrophilic infiltrateTuberculosis Thick exudates

Miliary granulomas

Hydrocephalus

Granulomas with caseation, lymphocytes,

Langhans giant cell

Cerebral infarctsMycotic infections Basilar meningitis

Intraparenchymal abscesses

Yeast forms

Macrophages

(Pseudo) hyphaeViral infections Bilateral hemorrhagic lesions

(herpes simplex encephalitis)

Subependymal calcifications

(cytomegalovirus)

Neuronophagia, intranuclear inclusion

bodies, perivascular cuffing, mononuclear

inflammation

From Nelson et al.33


large glial cells with mitosis, and chromatin fragmentation [Creutzfeldt cells]) may sug-gest on first sight a malignancy.

The pathology of osmotic demyelination (Fig. 6-26) involves the presence of well-demarcated lesions, reactive astrocytes, and axonal preservation. Stains for myelin include solochrome cyanin stain or Luxol fast blue-cresyl violet, silver impregnation for axons (documenting its lack of involvement), or immunohistochemistry for neurofila-ment proteins.30 Many areas of spared white matter are seen, and lymphocytic inflamma-tion is also absent. The mechanism is more likely apoptosis triggered by the inability of glial cells to overcome the osmotic challenge and failing Na-K surface pumps.

Neurotoxicity

Coma due to intoxications or poisoning has forensic implications. Many poisonings are accidental, but they can occur intentionally in the setting of suicide or homicide. It is use-ful to mention a few neurotoxins here, although they all remain uncommon. Many neu-rotoxins produce no apparent neuropathological changes in the CNS. With some, such as lithium poisoning, more specific abnormalities are seen, such as spongiform changes in the thalamus, midbrain, and cerebellum, with significant damage to the Purkinje cells (explaining cerebellar ataxia during presentation). Thallium (used in many rat poisons) produces cerebral edema with multiple white matter and cerebellar hemorrhages but also degenerative changes in the cerebral cortex, hypothalamic nuclei, and olivary complex. An important forensic question is whether death occurred from carbon monoxide poi-soning. The morphology is fairly characteristic, with bright redness of brain section at autopsy that remains after fixation. Often a significant brightness of the dura is seen at exposure of the brain. There is bilateral necrosis of the globus pallidus and pars reticulata of the substantia nigra. Cortical laminar necrosis and involvement of both hippocampi are expected.

FIGURE 6-26 Osmotic demyelination in pons. (See color insert.)


Acute fatal alcohol intoxication remains nonspecific, but brain edema and conges-tion can be found. Equally rare is a documented neuropathological confirmation of Wernicke-Korsakoff syndrome, with its characteristic changes that involve atrophy of the mammillary bodies, periventricular hemorrhages, and astrogliosis and capillary prolifera-tion in more chronic cases. Far more likely in alcoholics are multiple intracranial hem-orrhages, particularly subdural and intracranial hemorrhages. Elevated levels of serum ammonia in end-stage alcoholic cirrhosis will cause Alzheimer type II astrocytes that are characterized by periodic acid-Schiff (PAS) staining, with a large pale vacuolated nucleus and a dense nuclear membrane.49

DISEASE STATES

Pathology of Brain Herniation

Pathologists over the years have characterized brain herniation as brain tissue displace-ment from one compartment to another through dural openings (Chapter 1). How much brain tissue is displaced depends on the size of the opening (tentorium, foramen mag-num) and the anatomical relationship of the openings with the temporal lobe, cerebel-lum, and brainstem.

The major types of brain herniation are subfalcine, tentorial, and tonsillar. Subfalcine herniation is herniation of the cingulate gyrus under the falx. Compression of perical-losal arteries may cause secondary frontal parasagittal cortical infarcts, but a more local pressure necrosis can also be observed in the cingulate gyrus. The displacement of tissue underneath the falx is a common occurrence in patients with a frontally located expand-ing unilateral mass. It is easily visualized on pathological specimens, but its clinical rele-vance is unclear and its presence does not single-handedly cause coma or even an akinetic mutism due to cingulate gyrus necrosis.

Uncal herniation refers to herniation of the parahippocampal gyrus through the tentorium. It occurs in large hemispheric masses, causing flattening of the midbrain and compression of the aqueduct (Fig. 6-27). The presence of pressure necrosis of the parahippocampal gyrus is indicative of intra vitam increased ICP. Compression of the posterior cerebral artery may result in ischemic infarction of the thalamus and necro-sis of the temporal lobe and medial-inferior occipital lobe, but this is rarely seen in the acute setting; it is far more often seen in expanding tumors that gradually displace tissue and compress neighboring arteries. How the posterior cerebral artery is compressed and leads only to distal occipital infarctions—even bilateral in some cases—remains uncer-tain. Typical findings at autopsy are herniation of the parahippocampal gyrus through the


tentorial hiatus; herniation may also be visible when the uncus is pressed against the edge of the tentorium. In the most extreme cases, tonsillar herniation and necrosis can be seen, and often the medulla is engulfed by tonsillar tissue.

Central herniation—at least pathologically—is characterized by displacement of the mammillary bodies and the anterior lobe of the pituitary gland, and infarction in the anterior choroidal, posterior cerebral, and superior cerebellar artery territories has been noted.16 When downward displacement is seen, the diencephalic structures have been displaced downward, with buckling of the brainstem. Often, a gray discoloration and gliosis of the descending fiber tracts at the base of the pons and medullary pyramid can be seen in patients who have survived severe brain injury with increased ICP or cerebral edema. Diffuse cerebral edema may show compression (pinching) of the midline struc-tures and displacement of the uncus, although not necessarily herniation (Fig. 6-28).

FIGURE 6-27 Massive displacement from middle cerebral infarct and edema resulting in uncal her-

niation. Note secondary brainstem hemorrhage associated with brainstem shift. (See color insert.)

FIGURE 6-28 Diffuse cerebral edema and bilateral uncal displacement. Note compressed ven-

tricular system. (See color insert.)


In the posterior fossa, a sudden hematoma will displace the pons and press against the clivus. In many of these patients, there is also upward herniation of cerebellar tissue indirectly, noted as indentation of the occipital lobes (Fig. 6-29). Tonsillar herniation is a consequence of an acute mass in the cerebellum. Flattening of the medulla and hemor-rhagic necrosis of the tips of the cerebellar tonsils are hallmarks (Fig. 6-30).

Persistent Vegetative State

The pathologic changes in PVS can be divided into traumatic or nontraumatic injury, although overlap may occur (e.g., anoxic-ischemic injury due to cardiac arrest or shock in multitraumatized patients). The most frequently reported pathologic substrate of PVS in traumatic cases has been diffuse axonal injury, with a variable contribution of superim-posed ischemic lesions. Bilateral thalamic damage is a fairly constant feature.

When autopsy cases of head injury patients with PVS and MCS or other severely disabled cases are compared with each other, more severe injury is found in PVS. These findings include higher frequency of thalamic lesions and more often multiple areas of axonal shear injury (the usual triad of white matter, corpus callosum, and rostral brain-stem).25 One study found in this comparison that ischemic damage, thalamic injury, and white matter axonal injury were not found in severely disabled conscious patients but only in patients with PVS.

Anoxic-ischemic injury causing PVS usually affects the entire cortical mantle, not only all territories (parieto-occipital region more than frontotemporal) but also throughout

FIGURE 6-29 Upward herniation of cerebellar tissue in vermian cerebellar hemorrhage.

Compression of the inferomedial occipital poles creates a concave depression beneath the pos-

terior horns of the lateral ventricles (see also Fig. 6-10). (See color insert.)


the full thickness, replacing neurons and nerve fibers with gliosis, lipid phagocytes, and collagen. Cavities in caudate and lentiform nucleus are common. The thalamus may be preferentially involved. Disappearance of Purkinje cells and granular layers in the cerebel-lum are more common after anoxic-ischemic injury, and cystic softening in the periaque-ductal gray and dorsolateral brainstem is more often seen in posttraumatic causes of PVS.1 An example of cortical thinning and hydrocephalus ex vacuo is shown in Figure 6-31. The neuropathologist is able to document a catastrophic injury to the brain, but, as expected,

(A)

(B)

FIGURE 6-30 (A) Tonsillar herniation; (B) Fragmentation of necrotic cerebellar tonsil. (See color insert.)


cannot confirm the clinical diagnosis of PVS because considerable overlap exists with patients in MCS.

Brain Death

Neurosurgeon Walker described the neuropathology of brain death in considerable detail in the 1980s.50 Several variables have changed over time. Prolonged observation was more common in the earlier years of brain death determination and organ transplanta-tion, which contributed to the neuropathologic findings known as respirator brain. On gross examination, the brain was gray but also friable and mushy. Focal hemorrhages in white and gray matter were apparent, and much of the white matter was edematous and soft. The brainstem often showed congestion and hemorrhages, and the herniated tonsils were necrotic, with pieces having trickled down to the thecal sac of the spinal cord. In the

(A) (B)

(C)

FIGURE 6-31 Pathology of PVS. Macroscopy of the brain of a 23-year-old man in a PVS for

10 years after surviving massive brain edema from Reye’s syndrome and fatal bronchopneu-

monia. Brain weight 370 g (normal 1,300 to 1,500 g). (A) Gross picture of brain in situ, showing

marked atrophy of both frontoparietal areas. (B) Gross picture of whole removed brain, left-side

perspective with marked frontal atrophy. (C) Coronal section of brain with marked cortical atro-

phy and hydrocephalus ex vacuo. (See color insert.)


cerebellum, the granule cell layer was autolyzed. Inflammatory reaction was absent, but there were leukocyte infiltrations with hemorrhages in the upper segment of the cervi-cal spinal cord, optic nerve, and pituitary gland. The major findings are summarized in Table 6-9. The important forensic question is the time of brain death. Oehmichen and colleagues35 speculated that some criteria might be helpful, but again, there are reserva-tions about their accuracy. These criteria are as follows:

The gray color of the rim surface as well as softening occurs two days after a no-flow situation.

Myelin staining intensity is reduced after 16 to 21 hours.Eosinophilic neurons are seen more than 48 hours in the cerebral cortex and in the

medulla oblongata.Demarcating hemorrhages are seen after 30 hours.Demarcating immigration of leukocytes is seen as early as 24 hours.

Certainly, the absence of reactive changes is an important indicator of absence of intra-cranial circulation.35

Owing to effective and timely organ-harvesting programs, the pathological examina-tion after the clinical diagnosis of brain death is currently done within 36 hours and in many patients within 12 hours. We recently reviewed the neuropathological findings in brain death.54 The frequency of moderate to severe neuronal ischemic damage is shown in Figure 6-32. Neuronal loss was much less evident in the thalamus or brainstem. These findings demonstrate that the neuropathological patterns in brain death have changed due

TABLE 6-9 histopathology of Brain Death

Site Microscopy

Cortex Almost invariably damaged; frank infarcts, congestion, and edema. No glial or hematogenous

reaction.Diencephalon Periventricular edema; patchy, lytic changes in subthalamus, thalamus, and hypothalamus

(herniation effect)Pituitary May be spared (extracranial circulation) petechial or confluent hemorrhages. Karyopyknotic

changes in anterior lobe.Brainstem Flattened medulla oblongata, significant edema, hemorrhage, infarction, and necrosis in

mesencephalon, but pons may be normalCerebellum Swelling, congestion, fragmentation, granular layer washed out. Purkinje cell layer is normal,

edematous, or devoid of all cells. Molecular layer is preserved.Spinal cord Normal, except upper cervical segments, dislocated cerebellar fragments

From Walker,50 with permission.


FIGURE 6-32 Percentage of moderate (>5% to 75%) to severe (>75%) neuronal ischemic changes

in 41 autopsies of patients who fulfilled the clinical criteria of brain death.54

to a change in practice of organ retrieval. The neuropathological findings in the modern transplant era lack sufficient distinctive characteristics, “respirator brain” is uncommon, and the diagnosis of brain death, therefore, can only be determined clinically (Chapter 5).

CONCLUSIONS

Neuroimaging has evolved greatly, is highly useful for clinicians, and provides a real-time image of evolving brain injury. MRI is used now consistently in hospitals and has mark-edly reduced the number of patients with unexplained coma. MRI can fully delineate the shift and resulting compaction of the brainstem structures that leads to coma. MRI has been able to document diffuse cortical injury and white matter changes and provides a detailed picture of the abnormalities associated with disorders of consciousness unavail-able with a CT scan of the brain. Neurophysiology in coma has some value, but its place in the evaluation of comatose patients is currently being redefined. Continuous EEG is currently providing new insights, but whether it will become part of a practice model remains unclear, largely due to costs. Evoked potentials may also need reconsideration and may have value in continuous monitoring. Neuropathology in comatose patients may have lost some of its importance due to readily available neuroimaging. However, many clinicians place their trust in neuropathology findings; as always, it provides a final assess-ment or confirmation of a clinical diagnosis. Autopsy is a benchmark, and the neuropa-thologist usually provides the clinician with a keen sense of the underlying pathology that


caused coma. Of course, in reality, autopsy cannot resolve all cases, particularly unsatis-factorily explained cases associated with illicit drug use or poisoning. Autopsy in patients in MCS, PVS, and brain death may show findings that only reflect the severity of injury and are not specific.

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205

neurologic acumen is needed when deciphering physical find-ings in the comatose patient. This requires a strategy based on a combination of diagnostic steps and treatment decisions. In reality, diagnosis and management of a comatose patient are rarely separate steps. Normally, diagnosis takes primacy over treatment, but certain management decisions are diagnostic. Common examples are intravenous glucose in a sweaty, tachycardic, hypoglycemic comatose patient or effectively managing a presumed heroin overdose with naloxone.

There are multiple causes of coma but, after an initial evaluation, physicians often can narrow the range of possibilities. For the physician in charge, finding the patient in a spe-cialized hospital unit may also narrow the differential diagnosis of acute coma. Consulting in a transplant intensive care unit is in a different environment than consulting in a medi-cal intensive care or coronary care unit. Moreover, the nature of the primary illness for which the patient is admitted may provide sufficient leads.34 Nevertheless, comatose patients may present to the emergency department with no known course and little med-ical documentation, or patients are admitted to units and come as a complete surprise.

This chapter describes a multi-tier approach to the comatose patient. The chapter has two parts. It begins with mastering the “first things first”. The initial medical stabilization is followed by the neurologic examination, which should provide an anatomical localiza-tion to be integrated with the results of a CT scan of the brain. Using this combination should lead to the approximate cause of coma. Importantly, the physician should be able to find a treatable disorder and act accordingly.

Next, the chapter addresses more specific clinical situations and how to proceed accordingly. Approaches may differ when comatose patients are seen in the emergency department, hospital wards, or intensive care or transplant units.

Clinical Diagnosis and Decisions/ / / 7 / / /


CLINICAL DECISIONS IN THE COMATOSE PATIENT

The following steps will assist clinicians in their first approach to the comatose patient. Neurologists tend to start immediately with a neurologic examination, but even before trying to find out why the patient is in a coma and how deep it is, the vital signs must be noted and secured. Some clinical signs are immediately troublesome, such as inability to maintain an airway due to pooling secretions or due to abnormal respiratory drive, extremes in blood pressure, extremes in temperature, and serious cardiac arrhythmias.

Respiratory and Hemodynamic Stabilization

All four primary vital signs (respiration, blood pressure, pulse, temperature) need imme-diate attention. We should approach the patient first by judging the need for intuba-tion. Stridorous sounds may point to airway obstruction at the base of the tongue or hypopharynx and may be caused by a foreign object or detritus in patients found in the field. Intubation is most pertinent when the patient is tachypneic, desaturation on pulse oximetry is noted, or there are early diffuse pulmonary infiltrates on chest x-ray. Oxygen desaturation may occur rapidly and is defined as oxygen saturation less than 90% by pulse oximetry; it is even more worrisome if it occurs while the patient is provided 100% inspired oxygen. Oxygen desaturation may then progress very quickly, resulting in rapid arterial hemoglobin desaturation and cardiac arrest in a matter of minutes.

Intubation should be strongly considered when there is an indication that coma is deepening, which results in loss of protective airway reflexes.5 It has been determined empirically that patients who localize a pain stimulus, have an adequate cough, and are not pooling secretions may still be able to sufficiently protect their upper airway. Vomiting is a reason to protect the airway with placement of an endotracheal tube, where the cuff can prevent gastric regurgitation in the pulmonary bronchial tree. The techniques of intu-bation are outside the scope of this book; however, unnecessary increases in intracranial pressure (ICP) should be avoided with intubation. It is important to assess the ease of intubation and whether there might be traumatic cervical spine injury. A simple proce-dure such as jaw tilt and bag-mask ventilation can be injurious.28 Etomidate (2 mg/kg IV) is a useful anesthetic drug in rapid-sequence intubation. It can mute the rise in ICP associated with the procedure and has little hemodynamic compromise.4 Connection to a ventilator using pressure support ventilation (a flow-cycled mode with constant airway pressures at inspiration and triggered by the patient) and intermittent mandatory ventila-tion (preset and spontaneous breaths) will provide adequate ventilation in the major-ity of patients. Noninvasive ventilation (BiPAP) has been used in comatose patients,

Clinical Diagnosis and Decisions / / 207

particularly if the cause is rapidly reversible and no upper airway obstruction is present. BiPAP could be an important alternative to endotracheal intubation in patients with reduced ability to initiate a spontaneous breath such as with intoxications, hypercarbia, and prolonged postictal coma due to use of benzodiazepines. BiPAP may be dangerous if patient has vomited and might do so again.

Patients with marked hypothermia, defined as a core temperature of less than 34°C, should receive blankets. Other more sophisticated treatments (e.g., continuous arterio-venous rewarming) may be required if the core temperature is less than 28°C and coma is due to an accidental cause. Circulatory instability may remain if the temperature is not corrected first.

Next comes the assessment of circulation and blood pressure and the consideration of antidotes. Hypotension may have many causes, including exsanguinating hemorrhage, sepsis, or intoxication with potent vasodilators such as cyclic antidepressants, lithium, opi-oids, and phenothiazines. Hypotension is immediately corrected by placing the patient in the Trendelenburg position and infusing 500 cc isotonic saline and 50 mL of 50% dextrose if hypoglycemia is a possible cause. Further fluid resuscitation may be needed, typically using normal (isotonic) saline, but it may have to be adjusted depending on the cause of coma. If there is no response, vasopressors can be started with initially a bolus of up to 100 to 200 mcg of phenylephrine. Infusions with epinephrine, norepinephrine, dopamine, or dobutamine will have to run through a central access line that may have to be secured first.

Blood transfusion may be needed when the hemoglobin level is declining rapidly or is less than 7 g/dL. Patients with thrombocytopenia need platelet concentrates. The value of administration of platelet infusion (“six pack”) in patients with cerebral hemorrhage associated with antiplatelet therapy is currently being investigated because practices vary.

Treatment of hypertension probably should involve management of extremes (e.g., mean arterial blood pressure more than 130 mm Hg) using a short-acting alpha-1 and beta-adrenergic blocking drug such as labetalol (20 mg IV bolus every 10 minutes). Nicardipine (starting at 10 mg IV bolus followed by 5–15 mg/hour) may be needed to avoid further surges in blood pressure. Hydralazine (20–40 mg IV) and enalaprilat (1.25 mg every six hours) are preferred intravenous antihypertensive drugs when a baseline bradycardia is present.

Finally, one should consider using common antidotes for recently administered drugs. Midazolam is frequently administered during transport before patients enter the emergency department or ICU (e.g., during helicopter flights). Neuromuscular block-ing agents are often administered to facilitate transport but may also have been used in rapid-sequence induction in patients with a difficult airway. If there is any indication of previously administered benzodiazepines, intravenous flumazenil 0.2 mg over 30 seconds


can be administered followed by second and third doses if there is no effect. If opioid use is suspected, 0.4 mg naloxone is administered intravenously; it can be repeated up to five times every three minutes if there is no response. Another major potential confounder in clinical assessment is the prior use of neuromuscular blocking agents, and it should be routine to inquire about their use. Their administration is particularly concerning in patients with seizures or status epilepticus if it has been used to achieve airway control. They may create a situation where the patient is paralyzed while the brain is actively seiz-ing. Rocuronium has been frequently used (0.6 mg/kg IV) and has a half-life of 1.5 hours (half-life triples in liver dysfunction). Reversal of previously administered neuromuscular blockers requires neostigmine (2 to 4 mg slow IV) combined with glycopyrrolate (0.4 to 0.8 mg IV). Four twitches with maximal stimulation from a nerve stimulator is proof of reversal, but often return of tendon reflexes is as well.

To recapitulate, the vital signs can be best secured in the following sequence: air-way protection and ventilation support, correction of severe hypothermia, normaliza-tion of blood pressure (requiring fluids, blood products, or antihypertensive drugs) and possible use of antidotes to reverse recently administered sedative or paralyzing drugs. These decisions can be made within minutes and should precede any detailed neurologic examination. In fact, the neurologic findings may change after vital sign abnormalities are corrected.

Further Questions to Family or Bystanders

After the patient is medically stable, additional history should be obtained. Questions that should be asked of family members or bystanders—when appropriate—are the following:

To inquire about intoxications: What other pills or over-the-counter drugs or herbs does the patient have access to? Has the patient had prior suicide attempts or a psy-chiatric consultation? Are there problems at work? Has anyone complained about the patient’s drinking habits?

To inquire about environmental injuries: What did the scene look like, and where was the patient found? Has the patient been diving? Has the patient used medications that may increase heat production, such as salicylate drugs with sympathicomimetics such as cocaine, amphetamines, or Ecstasy?

To inquire about trauma: What was the nature of the accident? Was the patient breath-ing on arrival of the response team? Was there noticeable blood loss? Did the patient deteriorate during transport?


To inquire about infections: Did the patient use antibiotics for infection? Was there a rapid onset of fever and headache?

To inquire about resuscitation: Was a cardiac arrest documented? How long did the efforts last before circulation resumed?

To inquire about diabetes: Has the patient had prior episodes of diabetic ketoacidosis, or severe hypoglycemia, and has there been a recent change in insulin medications?

To inquire about stroke: Is the patient known to have atrial fibrillation or other cardiac disease and are they using anticoagulation, or has it recently been discontinued? Was hypertension poorly controlled?

Answers to these questions are informative and may provide direction as to how to pro-ceed with further testing.

Consolidation of Neurologic Findings

A detailed neurologic examination of the comatose patient is now key. However, before any examination is performed, potential confounding drugs should be considered, par-ticularly in transported patients or patients who have been intubated. The clearance of these drugs is shown in Table 7-1.

Familiarity with the terminology mentioned in Chapter 3 is necessary to comprehend the discussion of the following sections. The major coma categories should be kept in mind while examining the patient8,10,11,16 (Table 7-2). The next task is to identify either a bilat-eral hemispheric or brainstem syndrome. Subsequently, one should try to predict whether there is an intrinsic brainstem lesion or brainstem displacement due to brain tissue shift.

TABLE 7-1 Clearance of Drugs Used for Transport or Induction of Intubation

Drug Duration of Effect

Fentanyl 30–60 minutesLidocaine 10–20 minutesEsmolol 10–30 minutesEtomidate 3–5 minutesPropofol 5–10 minutesKetamine

Lorazepam

5–15 minutes

60 minutesThiopental 30–60 minutesSuccinylcholine 5–15 minutesRocuronium 45–70 minutesVecuronium 35 minutes


TABLE 7-2 Clinical neurologic signs in Drug-Induced Coma

Seizures • Tricyclic antidepressants

• Lithium

• Anticholinergic drugs

• Antihistamines

• Insulin

• Strychnine cyanideRigidity • Phencyclidine

• Strychnine

• Haloperidol

• Selective serotonin reuptake inhibitors

• Cyclic antidepressantsDyskinesias and akathisias • Lithium

• Fluoxetine

• Phenothiazine

• ButyrophenonesMyoclonus • Opioids

• Pesticides

• Penicillin or cefepime

• Calcium channel blockers

In some patients, all mesencephalon and pontine function is lost and only knowledge of the time course and evolving signs can differentiate between these two possibilities. Broadly speaking, acutely found comatose patients likely had a devastating ischemic or hemorrhagic stroke, became intoxicated, suffered a head injury, or have a major metabolic derangement, most likely acute hypoglycemia or hyponatremia. Rapidly progressive signs leading to coma indicate brain tissue shift from a mass (contusion, cerebral hematoma, or tumor) or encephalitis. Fluctuating responsiveness indicates a postictal state after a single seizure, nonconvulsive status epilepticus, or an embolus at the top of the basilar artery, causing ischemia to both thalamic structures.

Interpretation of Neuroimaging: Abnormal CT Scan Findings and Their

Consequences

The neurologic syndrome combined with an abnormal CT scan will narrow the possible causes of coma. A CT scan should confirm the clinical impression that brain tissue shift and brainstem displacement is causing coma, with the majority of cases due to stroke, traumatic brain injury, and infectious or tumorous hemispheric masses (Fig. 7-1). When


these CT scan features are present, increased ICP should be anticipated. Coma due to intrinsic brainstem lesions with an abnormal CT scan is often due to upper brainstem (pontine) hemorrhage, new mass, traumatic brain injury, or less commonly brainstem encephalitis. Pontine edema on CT may be prominent in acute hypertensive crises, but clinical signs are more often bihemispheric. If available, MRI is a required test.

Failure to acutely manage increased ICP most likely will lead to a much worse out-come and, in its extreme, brain death.3 The first clinical decision is to determine whether there is a resectable lesion that requires an urgent neurosurgical opinion. Clinical scenarios include patients with an acute expanding lobar hematoma, mass effect from a newly diagnosed glioma, space-occupying traumatic contusional lesions, or an acute sub-dural or epidural hematoma. Infectious causes of a new hemispheric (abscess) or extra-axial clot (epidural empyema) warrant neurosurgical evacuation in virtually all instances. Hydrocephalus associated with mass effect is more difficult to deal with. In patients with lobar hematoma or ganglionic hematoma, the clot often expands into the diencephalon, but ventriculostomy in these circumstances rarely affects outcome and as expected does not improve the level of consciousness. Hydrocephalus from compression at the level of the fourth ventricle (cerebellar mass) requires drainage and removal of compression.

The second clinical action to make is to reduce increased ICP while bridging to sur-gery or—if no surgical option exists—to at least temporize its damaging effects. Patients

Coma

Intubate-ventilatory support/blood pressure stabilization

Brain tissue andbrainstem shift

Intrinsic brainstem

CT brainCT brain

AbnormalResults

Causes Stroke TBIICH

Basilar arteryembolus

ThrombolysisClot retrieval

Medcare

Medcare

TBI

Biopsy

MassMass

Tumor Infection

Surgical evacuationCraniectomyRx ICP

Treatmentoptions

Neuro-imaging

Neurologicsyndromes

AbnormalNormal

FIGURE 7-1 Emergent evaluation and care of the comatose patient with evidence of brainstem

injury. (Coma is defined by 3 to 16 points loss on the FOUR Score.) TBI = traumatic brain injury;

ICH = intracranial hematoma; ICP = intracranial pressure.


should receive medical therapy with mannitol (20%) or hypertonic saline (3%, 7%, or 23%). Mannitol is given in boluses of 1 g/kg and followed by a maintenance dose of 0.50 to 1 g/kg every four to six hours. The incidence of acute renal failure associated with man-nitol is less common than appreciated, but it is prudent to keep the serum osmolality less than 320 mOsm/kg and to increase isotonic fluid intake in an attempt to keep the patient normovolemic. There is no evidence that mannitol worsens ICP gradients by dehydrat-ing the normal brain and therefore worsening the shift. In fact, most patients do clinically improve after a 1-g/kg bolus of mannitol and unappreciable change in shift on CT scan. Hypertonic saline can be used as an alternative to osmotic therapy, with repeated boluses of 3% to 10% solution (e.g., 1–2 mL/kg in 20 minutes) or as a bolus of 30 mL of 23.4% solution over 15 to 20 minutes. Infusion requires access through a peripherally inserted central catheter, which would need to be placed before infusing these highly osmolar fluids. Hypertonic saline is a less desirable option in patients who have congestive heart failure because they may not tolerate fluid overload. Severe hypernatremia, hypokale-mia, and hyperchloremic acidemia are other potential side effects of hypertonic saline administration.6,12,25

Hyperventilation remains an important additional measure and effectively reduces acutely raised ICP. It is recommended for periods of less than 30 minutes and with an arterial Pco2 goal of 30 to 35 mm Hg. There is renewed interest in the use of nonsteroidal anti-inflammatories (NSAIDs) in ICP control; they might be helpful for some patients. Indomethacin as a constrictor of cerebral arteries can minimize major increases in ICP, particularly plateau waves.18,26 There is insufficient evidence that indomethacin can pro-duce cerebral ischemia or hemorrhages, because it also interferes with platelet aggrega-tion. An intravenous bolus of indomethacin (30–50 mg) may reduce ICP immediately and is followed by an infusion of 0.2 mg/kg per hour. Refractory increased ICP has been managed with barbiturates, but this is a complicated therapy resulting in a high suscepti-bility to infections, myocardial depression requiring vasopressors, and the potential for liver failure. Propofol remains a good alternative drug, but high doses may be needed to control ICP. Current concerns with a propofol infusion syndrome (metabolic aci-dosis, fatal cardiac arrhythmias), linked to prolonged use with high doses, will limit its use for this purpose.27 The options of medical therapy for increased ICP are shown in Figure 7-2.

Corticosteroids should be administered in patients who have CT findings suspicious for a glioma. However, improvement cannot be anticipated when using corticosteroids in patients with increased ICP due to traumatic brain injury, ischemic stroke, or cere-bral hemorrhage. The dose of dexamethasone typically is a 10-mg intravenous bolus fol-lowed by 4 mg given intravenously every six hours. Patients may need an insulin therapy


protocol to control hyperglycemia, and gastric protection is necessary to prevent gastro-intestinal bleeding.

There are at least six major categories of causes of coma in patients with a hemispheric syndrome and an abnormal CT scan (Fig. 7-3). Multiple cortical lesions on CT (or later MRI) are mostly due to cerebral infarctions. In a young patient, isolated central nervous system (CNS) vasculitis is considered and requires a cerebral angiogram and biopsy, fol-lowed by aggressive immunosuppression. Early diffuse white matter lesions may indicate acute demyelination (e.g., acute disseminated encephalomyelitis [ADEM]) and early administration of intravenous corticosteroids (pulse methylprednisolone) is warranted. An acute hydrocephalus documented by the presence of markedly ballooned ventricles should be treated immediately by placing a ventriculostomy in the right frontal horn. Patients with aneurysmal subarachnoid hemorrhage and acute obstructive hydrocepha-lus may rapidly improve after ventriculostomy placement and cerebrospinal fluid (CSF) drainage.

Placement of a ventriculostomy may be precluded in patients on anticoagulation or those with an acquired coagulopathy. Fresh frozen plasma, recombinant factor VII, prothrombin complex concentrate, or platelet transfusions are needed to correct the international normalized ratio (INR) to less than 1.5 before a ventriculostomy is placed. Diffuse brain edema may be caused by organ failure (e.g., fulminant hepatic fail-ure), electrolyte abnormalities (hyponatremia),31 or acute hyperglycemia. CT scan is invariably diagnostic in comatose patients with aneurysmal subarachnoid hemorrhage. Mostly, CT scan shows a combination of blood in the basal cisterns and ventricles. The presence of subarachnoid hemorrhage is followed by a cerebral angiogram to demon-strate a ruptured aneurysm. However, the devastating consequences of increased ICP

Maintaintemperature

36–37º C

Mannitol1–2 g/kg

HyperventilatePaco2

28–30 mm Hg

OxygenateSpo2 95–100

Maintain MAP100 mm Hg

Pentobarbital3–5 mg/kg

infusion0.2–1.0 mg/kg/h

Indomethacin30–50 mg IV

infusion0.2 mg/kg/h

Propofol1–5 mg/kg/h

ICP20 mm Hg

FIGURE 7-2 Options for treatment of increased intracranial pressure (ICP). MAP = mean arterial

blood pressure.

Coma

Intubate-ventilatory support/blood pressure stabilization

CT brain

Hemispheres

AbnormalResults

Causes

Treatment options

Neuroimaging

Neurologic syndromes

Normal

Corticallesions Hydrocephalus

Whitematter

Brainedema

SAH PRES

BiopsyAC

Cortico-steriods

VentriculostomyRxICP

ClipCoil

RxBP

Toxin Statusepilepticus Infection

EndocrineMetabolic

AnoxicIschemic

AEDAntibioticAntiviral

drugs

Hypothermia

50%dextrose IV

insulin, thyroxine,and corticosteroids

Drugscreens

antidotes

FIGURE 7-3 Emergent evaluation and care of the comatose patient with evidence of bihemispheric lesions. (Coma is defined by 3–16 points loss on the

FOUR Score) AED = Antiepileptic drugs; CT = Computed tomography; IV = Intravenous; Rx = Treatment; ICP = Intracranial pressure; BP = Blood pressure;

PRES = Posterior reversible encephalopathy syndrome; AC = Anticoagulation; SAH = Subarachnoid hemorrhage.


due to arterial rupture may be a result of cortical ischemic injury not seen on CT scan initially. Acute hypertensive encephalopathy or posterior reversible encephalopathy syndrome (PRES) has been increasingly recognized as a cause of coma with lesions throughout the hemispheres and not just in the occipital regions.20 Both cortical and white matter lesions may be found on CT scan but are much better demonstrated on MRI.

Interpretation of Neuroimaging: Normal CT Scan Findings and Their

Consequences

This category of comatose patients with normal CT scan remains the most difficult to evaluate. The combination of clinical findings of an acute intrinsic brainstem syndrome but a normal CT scan most often points to infarction of the mesencephalon or pons due to an embolus to the basilar artery. Cerebral angiogram or CT angiogram is warranted and could lead to successful lysis or retrieval of the clot. MRI will be diagnostic for pon-tine or cerebellar infarcts.

A normal CT scan is most common in patients with bihemispheric findings. The clinical history may provide important clues for a CNS infection. It is then essential to proceed with a CSF examination. When the CSF findings are suspicious for an infection, full antibiotic coverage with ceftriaxone (2 g IV every 12 hours), vanco-mycin (20 mg/kg IV every 12 hours), and ampicillin (12 g IV every four hours) in combination with antiviral coverage (acyclovir 10 mg/kg every eight hours) is needed until final results become available. A screening CT scan is preferable when a patient suspected of having bacterial meningitis presents with coma, in particular when a CT can be obtained in a matter of minutes. However, empirical intravenous antibiotic therapy and dexamethasone (10 mg initially followed by 10 mg every four hours) are administered before transfer to the CT scanner and after blood cultures are obtained. If there is no cerebral edema, epidural, or subdural empyema, lumbar puncture is performed.

If laboratory results have excluded an acute metabolic disturbance, a search for tox-ins is appropriate. Only generalizations can be made here, but acute onset of coma is mostly due to suicide attempts or environmental exposure. For example, suicide attempts with cyanide, hydrogen sulfide exposure in the workplace, carbon monoxide inhalation, ingestion of narcotics or street drugs containing barbiturates (among others), bromides present in a hot tub, and photographic chemicals have such a rapid absorption that coma could result in hours. Rapid loss of consciousness may be preceded by seizures, myoclo-nus, tremor, dyskinesias, violent behavior, and acute delirium, and each symptom has a


differential diagnosis to consider (Table 7-3). The sudden presentation of an intoxicated comatose patient is a difficult situation. For most physicians (except clinical toxicolo-gists), the knowledge of toxins is rudimentary or even nonexistent, but they must effec-tively manage highly unstable patients. The topic is further discussed later.

THE COMATOSE PATIENT IN VARIOUS HOSPITAL LOCATIONS

The above-mentioned clinical steps necessary to evaluate a comatose patient will assist the physician in any clinical situation no matter where the patient is admitted.2 However, some causes are more common in certain patient populations: one may find acute intoxications more commonly in the emergency department and a major structural brain injury in surgical intensive care units after complex vascular surgery.13 In other hospital locations where the medical history is known and a dying patient has been closely observed, acute coma may not even represent an unexpected deterioration. This section, therefore, summarizes the assess-ment of the comatose patient from this vantage point and guides the clinician through dif-ferent locales in the hospital. It provides several useful maxims, but details on the causes of coma can also be found in the clinical vignette section (Part II, Chapters 12–112).

TABLE 7-3 Classification of Coma

Structural brain injury Hemisphere with mass effect Bilateral hemispheres Cerebellum with mass effect BrainstemAcute metabolic-endocrine derangement Sodium abnormalities Glucose abnormalities Liver failure Renal failure Hypercapnia Hyperammonemia HypothyroidismDiffuse physiological brain dysfunction Seizures Poisoning Drug use HypothermiaPsychogenic unresponsiveness Acute catatonia Hysterical coma


COMA IN THE EMERGENCY DEPARTMENT

Most patients entering the emergency department have been suddenly transferred from the ambulance or helicopter into critical care pods. On the receiving end there may be little information. Most of the time, screening basic laboratory tests and neuroimaging are quickly obtained. In the emergency department there is a fair amount of ordinariness, and fortunately for all of us the cause of coma is often rapidly clear after CT scan of the brain. These are patients who have traumatic brain injury, acute intracranial or subarach-noid hemorrhage, or early diffuse cerebral edema from anoxic-ischemic injury. If it is not so obvious, here are some guiding steps.

Maxim 1: Recall the key findings of the neurologic examination.

Going back to the basic findings of a neurologic examination can be helpful. First, note the abnormal motor responses—decorticate or decerebrate responses indicating acute structural injury to hemispheres or brainstem. Acute metabolic or endocrine derange-ments or toxins do not produce these reflexive subcortical motor signs. Second, these abnormal motor responses can be associated with brainstem findings such as pupil anisocoria, miosis, mydriasis, or skew deviation of the eyes, and then it points toward a brainstem lesion from compression (must be visible on CT) or an intrinsic brainstem lesion (must be visible on MRI). Recall at this point that a locked-in syndrome should be considered in any condition that damages the ventral pons (“locked-in” may also occur if patients have been paralyzed before transport but have been insufficiently sedated.)22 Third, if the only finding on examination is that the extremities are rigid or flaccid, this may point to certain drug ingestion as a cause of coma. Marked rigidity may indicate a serotonin syndrome or a neuroleptic malignant syndrome. Fourth, if twitching (eyelids, extremities) is observed, it may be from generalized myoclonus or from ongoing seizures.

Maxim 2: Review the CT and confirm it is normal.

What can possibly be missed on CT that could explain coma? The abnormality most often missed is a hyperdense basilar artery sign. The basilar artery is always “somewhat” hyper-dense and therefore not recognized as abnormal. Generally, an acute basilar artery occlu-sion is uncommon but clinically considered in acute coma if there are pointers such as acute anisocoria and bilateral extensor posturing. Its finding should immediately prompt a CT angiogram or MR angiogram and, if a clot is present, a cerebral angiogram for endo-vascular retrieval of the clot, assuming the presentation is less than 24 hours from onset.9

CT scan may show diffuse cerebral edema. Early brain edema may be difficult to recognize, but there may be poor white–gray matter differentiation and less sulci than


expected. (note here that there are less sulci in young individuals and more prominent sulci in older patients.) Subtle hypodensities in the posterior regions, in the thalami and pons, may indicate PRES, and careful review of recorded blood pressures may be needed to find episodes of systolic blood pressure over 200 mm Hg.

Cerebral venous thrombosis on CT scan should be considered in any patient with a small intracranial hemorrhage and a string sign in the temporal or occipital lobe. A hyper-intensity in the falx should be specifically sought; if present the next test ordered should be either an MR venogram or CT venogram. A bacterial meningitis often presents with a normal CT but may show a nonaerated sinus from mastoiditis, or more problematic, sphenoiditis that may extend into the cavernous sinus. Abnormalities in the posterior fossa usually go undetected, such as in an evolving cerebellar infarct.

Maxim 3: An MRI in the emergency department may demonstrate acute brain disorders not found in any other way.

A frequently question is whether MRI has a role in the evaluation of acute coma in the emergency department. CT is insensitive in early thalamic infarctions, basilar artery occlusion and brainstem infarction. MRIs may document severe leukoencephalopathies associated with illicit drug use, may demonstrate severe cortical laminar necrosis after anoxic-ischemic injury, and in extreme circumstances may find multiple emboli consis-tent with air, fat, or infectious material. Fulminant variants of cerebral vasoconstriction syndrome can be found with MRI or MRA. MRI is diagnostic in PRES.

Maxim 4: Think of a toxidrome and look for it.

When a CT scan is normal in a comatose patient with no noticeable neurologic signs, there is likely an intoxication. Think, ethanol or atypical alcohols, heroin or other opi-oids, and benzodiazepines. If intoxication is suspected, the general rules of evaluat-ing intoxication should be followed. A toxidrome-oriented physical examination may reveal evidence of poisoning due to opioids (miosis, sedation, absent bowel sounds, and hypoventilation) or cholinergic agents (increased secretions, diaphoresis, urination, and defecation). A summary of major toxidromes is shown in Figure 7-4. Taking, just one clinical sign, hypertension, in combination with other findings may direct atten-tion to several possible explanations. Some of these possible explanations are shown in Table 7-4.

Always measure an anion gap and osmolar gap. The mnemonic KULT can be help-ful (ketosis, uremia, lactate, toxin) when these gaps are increased. Toxicological testing rarely leads to an explanation of coma, and routine toxicological testing rarely changes acute management and usually adds little to the diagnostic evaluation. Evaluations


MiosisFasciculationsSalivationHypertensionTachycardiaSweating

MiosisFasciculationsHypothermiaHypotensionBradycardia

Opioids

MydriasisTremorHypertensionTachycardiaSweating

SSRIs

MAOIsLithium

Phenothiazines

RisperidolHaloperidol

Mydriasis

RigidityMyoclonus, hyperreflexia

TachycardiaLabile blood pressure

Rigidity, dystonia,

Muteakathisia

TachycardiaHypertension

CocaineAmphetaminesTheophylline

MydriasisTremorsHypertensionTachycardiaDry skin

AtropineAntihistamines

Organophosphates

Cholinergic

Sympathicominetic Serotonergic

ExtrapyramidalNarcotic

Anticholinergic

FIGURE 7-4 The major toxidromes. SSRI: selective serotonin reuptake inhibitor; MAOIs: mono-

amine oxidase inhibitors


TABLE 7-4 hypertension in a Comatose Patient With a normal CT

Signs Diagnosis

Hypertension PRES

Hypertension fever Cocaine-amphetamineHypertension rigidity Haloperidol (Haldol)Hypertension rigidity myoclonus SSRIHypertension miosis sweating OrganophosphatesHypertension mydriasis dry Atropine

Antihistamines

PRES: posterior reversible encephalopathy syndrome

SSRI: selective serotonin reuptake inhibitors

should also focus on identifying possible gaps. An increased anion gap (normal is 13 mEq/L) can be seen with methanol, ethanol, paraldehyde, and salicylate intoxica-tion and can be calculated from serum electrolytes. The anion gap is [Na+] − ([Cl–] + [HCO3

−]). Increase of the anion gap is mostly due to lactate from poor tissue perfusion. The presence of ketones with marked anion-gap metabolic acidosis suggests salicylate poisoning or diabetic-induced ketoacidosis. The absence of ketones in a patient with a marked anion gap indicates atypical alcohols.

An osmolar gap can be calculated, and this is important again to identify possible atypical alcohols such as methanol, ethylene glycol, and isopropyl glycol, all of which can increase the osmolar gap. The osmolar gap is calculated using the equation 2 × [Na+] + glucose/18 + BUN/2.8. Calculated osmolality should be no more than 10 mOsm/L from the measured osmolality.

Maxim 5: Electrophysiological studies such as an EEG are generally not helpful in acute coma.

EEG in the emergency department requires a least a five-minute screening recording and a 24/7 on-call clinical neurophysiologist to be able to read the recording, and many emer-gency departments are unable to provide this service. Artifacts in the emergency depart-ment due to ambient electrical noise (60-Hz artifact) may be present in at least 10% of the recordings. However, emerging EEG technology consisting of a portable device allows EEG testing on an emergent basis; the headset, which has pre-embedded electrodes, does not need to be applied by a trained EEG technician. The data are transmitted wirelessly and can be interpreted remotely.1,21,23 However, this technology requires validation.

Most studies on the value of EEG in the emergency department have been performed in patients with a prior seizure or “altered mental status” and not in unexplained coma.17 The detection rate of nonconvulsive status epilepticus was one in 50 consecutive patients


in a recent study.35 An EEG can confirm a psychogenic unresponsiveness, but this is a rare occurrence and hardly a justification for an emergent EEG. The EEG can also falsely sug-gest a “toxic-metabolic encephalopathy” when there is clearly a structural lesion. Thus, the added value of EEG after a neurologic consultation in a comatose patient with no prior seizure is very low.36 In our experience with over 100 EEGs in comatose patients, all had nonspecific findings most consistent with anoxic-ischemic injury but no seizures. Finding a nonconvulsive status epilepticus de novo is highly uncommon.

Seizures are usually not a presenting sign of drug-induced coma but there are excep-tions. Ethylene glycol ingestion is a far more common cause of seizures than ethanol intoxication. If drug ingestion is strongly considered, seizures may be a part of a symp-tom complex caused by tricyclic antidepressants, amphetamines, and salicylates. In each of these intoxications other clinical findings are evident (see vignettes for more details).

Maxim 6: Coma resolves quickly if an antidote is available, but many intoxications are best managed with supportive care.

The crucial factor in the management of these comatose patients is to predict whether sup-portive care alone will suffice, whether the toxins should be actively removed, or whether the effect of the toxin should be counteracted or at least minimized.19,30,32 Antidotes should be carefully considered but generally are discouraged because of their possible side effects, particularly when using naloxone and flumazenil. Naloxone can cause aspiration from rapid arousal and development of a major withdrawal syndrome characterized by agita-tion, diaphoresis, hypertension, cardiac dysrhythmia, and pulmonary edema. Flumazenil reverses any benzodiazepine intoxication and also has the disadvantage of arousal, vomit-ing, and aspiration. In addition, seizures may occur, particularly if the patient has concomi-tant tricyclic antidepressant intoxication. However several clinical trials using flumazenil for patients in unexplained comas showed variations in drug dose (1 to 10 mg) and also significant efficacy in reversing coma, with no adverse effects.21 Antidotes and other treat-ments are summarized in Table 7-5. Elimination of toxins can be facilitated using forced diuresis and manipulation of urinary pH. Forced diuresis and alkalinization of pH is pri-marily used in patients who have ingested salicylates or phenobarbital. The technique con-sists of increasing the urine flow rate from 3 mL/kg to 6 mL/kg per hour using isotonic fluids or diuretics. In addition, urinary pH is increased, aiming at a pH of greater than 7, which is achieved with intravenous sodium bicarbonate (1–2 mEq/kg every three hours).

Maxim 7: Any febrile comatose patient should get antimicrobial coverage.

The possibility of a CNS infection must be considered, and certainly when the patient had a rapid onset of fever, confusion, speech impediment and headaches.24,29 CT scan


TABLE 7-5 Treatment options in Coma Due to acute metabolic Derangements or Toxins

Diagnosis Usual Treatment Comments

Acute metabolic disordersHypoglycemia 50% dextrose Look for and treat precipitantHyperglycemia IV saline, insulin Look for and treat precipitantHyponatremia Hypertonic salineHypercalcemiaHyperammonemia Lactulose, dialysisRenal failure DialysisHepatic encephalopathy Lactulose, Rifaximin Look for and treat precipitantThyroid storm Anti-thyroid medications and

beta-blockers

Look for and treat precipitant

Myxedema coma Hormone replacement Look for and treat precipitantAdrenal crisis Hormone replacement and IV fluids Look for and treat precipitantPituitary apoplexy Possible surgery, hormone

replacement

Look for and treat precipitant

Wernicke’s encephalopathy IV thiamineToxins

Sedative-hypnotic agents Ethanol, barbiturates,

benzodiazepinesOpiates Naloxone Heroin, oxycodone, hydrocodoneDissociative agents Ketamine, phencyclidineMethylenedioxymethamphetamine

(MDMA)

Treat hyponatremia with fluid

restriction

Hyponatremia, likely due to SIADH

Inhalants Treat methemoglobinemia Alkyl nitrites, nitrous oxide,

hydrocarbonsToxic alcohols Fomepizole, bicarbonate Methanol, ethylene glycolHistotoxic agents causing hypoxia Hydroxocobalamin Cyanide, hydrogen sulfideCarbon monoxide Hyperbaric oxygenPsychiatric medications Bicarbonate (wide QRS on ECG) Antipsychotics, antidepressantsAntiepileptics Phenytoin, valproate,

carbamazepineSelected antihypertensives Naloxone (clonidine)

Hyperinsulinemia/euglycemiaIntralipid (beta-blockers)

Organophosphates Atropine, pralidoximeParalytic substances Tetrodotoxin, Elapid snakes,

Dermacentor ticks, botulismHypoglycemic agents Dextrose, octreotide (sulfonylureas) Sulfonylureas, insulin

Adapted from reference 8.


is also often normal in patients with acute CNS infection, and CSF examination should proceed rapidly if there is any evidence or trigger of a possible infection. The threshold for treatment should be very low. An unrecognized infection may be a major consequential error, and patients are best immediately treated with ceftriaxone (2 g IV every 12 hours), vancomycin (20 mg/kg IV every 12 hours), and ampicillin in patients older than 50 years of age. Acyclovir (10 mg/kg IV) is also added until the herpes simplex PCR results return.

Maxim 8: When the situation remains unclear, consider common explanations.

Avoid listing “fascinomas” while forgetting the essentials of the case. Review the time of onset, constitutional symptoms, neurologic signs at presentation, and social circum-stances (e.g., travel, time spent outdoors, and drug use). When neuroimaging and CSF findings are normal and coma is acute, an unidentified toxin (e.g., plant ingestion) should be considered.

Finally, although rare, psychogenic unresponsiveness may present in multiple ways and may remain difficult to recognize. The diagnosis of psychogenic unresponsiveness requires clinical expertise and demonstration of major inconsistencies (e.g., absent arm dropping when held in front of face, changing eye position with patient approaching and moving away from the examiner at each side). Patients may resist eye opening initially, and when the eyes are open they may very briefly focus and fixate on an object (Chapter 112). Some patients present with pseudo-status epilepticus followed by a prolonged unresponsive-ness. The movements are typically bizarre and eyes are open during flailing movements.

COMA IN THE ICU

Consultation in ICUs for coma happens relatively frequently and involves questions about a failure to awaken after surgery or after discontinuation of sedative drugs, acute coma in the setting of critical illness, and, most challenging, coma as one of the present-ing signs in a yet undiagnosed progressive critical illness.3,15

Maxim 1: Failure to awaken after surgery is often due to drug effects.

Much time during the evaluation should be spent evaluating recent medication adjust-ments or newly started medications. Failure to awaken after discontinuation of sedative drugs, usually a fentanyl infusion, may be related to marked associated hepatic injury that prolongs breakdown of these drugs. Failure to awaken or prolonged awakening in a medi-cal ICU often is a result of lingering polypharmacy. These patients gradually improve over time, particularly if no CT abnormalities are found.


Maxim 2: Failure to awaken after surgery may be a result of intraoperative events.

Before conducting a neurologic examination of the patient, the physician should have information on the following: Was there intraoperative cardiopulmonary resuscitation? Was there intraoperative hypotension? Is there evidence of an asymptomatic interval after surgery, or has the patient never awoken from surgery? Has there been at any time hypo-tension requiring vasopressors? Has there been marked hypoxemia for a prolonged period of time requiring complex mechanical ventilation? Has the nursing staff noticed myoclo-nus, eye deviation, or eyelid blinking or other possible evidence for seizures? Following this, the physician should proceed with a CT scan. In many medical and surgical ICUs, the CT scan is often normal unless there is overwhelming evidence of structural brain injury already noted on examination. CT scan may show scattered cerebral infarcts that do not necessarily correlate with clinical findings and is helpful only in certain conditions.

Failure to awaken after major cardiovascular surgery often indicates anoxic-ischemic injury even in the absence of a clearly identified marked hypotension or in the absence of an intraoperative cardiac arrest. Failure to awaken after organ transplantation is mostly associated with postoperative sedation initially because these severe critically ill patients are sedated, often paralyzed, and mechanically ventilated. In the absence of localizing signs, most patients will gradually improve when organ function improves. Central pon-tine myelinolysis has been described occasionally in patients who do not awaken after liver transplantation.14 Moreover, if liver transplantation has been considered for fulmi-nant hepatic failure, cerebral edema could have worsened during surgery and that may be a cause of failure to awaken.

Failure to awaken in a trauma unit after polytrauma may be due to evolving traumatic brain injury. Patients with major abdominal or orthopedic trauma may undergo surgery acutely, but failure to awaken may indicate new development of intracranial contusions or extraparenchymal hematomas. These are typically alert patients with an initial normal CT scan who acutely went to the operating room with life-threatening trauma. Such a deterioration is not always appreciated and CT scan should be repeated in all patients with evidence of traumatic brain injury.

Failure to awaken after surgery may be due to acute electrolyte imbalance in the post-operative phase, mostly because of severe hyponatremia from fluid overload. This can only be recognized if there are serial studies available.

Maxim 3: Coma after recovered sepsis in the medical ICU remains an enigma.

Failure to awaken in a patient who has been in a medical ICU from sepsis following dis-continuation of sedation remains challenging and difficult to assess, often because CT scan is normal. There has not been a satisfactory explanation for this entity. Patients


often had multiorgan failure with refractory hypotension and then fail to awaken after all parameters improve. It is a common end point in patients surviving severe refractory sep-sis and most likely a result of anoxic-ischemic brain injury watershed zones (Chapter 76).

COMA ON THE WARD

It is highly unusual for patients who have been admitted to the ward with a medical or surgical illness to suddenly deteriorate and become comatose. Acute coma is occasionally a reason for a rapid response team call. In these patients, acute metabolic derangements remain most likely. Acute hypoglycemia or acute hyperglycemia is also often a cause for immediate alarm.33 Here it is pertinent to consider the patient’s underlying condition. All causes can be considered, but some are far more common.

Maxim 1: Acute coma on the ward may represent a prior seizure.

Seizures are common in patients with advanced cancer and may be related to metasta-sis, recently administered chemotherapy, and less commonly a new CNS infection in an immunocompromised condition. The electrolyte abnormality to consider in a seizure is severe hyponatremia (<120 mmol/L) as a result of rapid lowering due to large amounts of fluids. Hypercalcemia does not cause seizures but in patients with multiple myeloma may lead to a marked decline in responsiveness often preceded by confusion.

Maxim 2: Acute coma may be due to hypoventilation.

Acute hypercarbic respiratory failure, often with Paco2 values more than 100 mm Hg, is a cause of coma and probably occurs more than recognized. Any patient treated with opioids for pain (e.g., postoperative orthopedic patients, oncology-related pain) may develop hypoventilation and significant hypercapnia. Long-acting opioids and dermal patches are notorious for producing a sudden decline in consciousness after the patient initially seems to tolerate the dose. Acute hypercapnia is not often mea-sured and requires an arterial blood gas assessment. In surgical wards, acute coma can be due to fat embolization in a patient admitted with a femur fracture. It is a rare complication in patients admitted to the surgical ward after orthopedic surgery. This complication is notorious for causing a rapid decline in level of consciousness but also new hypercapnia and hypoxemia.

Acute hypophosphatemia may occur in rapidly worsening patients with acute leukemias and may present with additional generalized weakness including neuromus-cular respiratory failure that may not seem obvious and may be attributed to the general critical illness.


Maxim 3: Acute coma may be due to a new intracranial hemorrhage.

On a surgical ward, polytrauma patients who appear to be stable and who do not require intensive care management may have a contusion that could enlarge within the first 24 hours of observation. On a medical ward, most acute complications are seen in patients with acute hematologic-oncologic disorders and may indicate an underlying of CNS localization. In others, there may be a hemorrhage into metastases. Development of a rapid paraneoplastic syndrome may occur. Breast cancer is the most frequent associated tumor, followed by lung, ovarian, head and neck and non-Hodgkin’s lymphoma. Each of these cancers can cause fairly specific and unique neurologic manifestations and in some instances can lead to rapidly developing coma.

Maxim 4: Acute coma after delivery of a healthy baby may points to a serious illness.

In this situation, most instances would indicate a catastrophic event.7 Pregnancies termi-nating with eclampsia are more commonly complicated by ischemic and hemorrhagic strokes. This may also include cerebral venous thrombosis, and this rare complication is generally seen postpartum, often with a prior unrelenting headache.

Pregnancy-specific disorders such as eclampsia, HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome can be causes for pregnancy associated coma. Cerebral hemorrhage is more common in patients developing eclampsia and in any patient with a severe coagulopathy. In this syndrome, seizures, cortical blindness, and reduced level of consciousness are the most common manifestations. There is an increased risk for intracerebral hemorrhage due to hypertension and thrombocytopenia.

Amniotic fluid embolization may occur at any time during pregnancy, from the first trimester to 48 hours postpartum. The critical condition immediately becomes apparent because of hypotension, depressed ventricular function, and profound hypoxemia.

CONCLUSIONS

This chapter reviewed the logical sequence of clinical diagnosis and treatment, from providing initial medical support to finding the cause of coma and treating it. Using a combination of neurologic findings and neuroimaging, clinicians can elucidate the cause of coma. In the vast majority of patients, coma is due to traumatic brain injury, the complications of stroke, anoxic-ischemic brain injury after resuscitation, and drug overdose. After a diagnosis is established, specific measures are taken to reverse the clinical presentation or to support a damaged brain. The emergency department is commonly the first location where comatose patients are seen. The cause may be puzzling and finding a reason for coma can be a daunting task. Anticipating certain


causes of coma in certain medical and surgical disorders can be useful in narrowing the differential diagnosis.

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229

acute medical or neurosurgical interventions are required in most comatose patients. The result of these interventions determines long-term care. Decisions to pursue long-term care are simply based on whether a good (or acceptable) outcome is anticipated, and the critical turning point is often the decision to go ahead with trache-ostomy and gastrostomy. Long-term care is multifaceted and collectively involves every organ. Care includes the treatment of neurologic and medical complications, but also the development of a rehabilitation plan with defined achievable goals. Comprehensive care often starts first in an ICU but continues in rehabilitation units or skilled nursing facili-ties. In essence, medical care of the comatose patient is two fold: supportive care of the patient and close communication with the family.

Supportive care of the comatose patient—if provided early—allows recovery from brain damage. The initial care of the comatose patient is for the most part in the hands of specialized nursing and allied health care staff. The importance of daily care is piv-otal: keeping the patient positioned well in clean sheets with clear lungs, intact skin, adequate fluid administration, and proper nutrition. All care is directed toward prevent-ing any further brain injury—more specifically, toward reducing the risk of systemic manifestations that could be detrimental (e.g., fever, hyperglycemia, hypotension, and hypoxemia). There are major long-term consequences of immobilization, and nosoco-mial infections are bound to occur.

Care also involves good communication with the family, particularly when they are in the midst of a catastrophe. This requires a sympathizing physician. Families are overcome with grief from an ordeal that undermines all their coping mechanisms, and many reach the end of their tether before long.

medical Care of the Comatose Patient

/ / / 8 / / /


SUPPORTIVE CARE OF THE COMATOSE PATIENT

In this chapter, we accept the need for continuing care. End-of-life care is common in comatose patients, usually when the anticipated recovery does not happen, mostly after a considerable period of waiting and growing certainty about a major disability. This sec-tion addresses the medical aspects of care in a comatose patient. The aim of this section is to concentrate on the major components of care, some quite complex and medically sophisticated. More specific care is discussed in the clinical vignettes of Part II of the book.

Systematic Approach to Care

After the neurologic disorder is actively treated and under control there is waiting for improvement. Systematic care involves a careful review of all the patient’s systems. This requires a full medical physical examination every day. Hospital practices have recog-nized certain themes and have organized care in so-called bundles (most notable is the ventilator bundle). Every day questions will have to be asked concerning the level and appropriateness of care. An overview is shown in Table 8-1.

Infection Control

The most common health care-related infections are pneumonia, urinary tract infec-tions (UTIs), and infections involving indwelling venous catheters. Microorganisms that can be difficult to eradicate are Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spe-cies. Clostridium difficile infections are also on the rise, particularly in patients with long hospital stays.9,14,58 Unfortunately, combination therapies—to broaden the spectrum and to double-cover gram-negative bacilli—lead to antibiotic resistance. The dilemma physicians face is that delayed initiation of antibiotics increases mortality from sepsis. Antibiotic therapy is complex and often changing as a result of infectious disease consul-tation. Some generalizations may be useful here. Aspiration pneumonia is very common and is best initially treated with levofloxacin combined with metronidazole or treated with a beta-lactam and a macrolide using seven-day treatment. Empiric treatment of health care-associated pneumonia is levofloxacin or ceftriaxone with azithromycin, but, if there is a suspicion for multidrug-resistant organisms, piperacillin-tazobactam and levo-floxacin with vancomycin are preferred. Empiric treatment of UTI is with levofloxacin or an extended-spectrum cephalosporin. If enterococci are suspected, vancomycin needs to be added; if enterobacteria are resistant, tigecycline is recommended. Any central line

medical Care of the Comatose Patient / / 231

infection requires 14 days of treatment after removal of the catheter tip with cultures. Most antibiotic regimens should be with stop dates (seven to 14 days, and often seven days is sufficient).

The incidence of antimicrobial resistance is increasing explosively. Over the past decade, many nosocomial pathogens have become resistant to several drug classes. The most impressive increase has been seen in methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci (VRE). Other increases include fluoroquinolone-resistant P. aeruginosa and third-generation cephalosporin-resistant Escherichia coli. Prolonged coma, multiple antibiotics, and older age (over 60 years) increase the risk of colonization with antibiotic-resistant microorganisms.24 Less fre-quent administration of third-generation cephalosporins and clindamycin, ceftazidime,

TABLE 8-1 Daily Concerns in Care

Lungs Mechanical ventilation settings

Weaning option

Tracheostomy care

Chest x-ray for infiltratesHeart Cardiac arrhythmias

EKG changes (i.e., QT prolongation)

Inotropes/vasopressors/beta blockadeGastrointestinal Oropharyngeal hygiene

Nutrition and choice of formula

Targets glucose/insulin drips

Motility assistanceBladder Indwelling catheter

UrinalysisSkin Decubitus

Conjunctiva/eye careProphylaxis Unfractionated heparin

Surveillance ultrasound of venous system

GI prophylaxis

Fever controlAccess Peripheral catheter

PICC

Subclavian Medication Medication reconciliation

Antibiotic stop dates

Drug-drug interaction

Sedation/analgesia needs


and ciprofloxacin has reduced the prevalence of MRSA. Overcrowding of patients and inadequate infection control are other risk factors. Antibiotic-resistant organisms are listed in Table 8-2, and isolation is mandatory. Most hospital policies are modeled after Centers for Disease Control and Prevention (CDC) recommendations. (For current information and guidelines, see www.cdc.gov) Strict isolation guidelines include sev-eral procedural changes before entering the room. This pertains to applying a gown before gloving, avoiding contamination of clean supplies, changing gloves to prevent cross-contamination of different body sites, and sanitizing hands after glove–gown removal.

Blood Glucose Control

There is a reasonable sense of agreement among intensivists that hyperglycemia and insu-lin resistance should be aggressively controlled. The NICE-SUGAR Study has shown benefit with “conventional” glycemic management. This implies treatment with insulin if the glucose concentration exceeds 180 mg/dL (10 mmol/L), with a target of 140 to 180 mg/dL (0–10 mmol/L).21 An HbA1c level of more than 6.5% defines prior diabetes and the optimal blood glucose concentration could be different than in nondiabetic patients, but in any event hyperglycemia requires control.19,31,45

TABLE 8-2 antibiotic-Resistant microorganisms Requiring Isolation

Organisms Resistance Isolation Type

Escherichia coli Ceftazidime ContactKlebsiella Ceftazidime ContactStenotrophomas Bactrim ContactOther bacilli Ceftazidime

Cefepime, imipenem

Piperacillin-tazobactam

Gentamicin

Ciprofloxacin

Levofloxacin

Gatifloxacin

Contact

Enterococci Vancomycin (MIC > 16 µg/mL) StrictStreptococcus pneumoniae Penicillin (MIC > 1 µg/mL) DropletStreptococci viridans Levofloxacin (MIC > 8 µg/mL) ContactStaphylococcus aureus* Oxacillin (MIC > 2 µg/mL) StrictCoagulase-negative staphylococci Oxacillin (MIC > 4 µg/mL) Standard precautions

* Resistant to methicillin (MRSA) and often multiply resistant.

www.cdc.gov


Both hypoglycemia and hyperglycemia may further injure an already severely injured brain. Hyperglycemia increases the lactate level and acidosis; hypoglycemia increases oxygen extraction and acidosis as measured by abnormal lactate pyruvate ratios when studied.4,74 There are, however, no consistent data proving better outcome in severely affected (comatose) patients, and concerns about hypoglycemia induced by insulin protocols persist. However, virtually all ICUs have a nurse-managed protocol in place. Hypoglycemic events are not common or serious.59

Temperature Control

Fever in comatose patients is mostly associated with an intercurrent infection and will defervesce after antibiotic treatment. Lingering infections have to be excluded before attributing fever to the brain injury (central fever).52 Control of fever is an important intervention because it may assist in management of increased intracranial pressure (ICP) or status epilepticus. Fever may also cause increased excitotoxicity, increase blood–brain barrier breakdown, and facilitate brain edema. Fever also increases oxygen consumption, carbon dioxide production, and energy expenditure.

Paroxysmal sympathetic hyperactivity (PSH) syndrome is a common cause of “unexplained” fever of comatose patients. PSH or dysautonomic storming all too fre-quently remains unrecognized and untreated.2 These spells are most common in young patients with diffuse axonal traumatic brain injury but can occur with any other brain injury. Episodes of PSH can begin acutely and continue into the rehabilitation phase.

The denomination PSH includes the three terms that describe the main features: rapid and episodic (i.e., paroxysmal) manifestations of excessive sympathetic activity. Patients become tachycardic, hypertensive (with increased pulse pressure), tachypneic, febrile, and diaphoretic (VC 8-1). They often develop markedly increased muscle tone, which may result in dystonic postures. Pupillary dilatation, piloerection, and skin flushing can also be seen.

The spells are typical for the diagnosis and should be readily apparent to the expe-rienced examiner. However, it remains prudent to consider other causes of sudden, exaggerated sympathetic response. Pulmonary embolism and early sepsis with bactere-mia should come to mind. However, pulmonary embolism is distinctly associated with hypoxia and an increased alveolar–arterial oxygen gradient, unlike PSH. Meanwhile, sep-sis does not present with hypertension, as PSH does.

There are effective therapies for this condition. Acutely, the manifestations of PSH respond best to bolus doses of morphine sulfate (2–8 mg IV). This favorable response is not related to the analgesic effect of opiates, but rather to modulation of the central


pathways responsible for the autonomic dysfunction. The response to morphine is rapid and quite reliable in aborting spells of PSH, but patients may require much larger doses than usual (up to 10–15 mg). Other effective medications for the treatment of PSH include noncardioselective beta-blockers (such as propranolol), clonidine (a central alpha 2-receptor agonist), dexmedetomidine (another central alpha-2 receptor agonist), bromocriptine (a dopamine D2-receptor agonist), baclofen (a GABAB receptor ago-nist), benzodiazepines (GABAA receptor agonist), and gabapentin (which binds GABA receptors and voltage-gated calcium channels in the dorsal horn of the spinal cord). Beta-blockers and clonidine are useful for controlling the tachycardia and hypertension. Baclofen and benzodiazepines (especially diazepam) do cause muscle relaxation but may not improve the other hypersympathetic features.

In patients with a high fever burden, cooling is most effective with directly applied pads or, if they are not available, by “sandwiching” the patient with cooling blankets and additionally using axillary ice packs or intravenous fluids at refrigerator temperatures. Quick cooling can also be achieved by infusion of 500 mL saline at refrigerator tempera-ture and through a central catheter. This infusion can be repeated every 30 minutes until a cooling device is available. Cooling devices have evolved into reliable closed systems; there is a interest in local cooling (such as pharyngeal cooling) but it has an uncertain effect.27,66,70

Shivering with hypothermia is best treated with propofol, meperidine, opioids, or clonidine. High doses of acetaminophen are rarely successful long term.10,57

Eye and Mouth Care

Inability to close eyelids completely after trauma and, in particular, nocturnal lagoph-thalmos are risk factors for conjunctivitis and corneal erosion. A prospective study in an adult ICU found one in three patients—all sedated—developed exposure keratopa-thy, and most cases could be recognized using fluorescein and a penlight with a blue fil-ter.47 Severe proptosis may also cause exposure keratitis. Mechanical ventilation reduces venous drainage from ocular tissue and may cause conjunctival edema, further compro-mising eye closure. In the ICU, eye infections are commonly due to P. aeruginosa, and a correlation with ventilator-associated P. aeruginosa infections of the lungs could exist.53 Polyethylene moisture chambers are required to prevent early epithelial breakdown, but some patients may have to be treated with lateral tarsorrhaphy.29,65 Filamentary keratopa-thy is a common dry eye syndrome in patients in prolonged coma (VC4-1). Prolonged eyelid contact with the cornea and reduced blinking impairs lacrimal fluid turnover and may be a trigger.39


Vaseline or lip balm protects the lips from dryness and cracking. Frequent mouth sponging is needed. Candida albicans is part of the gastrointestinal tract flora and a com-mon cause of infection in critically ill comatose patients. Infections with C. albicans are recognized easily by white-reddish patches and can be quickly treated with nystatin (Fig. 8-1).

Patients may develop severe bruxism (jaw clenching and teeth grinding) and may damage the tongue and teeth. Fractures of teeth may lead to periodontal abscesses. The presence of bruxism has been recognized as a poor prognostic sign, and it may occur with paroxysmal dysautonomic manifestations such as profuse sweating and tachycar-dia. Bruxism disappears with improvement of consciousness. Therapy consists of intra-oral mouth guards or placement of stainless steel crowns on molars. Botulinum toxin A (5 to 15 units) into the masseter muscles alone leads to effective management for sev-eral months.56 Some patients may develop lip and tongue swelling and even macroglos-sus, and it has been associated with the use of barbiturates and angiotensin-converting enzyme (ACE) inhibitors.

Airway and Pulmonary Care

Most patients who remain comatose will be intubated and mechanically ventilated, usu-ally with synchronized intermittent mandatory ventilation (SIMV) but often rapidly moving toward continuous positive airway pressure-pressure support (CPAP/PS) ven-tilation. Avoiding overdistention of alveoli, while efficiently recruiting alveoli, is theo-retically ideal but difficult to assess clinically. There is an incentive on the part of the physician to reduce tidal volumes (<6 mL/kg), oxygen supply (Fio2 <0.8), and positive end-expiratory pressure (PEEP) (<10 cm H2O) and see if the patient tolerates that. How to wean from the ventilator has not been well studied in patients improving in conscious-ness, and there are only general recommendations.26 Even when a protocol is in place,

FIGURE 8-1 Oral Candida albicans infection; note white patches.


compliance may be low.48 If no pulmonary infiltrates are visible on chest x-ray, secretions are minimal, oxygen requirements remain low, spontaneous breaths are generated, and the patient is hemodynamically stable, a spontaneous breathing trial of 30 to 120 minutes can be considered. This can be a T-piece trial (Fig. 8-2) or a CPAP/PS trial (using 5 to 7 cm of water). If the patient tolerates that low level of support it may indicate weaning readiness. When two hours have passed with no change in respiratory pattern and hemo-dynamic status, this trial can be followed by extubation.42

In patients who cannot be easily weaned, tracheostomy provides better pulmonary toilet and is usually considered during the second week of intubation. The benefits of tracheostomy are reduced anatomical dead space, resulting in better alveolar ventilation, better oral hygiene, and better clearing of airways. There is also evidence that, with the placement of a tracheostomy, less sedation is needed to control agitation in recovering patients.51 Percutaneous dilatory tracheostomy (PDT) is an alternative to surgical tra-cheostomy and can be performed at the bedside by a general surgeon but requires con-siderable skill. PDT is the preferred method in most ICUs. The atraumatic dilatation and small incision site may reduce postoperative infections and bleeding. There is insufficient evidence that loss of airway is more common in PDT compared to traditional surgical tracheostomy.16,35 Usually, the tracheostomy will be replaced later by a softer tube and eventually buttoned and removed (Fig. 8-3).

Coma affects lung function through several possible mechanisms (Table 8-3). A supine position changes breathing mechanics. Abdominal breathing, much more than ribcage expansion, participates in tidal volume generation. The movement of the diaphragm crani-ally with this body position reduces coughing and reduces functional residual capacity, resulting in pooling of secretions and stopping up of alveoli. Mucociliary function decreases simultaneously during immobilization, and this may cause further injury. Reduced cough-ing in comatose patients facilitates oropharyngeal colonization and commonly involves

FIGURE 8-2 T-piece trial in a comatose patient with tracheostomy.


Streptococcus pneumoniae, Haemophilus influenzae, and S. aureus. Any comatose patient is at high risk for nosocomial pneumonia (incidence estimated at 40% to 70% in traumatic brain injury),6 and the microbiology of pathogens may be affected by prior use of antibiot-ics. P. aeruginosa is less common in comatose patients who have been treated with antibi-otics.60 Nosocomial pneumonia remains the most common pulmonary complication in patients with aneurysmal subarachnoid hemorrhage and traumatic brain injury.22,68 Risk factors in comatose patients are older age, poor nutrition, chronic obstructive pulmonary disease (COPD), and nasogastric intubation.49 In most patients, a third-generation cepha-losporin with vancomycin is given to cover the possibility of S. aureus pneumonia. The reduction of oropharyngeal colonization is a major goal. A recent study documented a substantial (threefold) reduction of ventilator-associated pneumonia using nasopharynx–oropharynx rinses. These rinses include 20 mg of 10% povidone–iodine aqueous solution reconstituted in 60 mg sterile water, followed by saline solution.64

The criteria for nosocomial pneumonia are strict and best summarized in the surveil-lance data from the National Nosocomial Infection Surveillance System (Table 8-4).32 The challenge remains—and perhaps it is simply impossible—to correctly diagnose

FIGURE 8-3 Silicone talking tracheostomy for recovering patients. A “button” is used; it is

removed and followed by a simple adhesive bandage to allow closure of the opening in two to

three weeks.

TABLE 8-3 Coma and the Lung

Mechanism Result

Reduced coughing Bronchus obstructionReduced ventilatory drive AtelectasisCatecholamine surge Pulmonary edemaGastric reflux Aspiration pneumoniaTrauma Pulmonary contusion, pneumothoraxVenous clot (upper or lower extremities) Pulmonary emboli


pneumonia in its early stages. The diagnosis of nosocomial pneumonia requires the pres-ence of atelectasis and thick tracheal secretions typically seen after prolonged intubation. Endotracheal aspirate may show 105 cfu/mL, but this finding does not necessarily imply infection. Moreover, radiological features are nonspecific (Fig. 8-4). It also requires sepa-rating findings from other causes of fever (e.g., intravascular catheters). The optimal diag-nostic approach to the diagnosis of ventilator-associated pneumonia has been recently studied, comparing bronchoalveolar lavage fluid culture and endotracheal aspiration. No differences between the two methods were found, but culture of bronchoalveolar lavage more likely results in modification of the broad-spectrum regimen.23 The recom-mended antimicrobial therapy in ventilator-associated pneumonia is a third-generation cephalosporin or beta-lactam–beta-lactamase inhibitor combination. When prior anti-biotics have been used, aminoglycoside or ciprofloxacin with piperacillin–tazobactam is considered.73

Pulmonary infections and respiratory compromise from pneumonia are more com-mon in patients with COPD. Mechanical ventilation also increases the risk of mortality in patients with COPD. COPD is often associated with a history of smoking and also increases the risk of sepsis and acute respiratory distress syndrome. In these patients, there is not only a higher risk but also a higher incidence of P. aeruginosa.33,61 COPD with advanced age and severe respiratory disease before an acute neurologic injury and also cardiovascular or renal organ dysfunction all increase mortality.

Acute pulmonary edema presents with markedly impaired oxygenation. Therefore, a wide alveolar–arterial gradient (A-a gradient) is present, but it can be far more sub-tle initially and then evolve rapidly (Fig. 8-5). Neurogenic pulmonary edema has often been implicated, but pulmonary edema may be caused by marked ventricular dysfunc-tion (stress cardiomyopathy) and thus may be secondary. In subarachnoid hemorrhage, pulmonary complications are much less caused by neurogenic causes.22 Nonetheless,

TABLE 8-4 Criteria for nosocomial Pneumonia

• Rales or dullness to percussion on chest examination and any of the following:a. New onset of purulent sputum or change in character of sputumb. Isolation of pathogen from transtracheal aspirate, bronchial brushing• Chest radiograph shows new or progressive infiltrate, consolidation, or pleural effusion and any of the

following:a. New onset of purulent sputum or change in character of sputumb. Isolation of pathogen from transtracheal aspirate, bronchial brushingc. Organism isolated from blood cultured. Diagnostic single-antibody IgM titer or 4-fold increase in paired IgG serum

Data from reference 32.


FIGURE 8-4 Evolving bibasilar infiltrates from MRSA pneumonia in a comatose patient with puru-

lent thick sputum and fever. The infiltrates resolved after vancomycin treatment (bottom right).

FIGURE 8-5 Evolving neurogenic pulmonary edema on sequential chest x-rays in a patient with

cerebellar hematoma.


oxygenation abnormalities may be more common than appreciated and may represent a subtle manifestation of neurogenic pulmonary edema.75 Treatment is mechanical ventila-tion, and high levels of PEEP will recruit more alveoli and improve oxygenation. In ani-mal experiments, 20% mannitol or 5% to 7.5% hypertonic saline has reduced lung water, and this may be a novel approach to the treatment of persistent neurogenic pulmonary edema.72

In many patients treated for a prolonged period, pleural effusions, segmental infil-trates, and hilar enlargement occur. Most commonly, accumulation of fluids, as a result of aggressive fluid resuscitation and large volumes associated with drug administration, contributes. Pleural effusions are also found in patients with anasarca (low hypoalbumin-emia and soft tissue swelling of extremities). A thoracocentesis may be needed to remove these transudates.

Any acute worsening with tachypnea or tachycardia with an increased A-a gradient and reduced Pao2 and PaCo2 is suspicious for pulmonary emboli. Computed tomography angiography (CTA) of the chest is highly sensitive and specific except for distal segmen-tal areas, which can be obscured by atelectasis. Treatment usually requires high-intensity anticoagulation with intravenous heparin. In the more severely affected patients with right ventricular strain and hypotension, transient use of inotropes and possibly thrombolytics may be indicated. Retrievable filter devices may have to be placed in patients with recent spontaneous or traumatic intracranial hematomas. Pulmonary emboli may come from the upper extremities in particular when a central line is in place. Central lines need to be removed, and ultrasound follow-up is needed to monitor for clot propagation.

Cardiac Care

Acute brain injury can damage the myocardium. This insult has been named neurogenic stress cardiomyopathy. There is some evidence that the diencephalon and right insular cor-tex sympathetic neurons in the ventrolateral medulla oblongata play a role. In traumatic brain injury, direct trauma to the heart or vascular structures can also be a cause of cardiac arrhythmias or cardiac dysfunction. Cardiac abnormalities likely occur due to a sudden multifold increase in catecholamines and can result in direct myocardial damage and con-traction band necrosis. Increased systemic levels of catecholamines result in increased peripheral vascular resistance, leading to ventricular stress and tachyarrhythmia. Calcium channels open, resulting in a hypercontracted state. Potassium efflux could explain the so-called cerebral T-waves on the EKG. Catecholamine release could potentially cause coronary vasospasm. However, there are very few reported coronary angiograms in these patients with a neurocatastrophe, and none had Prinzmetal-like changes. (Moreover,


Prinzmetal’s angina rarely causes increased troponin levels.) It is unclear whether under-lying coronary artery disease predisposes to myocardial damage under these circum-stances (Fig. 8-6).40

The diagnosis of stress cardiomyopathy is based on several criteria: (1) a major acute unexpected stressful event or acute brain injury; (2) transient left ventricular wall motion abnormalities involving the apical or midventricular myocardial segments but with wall motion abnormalities extending beyond the single epicardial coronary distribution; (3) absence of obstructive coronary artery disease or angiographic evidence of acute plaque rupture that could be responsible for the observable wall motion abnormality; and (4) new EKG abnormalities such as transient ST elevation or diffuse T-wave inver-sion or troponin elevations.7 An apical ballooning syndrome often predominates, and as alluded to, may be the major cause of flash pulmonary edema.

EKG abnormalities have been associated with aneurysmal subarachnoid hemorrhage, traumatic brain injury, acute ischemic and hemorrhagic stroke, and status epilepticus but may occur in any type of acute brain injury. The EKG abnormalities are nonspecific, although certain morphological changes are more common. For example, EKG changes in subarachnoid hemorrhage are ischemic ST segments, ischemic T-waves, or prominent U-waves. In many instances, there is ST-segment sagging in leads 1 and AVL, inverted T-waves, and a prolonged QT interval. Large peaked T-waves (cerebral T-waves) are less common. These EKG changes can be associated with ventricular dysfunction and reduced ejection fraction. Inverted T-waves and QT-segment prolongation are more frequently associated with left ventricular dysfunction, but EKG changes are usually not predictive of wall motion abnormalities. The echocardiographic abnormalities are typically regional,

FIGURE 8-6 The “three” hypothesis of brain injury-induced neurogenic stress myocardium:

(1) multivessel coronary artery spasm, (2) microvascular dysfunction, and (3) catecholamine

hypothesis showing contraction band necrosis.40


do not fit coronary distribution regions, and are scattered throughout, consisting of hypo-kinetic and akinetic segments. These echocardiographic changes are potentially reversible.

Currently, cardiac troponin is a sensitive test to detect myocardial injury. Several studies have documented that cardiac troponin levels will not accurately predict left ven-tricular dysfunction, but results are conflicting.15 An independent relationship was found between elevated troponin 1 levels (defined as >1.0 µg/L) and the severity of subarach-noid hemorrhage. In this study, comatose patients had a several-fold higher percentage of troponin release than other patients, suggesting that troponin increase is a marker of severity of brain injury.72

The correlation between elevated troponin levels and outcome is also unresolved.63 In cerebral hemorrhages, elevations in troponin are frequent, occurring in 20% of the patients, but are not associated with EKG changes. No correlation was found between the location of the hemorrhage and mortality at 30 days.43 In cerebral hemorrhage, increased cardiac troponin most likely represents subclinical myocardial injury, particularly when clinical or EKG manifestations of myocardial ischemia are absent.

The major issues concerning cardiac care are summarized in Table 8-5. Management of cardiac manifestations is not different from any other causes. Management of stress cardiomyopathy may involve hemodynamic augmentation, but not pressor agents such as phenylephrine or norepinephrine to combat hypotensive effects; a better choice is ino-tropic medications such as dopamine or other inotropic agents such as milrinone. Most cardiac arrhythmias are ventricular cardiac arrhythmias. Depending on the population studied, life-threatening arrhythmias such as torsades de pointes, ventricular flutter, and ventricular fibrillation may occur. The presence of cardiac arrhythmia obviously should

TABLE 8-5 Coma and the heart

• Obtain transthoracic echocardiogram (TTE) if,• Cardiac arrhythmias• EKG abnormalities• Increased creatine kinase MB isoenzyme (CK-MB) or troponin• Increased brain natriuretic peptide (BNP)• Bilateral pulmonary edema

• Regional wall motion abnormalities and single vascular territory on TTE

• Observe cardiac enzyme pattern

• Cardiac catheterization

• Coronary angioplasty or stenting

• Cardiogenic shock

• Inotropic agents

• Intra aortic balloon pump, ECMO


prompt continued stay in an ICU for further monitoring, and emergency cardiology con-sultation is necessary.

Circulation Care

Fluid resuscitation has been discussed in Chapter 7. There is an ongoing debate on the type of fluids but crystalloids, such as lactated Ringer’s solution or colloids such as albu-min, should be avoided in traumatic brain injury.20 Continuous volume replacement is needed for long-term care.44,55 An adequate intravasc ular status is determined by satis-factory organ perfusion (urinary output, capillary refill, cold or warm extremities, serum lactate, and mixed venous oxygen saturation) and normal mean arterial pressure. Tissue edema may form over time (anasarca) and as a result of overzealous resuscitation (fail-ure to adjust fluid intake while advancing tube feeding, failure to concentrate medica-tion administration). Volume depletion is less common long term but may occur in new onset sepsis. In patients who have developed oliguria and a rise in the blood urea nitrogen (BUN)/creatine ratio (>20) dehydration is very likely; it should result in discontinua-tion of all diuretics and possible administration of large amounts of normal saline (often 5 L initially). A controversial management technique is to use albumin administration in patients in a state of anasarca. Some have used albumin daily and found significant improvement in the plasma albumin concentration and improving respiratory function due to reduction of pleural effusion.8

Gastrointestinal Care

A nasogastric tube is placed to ensure adequate nutrition, and its position requires veri-fication with abdominal x-rays (Fig. 8-7). Standard enteral formula or calorically dense formula should suffice. Prolonged comatose states warrant nutrition through gastrosto-mies. The care of the percutaneous endoscopic gastrostomy (PEG) tube is not simple and requires expertise (Table 8-6).28 Indications for PEG placement should be clear; place-ment indirectly implies that the decision has been made to proceed with long-term care. Unfortunately, one study found that 30% of patients died in the hospital after PEG place-ment, and it included examples of PEG placement in patients with terminal conditions.50 The procedure, however, is very safe and provides sufficient nutrition; a large study of 674 patients reported that reversible complications occurred in 2%.62 Complications include wound infection, peritonitis, leakage, self-extubation, and hematemesis. The risk of gas-trointestinal hemorrhage may be increased.17 Compared with a nasogastric tube, the inci-dence of regurgitation is lower in patients with a PEG17,46 (Fig. 8-8).


A bowel care regimen should be initiated.18 Bowel incontinence is present, and the task is to keep the skin clean and dry. Diarrhea may have many causes but can be attributed to certain nutritional formulas and resolved by reducing the fiber content. Antibiotics and E. coli or Clostridium difficile infections are other possible causes for diar-rhea. Failure to pass stool or marble-like stools should be treated with rectal enema or manual removal. Glycerol suppository can be helpful, but senna (10 mL) and lactulose (20 mL) are common maintenance therapies. Comatose patients are at risk of adynamic ileus (Fig. 8-9). Marked abdominal distention and auscultatory silence are early signs. Metoclopramide (10 mg IV) or erythromycin (500 mg) can be very effective to resolve the colonic distention.

TABLE 8-6 Coma and the Gastrointestinal Tract

Care of percutaneous endoscopic gastrostomy (PEG)• Infusion pump to regulate flow• Increments in flow rate limited to 25–30 mL/h/d• Discontinue PEG feeding every 4 h to assess for gastric distention• Elevate bed 30 degrees during and 1 h after tube feedingsCare of bowel function• Presence or absence of bowel sounds• Observation of the volume of nasogastric aspirate according to enteral feeding guidelines• Visual inspection and palpation of abdomen: tenderness, pain, distention• Monitor the frequency of bowel actions, quantity and nature of fecal matter

FIGURE 8-7 Portable abdominal x-ray showing normal positions of nasogastric (NG) tube (proxi-

mal and in the fundus).


FIGURE 8-8 Percutaneous endoscopic gastrostomy in situ.

FIGURE 8-9 Worsening adynamic ileus on plain abdominal x-ray.


Bladder Care

The care of the urinary tract is shown in Table 8-7. There are no good alternatives to the placement of an indwelling catheter. Diapers, pads, or condom catheters may promote colonization and skin breakdown. Suprapubic catheters may have some benefits in the short term, but there is demonstrated evidence of a higher prevalence of bladder stones and no consistent evidence of a marked decrease in UTIs, and there are practical prob-lems, with mechanical complications. Nosocomial UTIs will likely occur in comatose patients with long-term indwelling catheters. Bacteriuria involves E. coli and P. aerugi-nosa in two-thirds of all cases, with less frequent pathogens such as Enterococcus spp., Acinetobacter acinus, Klebsiella, and Proteus spp. Risk factors for bacteriuria in patients admitted to the ICU are female gender (short urethra and flora contamination), length of ICU stay, antibiotic use, and duration of catheterization, and thus are mostly unavoidable. The types of drainage system, aseptic handling, and other avoidance mea-sures have been successful in reducing infections. This includes preventing the collect-ing tube from kinking, regularly emptying the collection bag, keeping the collection bags continuously below bladder level, providing meatal care, using silver-impregnated urinary catheters, or providing vesical irrigation with neomycin/polymyxin.41

The risk of UTI remains considerable over time, particularly when bacteriuria leads to urosepsis (15% fatality rate). The clinical symptoms of UTI are a spike in tempera-ture and pyuria. Patients with impaired consciousness do not signal suprapubic ten-derness, and therefore nonspecific signs of a systemic infection such as tachycardia, tachypnea, and respiratory alkalosis, with initially relative hypothermia, may be the only manifestation of the transition to urosepsis. Shock, hypoxemia, lactic acidosis, oliguria, and marked liver function abnormalities are possible consequences of urosepsis and the development of multiorgan failure has a high (>50%) mortality.

MEDICAL COMPLICATIONS OF IMMOBILIZATION

The two major concerns associated with prolonged supine immobilization are deep venous thrombosis (DVT) and decubitus ulcers, but one of the most feared complica-tions is a pulmonary embolus. The risk of fatal pulmonary emboli in comatose patients

TABLE 8-7 Coma and the Urinary Tract

• Aseptic techniques, catheter insertion by trained nursing staff, cleansing of catheter–urethral interface• Avoid violating seals of catheter• Avoid retrograde urine flow from collection bag to bladder (during transport for tests)• Avoid irrigation with saline or antiseptic solutions• Avoid antimicrobial prophylaxis


admitted to neurologic or neurosurgical ICUs depends on several factors. Clearly, the risk of DVT after traumatic head injury and acute major orthopedic surgery in poly-trauma is much higher than in a patient with, for example, coma associated with drug intoxication. DVT is more common in patients with a hemiplegia that reduces venous flow and increases pooling due to absent muscle contractions. There is a low incidence of DVT after one month, but the incidence increases with intercurrent illness.30,37

Prevention of DVT has been summarized in the 9th ACCP conference on anti-thrombotic and thrombolytic therapy in 2012.25 The recommendations are the result of evidence-based analysis and are applicable to comatose patients. Risk factors for venous thromboembolism in comatose patients include previous thromboembolism, older age, cardiac or respiratory failure, obesity, smoking, varicose veins, and central venous catheterization. Generally, high risk for DVT has been associated with increasing age, malignancy, mechanical ventilation, neuromuscular blocking agents, recent insertion of a femoral venous catheter, and emergency surgical procedures. Percentages, although derived from patients not receiving DVT prophylaxis and with objective diagnostic test-ing, are useful to summarize here. The absolute risk of DVT in hospitalized patients is generally 10% to 20%. Major trauma or spinal cord injury places the patient at a 40% to 80% risk of calf DVT and a 10% to 20% risk of proximal DVT (with a 4% to 10% risk of clinically apparent pulmonary embolus). Fatality occurs in 5% of patients with a pulmo-nary embolus, but this figure may be underestimated.

Subcutaneous heparin remains the most protective agent and is administered at 5,000 units three times a day. In high-risk patients, the use of low-molecular-weight heparin is con-sidered. The use of low-molecular-weight heparin (enoxaparin, dalteparin, ardeparin) daily, or the use of intermittent pneumatic compression devices and graduated compression stock-ings, reduces the incidence of DVT in this category of patients. Patients with traumatic brain injury and acute spinal cord injury should receive prophylaxis with low-molecular-weight heparin or a combined use of intermittent pneumatic compression devices and low-dose unfractionated heparin (Fig. 8-10). With patients followed up for three months, a recent study on DVT in patients with acute intracerebral hemorrhage found that pneumatic com-pression devices significantly decreased the incidence of asymptomatic DVT.36

Treatment of DVT is a bolus injection of 5,000 units, followed by 1,200 units per infu-sion pump, aiming at a clotting time (aPTT) of twice the control value. Filter devices should be placed in patients with a contraindication to anticoagulation. This particularly applies to patients who are comatose from any type of cerebral hemorrhage and manifest early DVT appearance, but not necessarily to patients with diffuse axonal injury or a repaired ruptured aneurysm. Anticoagulation in patients with herpes simplex encephalitis has the potential for hemorrhagic conversion of the necrotic temporal lobe, but the actual risk is unknown.


A continuing concern in immobilized patients is the development of decubitus ulcers.69 The incidence in comatose patients is uncertain5,54 and increases in patients even-tually transferred to a long-term facility.3 Pressure effects may already occur if the stay in the ICU is more than three days (Fig. 8-11).71 Decubitus pressure ulcers are inevitable in patients in a prolonged comatose state, despite repositioning by nursing staff. When the patient is supine, the pressure is greatest on the skin covering the spinous processes of the sacrum and sacroiliac joints. The greater tuberosity of the femur may blanch the overlying skin if patients are kept in a side-lying position for a prolonged time. When hip flexion contractures occur (invariably so in this clinical state), the rotation of the pelvis

FIGURE 8-10 Subcutaneous injections with heparin (left) and intermittent compression devices

(right) to prevent deep venous thrombosis.

TABLE 8-8 Coma and the skin

Grade Description of Decubitus Ulcers

Grade I Discoloration of intact skin, including nonblanchable erythema, blue/purple, and black

discolorationGrade II Partial-thickness skin loss or damage involving the dermis or epidermis

Grade III Full-thickness skin loss involving damage or necrosis of subcutaneous tissue, but not through

the underlying fascia and not extending to underlying bone, tendon, or joint capsuleGrade IV Full-thickness skin loss with extensive destruction and tissue necrosis extending to underlying

bone, tendon, or joint capsule

Data from Theaker et al.71


additionally exposes the distal sacrum or ischial tuberosities. When body fat disappears despite attempts to improve nutritional intake, the additional areas exposed include spines of scapulae, ribs, and spinous processes of the thoracic spine. Rating the severity of decubitus ulcers has been proposed (Table 8-8).

Nutritional status is a possible risk factor for decubitus ulcers and inevitably worsens over time with reduction in albumin level and reduction in weight and body mass index. Nonetheless, insufficient monitoring of food intake, with a tendency to overestimate intake, has been noted as a risk factor for decubitus ulcers. There is very little evidence that certain support surfaces reduce pressure ulcers, but most patients will be nursed in air-fluid beds. The data on foam mattresses are inconclusive.

COMMUNICATION WITH THE FAMILY

The patient’s family needs to be informed as appropriate and should be involved with decisions to continue supportive care or to withhold resuscitative efforts and provide comfort care. There are two components of communication with the family: explanation of the comatose state and discussion of the level of care.

How can physicians best explain coma to family members? This requires the use of analogies that families can easily understand. It may help to explain that a comatose patient is in a state of deep anesthesia (as if undergoing surgery) and completely unaware.

FIGURE 8-11 Decubitus ulcers in stages I and II.


Patients who are in coma are not dreaming or in a deep sleep, nor will they remember anything when they awaken. Most patients may not even remember the entire hospital or nursing home stay except the few days before dismissal. Families observe a patient with his or her eyes closed but with responses to touch and responses during procedures. Some patients may have eyelid twitches and blinking or more generalized limb twitches or spontaneous movements. Patients may flex or extend the arms and even squeeze a hand when touched, although unaware.

Patients have automatic responses that include a breathing drive but their airway collapses easily, requiring support through a tube. A tracheostomy is needed to improve the removal of secretions and to reduce the chance of lung infections. Frowning and grimacing can be due to reflexes that need only a functioning brainstem and not the higher brain. Speech is absent but moans may reappear. Feeding is not possible, not even spoon-feeding. The gag reflex is present but it does not protect against aspiration. Feeding through a gastric tube is needed. Medical organizations consider tube feeding a medical intervention. One could argue that even spoon-feeding would be considered a medical intervention because it needs medical supervision to minimize aspiration and cannot be done by family members, if it is possible at all. Fluids have to be administered, and medi-cation is needed in some patients to minimize seizures.

Some details will have to be provided when there is reasonable certainty about the outcome. Poor outcome is usually communicated to the family as a permanent vegeta-tive state (PVS), a minimally conscious state, or a state of severe disability with some appreciation of daily happenings by the patient. Only 5% to 10% of all comatose patients enter a PVS. Patients may open their eyes after being comatose for several weeks, and sleep–wake cycles may occur. The eyes may wander. This moment could define the transi-tion to a PVS. A PVS would have to be explained as “eye-open coma.” Patients do not see, hear, feel, or sense discomfort. Those parts in the brain needed to generate normal senses are badly destroyed. Patients do not feel hunger or sense thirst. (It may be good to point out that many very sick patients do not sense hunger; in fact, it is one of the first senses to disappear.) Patients in PVS are in limbo between life and death, a shell of themselves, and their lives will be unnatural. There may be a request for fMRI in patients who fail to awaken, but demonstrating brain activation on fMRI (or none) cannot and should not influence decisions, particularly when patients are assessed early. There is a high likeli-hood that the results are ambiguous, and our current clinical experience cannot be sub-stituted by fMRI unless more solid data become available (Chapter 4).

Improvement from coma may occur in many other patients; however, the disability that follows in a patient with a minimally conscious state would have to be explained. Patients would need full nursing care, physical therapy, and feeding. They would be


doubly incontinent and would not remember even parts of the day. They would live in the moment and would have no normal emotional reactions. Some would be able to fol-low a complex command, but the normal challenges we face as human beings would be easily overwhelming. When support is continued, patients would eventually be moved to a nursing home and not to a rehabilitation center, which requires cooperation with simple programs that are too demanding to the patient. Slow-paced gains spreading out over months and even years are made, and the outcome may remain undefined in many. For a prolonged period, they would not think consecutively. However, young head injury survivors can make great strides, and a positive outlook is appropriate in these patients, who truly have the best chances. Some families will ask for a prediction, while others understand it may be very difficult to do. Good outcome prediction is far more difficult for physicians than poor outcome prediction.

When the clinical situation is dire, the discussion of important decisions on the level of care requires a formal family conference. This requires a separate, quiet room where all involved can sit down comfortably. The conference should last at least one hour to provide a comprehensive summary of the current situation. Failure to do so will leave families with only the haziest notion of the neurologic catastrophe. Time is needed to dampen the uneasiness of being confronted with the reality. If available, pamphlets on the neurologic disorder can be provided. A recent study found that providing a brochure on bereavement was helpful to family members in decreasing stress and anxiety.38 Websites on prolonged coma are currently not sufficiently informative and may even be deceptive and slanted toward consideration of seeking compensation and recovery through legal means (Chapter 9).

A family conference usually includes a representative of the clergy, nurse manager, attending physician, neurologist or neurosurgeon, and all involved family members. The skills needed to lead a family conference are substantial and part of sophisti-cated, high-quality care. In a room full of people, there may be an inclination for everyone involved to share his or her thoughts. On the medical side, it is advisable to agree upon one major communicator, most often the attending physician. The goal is full disclosure of the patient’s medical and neurologic condition, estimate of progno-sis and cognitive capacity, and the likely futility of medical or surgical interventions. The family is asked what the patient’s wishes would have been. It is important to point out to the family that the presence of an advance directive is an indication that the patient had a desire to limit medical care if permanently disabled. However, the absence of an advance directive is not an indication that the patient wanted all pos-sible medical care to be provided (the number of patients with an advance directive remains small).


The interaction between the physician and the family is important, and the outcome of these interactions is determined by clinical experience and personalities. Too often, emphasis is placed on the “difficult family,” but the physician’s demeanor plays an equally important role. Physicians who present their own professional opinion may be biased by their own personal values. For example, religion may play a considerable role in U.S. physi-cians: a majority believe in a positive effect of spirituality on health, and almost two thirds of physicians in the Midwest and South believe in the possibility of divine intervention.11

Physicians can be arbitrarily characterized. There are hopeful physicians who may always see something optimistic in bad news; they believe that other physicians give up too often. Physicians with such a hopeful disposition against all odds posit that the negative attitude of those physicians leads to negative expectations. These physi-cians are always enthusiastic and will care for the patient until all options are tried. The uncertainty of the prognosis may breed optimism, and an optimistic or hopeful attitude is much easier to discuss with the family and creates an air of confidence in the physician. A pessimistic outlook is unpleasant and potentially confrontational, and there are fewer physicians with this attitude. Optimism releases tension in the physi-cian and family interaction—pessimism builds it. Other physicians are unsure, vacil-late, and display doubt. They would be pessimistic when patients do not awaken and neuroimaging confirms the devastating damage to the brain. In other situations, they do not wish to confront the issue or want to closely explore what matters to family members. They believe in the unpredictability of recovery.

It may be presumptuous and naive to define the ideal physician. To assess these patients adequately and to understand the needs of families requires many years of expe-rience. Adroit physicians stand guarded, have searched all the evidence to make decisions and are not biased by strong personal values.

A similar spectrum of values is present in families. There are realists who understand the gravity of the situation and know that prolonged care of a comatose patient is futile. The “fighters” are usually families who may never have been confronted with such deci-sions, have never been challenged by the worst of times, and feel they can “pitch in” with the help of their close community. Some have not come across failure, and they will never accept failure. Of course, for them, to do everything is what medicine is about. This group also comprises those who are willing to “sacrifice themselves” for the patient, no matter how much care the patient will require in the long term—missing the point that they are making the decision for the patient and not for themselves—and those who will put trust in a “miraculous” recovery. Within these extremes are those who are not so sure, pro-crastinate, and have heard of unexpected recoveries and cite unrepresentative anecdotes. Putting these traits together (Fig. 8-12), one can easily imagine that certain combinations


may lead to resolution and a decision, while other combinations would lead to failure to address the pertinent questions, postponement of decisions, and sometimes even involvement of the courts.76,77

Withdrawal of care in a hopelessly injured comatose patient may lead to a conflict when family members disagree and when attending physicians do not wish to pro-ceed. Families may still express doubt and ignore reality, which may eventually shift to anger, distrust, and denial. In these instances, it is important to ask the family what their worst-case—unacceptable—outcome would be. For some families, it will be death from complications after maximal uninterrupted prolonged treatment and prolonged resus-citation, and even brain death may not be defining. Medical intervention in the dying process is seen by them as an obligation. There is no solution to this intransigence, and much of it may be due to strong values.

Recent studies (audiotaping of family conferences) have provided a glimpse into these proceedings, with interesting results. Missed opportunities to explore families’ wishes and to explain key tenets of palliative care, emphasizing that the patient will not be abandoned, occurred in about one third of the taped conferences. More troubling were the results of another ICU study in which 16% of patients who were admitted to a medi-cal ICU had no decision-making capacity, nor was a surrogate decision maker available, and decisions to limit support were made by physicians.1,12,13,67

CLINICAL PRACTICE OF WITHDRAWAL OF SUPPORT

It is the physician’s moral obligation to offer neuropalliative care, and when the deci-sion is made, it is best to follow a strict protocol. The withdrawal of care in mechanically

Realists Procrastinators Fighters

AdroitUnsureHopefuldespite odds

Physician

Family

FIGURE 8-12 Family–physician interactions can be determined by personal values, clinical expe-

rience, and personalities.


ventilated patients with other pharmaceutical critical support is different from with-drawal in patients in prolonged states of unconsciousness in a hospice. Withdrawal of support includes withdrawal of not only the endotracheal tube but also intravenous or intra-arterial access. Extubation—except in patients fulfilling the criteria of brain death—will not lead to apnea in patients but gasping or irregular breathing with signs of upper airway obstruction. Breathing can become noisy due to accumulating bronchial or naso-pharyngeal secretions. The change from the quiet mechanical sound of the ventilator to loud breathing of the patient is hard to fathom for some families.34 This type of breathing is easily treated with scopolamine, 400 µg subcutaneously, but a change in head position and frequent suctioning may also be effective. Most compassionate palliation is provided with opioids. In many instances, nebulized morphine 2.5 mL (1 mg/mL) is sufficient to provide rest and tranquility. Morphine can also be given intravenously, with a starting dose of 10 mg every four hours.

Cardiac and respiratory arrests follow within one to two weeks, but often on the same day in comatose patients with acute brain injury. If recurrent seizures have occurred during the clinical course, it is good palliation to continue antiepileptic drugs. Withdrawal of nutrition and hydration results in death from dehydration, but there is no evidence that patients sense thirst. The patient’s eyes will close and sleep–wake cycles will disappear. Within some days, the patient becomes oliguric, and metabolic acidosis occurs. This may lead to compensatory hyperventilation, but it is seldom inter-preted by family members as more labored. In the following days, poorly circulated hands and feet will become cold to the touch. The pulse becomes weaker and barely palpable. Drying of mucous membranes can be minimized with mouth swabs and eye drops. Facial features may change due to less subcutaneous fluid, and the patient may become more recognizable—an additional distress to some family members. The patient’s discomfort put forward by those against withdrawal of support has included an alleged bleeding of mucosa, parched lips, and burning of the bladder due to concen-trated urine, and difficult breathing due to tracheal secretions is not observed. Death in these patients is dignified and humane.78

Withdrawal of support is ordered in patients declared brain dead who are not can-didates for organ donation. There is no legal requirement to ask the next of kin for per-mission to withdraw support, but there may be objections (Chapter 5). The mechanical ventilation is disconnected, and the endotracheal tube can be left in place. The moni-tor can be turned away. Connections with infusions are released. The oxygen saturation declines within minutes to immeasurable values, and the blood pressure may stabilize at 20 to 30 mm Hg systolic. With the decline of oxygenation, cyanosis may occur and brief (very slow) body movements may occur. This may be a shoulder shrug, head turning, or


arm or leg movement. (This can be noticed by the family holding hands or heard when the leg rubs against the linen.) Partial eye opening may occur, and the jaw becomes slack. The heart rate accelerates and then becomes bradycardic, with agonal deflection followed by sudden arrest. The patient’s color gradually changes from pink to blue-gray. This might be a very stressful experience, and families may decide to say their last goodbyes before withdrawal of support.

CONCLUSIONS

Most of the medical care of the comatose patient is difficult and requires intensive care expertise (Fig. 8-13). Care of the comatose patient is cause-specific, but after a certain period has passed, supportive care and avoidance of infections and complications associ-ated with immobilization become the main part of daily management. The complexity of care requires a significant amount of commitment and compassion. Multiple organ systems require attention, and they must be reviewed carefully every day. Early commu-nication with the family is needed to establish rapport and to gain knowledge about the patient’s prior wishes. After patients are transferred to the ward, some may qualify for a rehabilitation program. A substantial proportion of patients in prolonged coma require care in a specialized nursing facility. End-of-life care is an important part of decisions in comatose patients.78

FIGURE 8-13 ICU care of the comatose patient.


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75. Vespa PM, Bleck TP. Neurogenic pulmonary edema and other mechanisms of impaired oxygenation after aneurysmal subarachnoid hemorrhage. Neurocrit Care 2004;1:157–170.

76. White DB, Braddock CH, 3rd, Bereknyei S, Curtis JR. Toward shared decision making at the end of life in intensive care units: opportunities for improvement. Arch Intern Med 2007;167:461–467.

77. Wijdicks EFM, Rabinstein AA. The family conference: end-of-life guidelines at work for comatose patients. Neurology 2007;68:1092–1094.

78. Zib M, Saul P. A pilot audit of the process of end-of-life decision-making in the intensive care unit. Crit Care Resusc 2007;9:213–218.

260

INTRODUCTION

Emerging from coma allows rehabilitation for most patients. When the duration of coma has been short, recovery may be quick and complete and there may be little need for reha-bilitation. As one might expect, late recovery (after weeks or months) portends a prob-lematic outcome, but that may not be a completely correct statement because outcome is closely related to the cause of coma.29,54 For example, recovery from refractory status epi-lepticus may be different than recovery from traumatic brain injury or anoxic-ischemic encephalopathy.63 Recovery from coma is mostly gradual and slow, with eye opening and attempt at fixation, head turning to voice, and more brisk purposeful movements. In some patients family members may notice hand squeezing and finger wiggles to their request, and such a response may be followed by more improvement in the following days. Awakening may be far more rapid if sedative drugs (e.g., when used to facilitate mechanical ventilation) are stopped, and this has surprised an occasional physician and certainly families. Neurologists cannot accurately predict the time course of awaken-ing simply because there are too many variables during the first weeks of care and also because the course followed is capricious at best.

This chapter provides some insights into rehabilitation options. There are excellent rehabilitation programs in specialized rehabilitation centers throughout the world. Inpatient rehabilitation is of great benefit for many patients after severe acute brain injury who make good strides, but there is also a lack of programs for patients who are very slow to recover. The decision to admit a patient to a hospital-based reha-bilitation center is predicated on an assumed probability of continuing improvement, but the patient must be able to participate in several daily therapy sessions. A study in traumatic brain injury found approximately one third of patients emerged from

Recovery and Rehabilitation/ / / 9 / / /

Recovery and Rehabilitation / / 261

minimally conscious state, but only one of six patients reached partial functional inde-pendence three months after the injury.30 Another study found functional gains already in 6 weeks after the injury.23

Rehabilitation physicians know too well that many patients may need assistance at home, may not go back to work, or will return to jobs with much less responsibility. It is often assumed that many patients reach their maximal achievable level at 12 months, but this remains a moving target. Rehabilitation of the comatose patient involves multiple disciplines and requires patience and a clear outline of expecta-tions.22,56 We, as health care providers, can all agree that some instances of catastrophic brain injury tax all resources and composure. Families have to prepare themselves for a long-lasting experience and a lingering painful uncertainty—and that is a problem a rehabilitation physician wrestles with.

There are stimulation therapies with unjust claims of efficacy. The frustration of seeing a patient “lying there” often fosters a strong urge to “do something,” even if spe-cific therapy is not available. The most difficult situation arises when families seek out therapies with spectacular claims, high costs, or tremendous time commitment. Some health care workers would dismiss these “therapies” simply as quackery; others would encourage families to go out and try. Many physicians should be honest and highly skeptical; moreover, health insurers are not covering these treatments thus leaving des-perate families with high costs of treatment. Nonetheless, each of these approaches needs detailed discussion in this chapter.

Rehabilitation of comatose patients requires pharmaceutical trials, physical and occupational therapy, and speech therapy. Equally important roles are played by rehabilitation nursing, neuropsychology and social services. In this chapter the fun-damental principles are outlined, starting in the ICU with physiotherapy and assess-ment for rehabilitation. This chapter provides an overview of the possibilities, but a comprehensive discussion of neurorehabilitation programs is outside the scope of this book.

EARLY INTERVENTIONS

Rehabilitation physicians should make a careful assessment early in the clinical course to establish a plan of care. Close medical support, which includes aggressive surveil-lance measures (as outlined in Chapter 8), continues. The initial neurorehabilitation options may be truncated to physiotherapy and pharmacological improvement of responsiveness. Disposition requires early review by social services in order to appoint a case manager.

262 / / The ComaTose PaTienT

Physiotherapy

Initial care provided involves physiotherapy, and this should start in any comatose patient as soon as feasible. Three weeks’ duration of coma is sufficient to develop the early sign of contractures, but patients in a persistent vegetative state (PVS) will eventually develop lower limb contractures. Muscle shortening and loss of tissue elasticity begins in days and passive range of motion may be useful initially if not physiologically disruptive. It has been noted that frequent motions in the upper limbs may prevent flexion contractures, but the spastic hyper-reflexic state in the legs is profound and invariably leads to ankle contractures. No physical therapy program has been able to prevent major contractures in patients with PVS. Patients will eventually develop flexion contractures in the elbows, wrists, and fingers, with legs rigid and feet positioned in equinovarus (as in a classic ballet stance). Nonetheless, when coma is of short duration, early stretch exercises may maintain range of motion. The factors that play an important role are loss of sarcomeres, impaired cross-bridging of myosin and actin, connective tissue accumulation in muscle, reduction of hyaluronic acid in synovial fluid,65 and atrophy of cartilage. Splints, passive stretching, electrical stimulation, and botulinum toxin, alone or in combination, all have limited efficacy. Gentle, passive range of motion and stretching are the most commonly used techniques (Fig. 9-1).

Pharmaceutical Interventions

There has been considerable interest in pharmaceutical intervention in patients who stagnate in recovery from coma. Patients may remain in a minimally conscious state or slightly better with some hours of relative lucidity. Under these circumstances consciousness-enhancing drugs have been considered, often early in the recovery phase. Until recently, in none of the reported studies was it possible to accurately judge the alleged improvement (e.g., increased verbalizations, pointing to objects, more consis-tency in following commands) or to distinguish it from spontaneous improvement.

One study suggested the use of bromocriptine specifically for patients with marked abulia who were recovering from traumatic brain injury.70 Bromocriptine may also be effective in patients with akinetic mutism. There have been occasional reports of some improvement with dopamine agonists in patients with akinetic mutism.13,46,51,55 Patients with cingulate lesions may have damaged but still functional dopaminergic tracts and could respond to amantadine or other drugs. Responses are more often seen after traumatic axonal brain injury and are much less common (if they occur at all) after anoxic-ischemic brain injury from cardiopulmonary resuscitation. In addition, amanta-dine has been reserved for posttraumatic amnesia with agitation.


(A)

(B)

(C)

FIGURE 9-1 Physical therapy stretch maneuvers: before and after photographs of upper and

lower limbs stretching. (A) Scapula mobilization. (B) Stretching of the upper extremity. Range of

motion of knee (C).


Amantadine was initially studied in a crossover study with 35 patients; the results showed that patients improved functionally more rapidly,43 but the rate of change in the first six weeks was not significant. More recently, a major international randomized trial in patients with posttraumatic disorders of consciousness found that four weeks of treatment with amantadine (100 mg twice daily for 14 days increasing to 150 mg b.i.d.

(D)

(E)

FIGURE 9-1 Continued. Hip (D) and heel cord stretching (E)


on week 3 and 200 mg b.i.d. on week 4) significantly improved functional outcome, as noted by improved communication and responses to commands.23 The trial also noted worsening with discontinuation of the drug. Table 9-1 summarizes the dopaminergic agents.

There is considerable interest in lamotrigine as a stimulant, but studies are incom-plete, although they claim a better-than-expected recovery.61 Several reports have shown improved speech or motor performance with zolpidem.7,11 However, it seems more spe-cifically effective in patients with aphasia and catatonic symptomatology than in patients with more diffuse brain injury. Sudden improvement in speech and responsiveness has been reported even after years of major disability.7,11,64

Another relevant question is whether antiepileptic drugs could hamper recovery (estimated use in 25% to 50% of patients). One retrospective study found no difference in recovery pace.4

The current practice is not entirely known, but many rehabilitation physicians will administer dopaminergic or antidepressant drugs alone or in combination—mostly amantadine, and perhaps zolpidem or lamotrigine. SSRIs have not been adequately stud-ied for effect, but there has been experience with tricyclic antidepressants. Amitriptyline (50 mg daily) or desipramine (75 mg) demonstrated improvements in verbalization (defined as more consistent use of two-word phrases) and following commands that

TABLE 9-1 Dopaminergic agents

Drug MechanismDose Range (mg/d) Comments

Levodopa/carbidopa

(Sinemet, others)

Directly converted to dopamine

(via dopa decarboxylase)

250–2,000 Initiate at 25/100 mg t.i.d.; increase

gradually to 25/250 mg tablets,

maximum of 2 q.i.d.Amantadine (Symmetrel,

others)

Stimulates presynaptic release

of dopamine; possible direct

agonist effect

100–400 Initiate at 50 mg q.d. or b.i.d.;

increase by 100 mg per week to

200 mg b.i.d.Bromocriptine

(Parlodel)

Direct agonist at receptor site 7.5–100 Initiate at 2.5 mg t.i.d.; increase

weekly to 5 mg t.i.d.; then 10 mg

t.i.d.; then by 15 mg/wkPergolide (Permax) Direct agonist at receptor site 1–4 Initiate at 0.05 mg q.d. or b.i.d.;

increase by 0.1–0.25 mg every 3 d;

usually given t.i.d.Selegiline (Eldepryl) MAO type B inhibitor 5–10 Initiate at 5 mg in the morning; can

increase to 5 mg b.i.d. (midday)

Data from Wroblewski and Glenn.70


were not present before initiation of the medication—the improvements disappeared after discontinuation of therapy.52

There is currently no standard of care for pharmacological treatment of disorders of consciousness; all use is empiric and off label, with no evidence to support any specific intervention.

Stimulation Programs

The Multisociety Task Force on PVS in 1994 concluded, “There are no verified controlled studies reported in peer-reviewed journals.”1 However, studies have claimed shortening of coma duration39 or improved cognitive scores.28 Part of the premise is the unproven assumption that “sensory deprivation” occurs in ICUs.

Sensory stimulation has been used as an adjuvant to neurorehabilitation. This may involve stimulation of all senses (multimodal) or one sense (unimodal) or electrical stimu-lation (median nerve). Stimulation may involve music therapy.40 How (and if) comatose patients respond to stimuli depends on level of consciousness, prior evidence of opposi-tional behavior, and familiarity with the response. One recent study found that augmenta-tion of the stimulus with familiar objects (which could incite emotions before the injury) increased the response rate.20 Sensory stimulation programs may be very time-consuming. One “coma arousal” program required “treatment” involving vigorous multisensory stimu-lation for up to eight hours a day, seven days a week until improvement at a rehabilitation facility.49 The familiar auditory sensory training study48 uses recorded stories (mix of sad and happy) for 40 minutes daily for six weeks. The underlying rationale of sensory stimu-lation is the assumption of further neuronal degradation (or lack of improvement) when neurons are not involved in tasks. It is also supported by experimental data that motor cortex of rats improves after skill training tasks (“use it or lose it” principle).48

All reported studies were case series or nonrandomized clinical trials, with one small randomized study lacking adequate methodology and endpoints, and all but two studies claimed increased rapidity of awakening, improved wakefulness, and decreased length of stay. The number of patients tested ranged from six to 31 patients. Efficacy, therefore, is unproven.42 A recent Cochrane evaluation of sensory stimulation programs found no evidence of benefit. There was also lack of blinded assessment, in addition to other insuf-ficiencies in study designs.37

Most recently, stable comatose patients were subjected to an intensive program of auditory stimuli. It consisted of music, taped familiar voices, bell blocks and claps, radio, or television. The effect was measured using complicated scales or combined eye and motor responses. Safety was monitored by simultaneous recording of the effect on blood pressure and intracranial pressure. This therapy was ineffective.18


In addition, multimodal stimulation therapy has been tried. This includes subject-ing patients to not only sound but also favorite perfume, favorite food taste, favorite clothes, toys, or pictures showing the patient’s hobbies. Signs of improved arousal in this study were based on soft endpoints such as more time spent with eyes open and the presence of spontaneous movement. Significant differences in responses were found between multimodal and unimodal stimulation, but this unconvincing study lacked proper neurologic assessment and none of the patients showed unexpected vitality.67

Music therapy using patients’ preferences has been studied in one series of 13 patients and, oddly, was even combined with vertical motions on a trampoline timed to the music’s beat. Treatment effect was seen in responsiveness of the patients in PVS. Many neuroscience care units play patients’ favorite music, but effectiveness is not proven, and many patients do not remember their stay.26

In summary, these sensory stimulation programs, based on the premise of provid-ing “sensory input to the damaged reticular activating system promoting reorganiza-tion of undamaged neurons or regeneration,” not only are of unproven benefit but also fail to provide a credible biological insight into the mechanism of recovery using these interventions.18,67

Other Adjunctive Therapies

Electrical stimulation has also has included median nerve stimulation or vagal nerve stim-ulation. These studies, if used daily up to 12 hours, increase median nerve stimulation up to 1.5 times the motor threshold (as high as 20 milliamps). This intervention is based on the presumption of activation of ascending reticular formation and cortex through peripheral electrical means. Results were inconclusive42 or statistically insignificant despite reporting more rapid awakening from coma.14 One study documented improved cerebral perfusion and increased dopamine levels but found no definitive correlation with improved consciousness.35 One patient in a minimally conscious state reportedly improved in terms of social functioning and reduced impulsivity after low-frequency (1 Hz) transcranial magnetic stimulation.47

The most recent study of corticomotor facilitation in PVS in six patients included transcranial magnetic stimulation combined with visual facilitation, asking the patient to open and close the hand or imitate the action. No improvement was seen with tran-scranial magnetic stimulation alone. The concept is that this visual stimulation with transcranial magnetic stimulation increases excitability and synergy in interconnected cortical-subcortical networks. Marked improvement in CRS-R scores (recovery scale revised score) was claimed.50


Transcranial direct current stimulation (low-level current to alter neuronal firing) has been used in patients with marked memory difficulties and for patients with impulsive behavior, but there are few hard data on efficacy. Similar claims have been made using low-level laser therapy and transcranial Doppler sonography, but usually support for these modalities comes from uncontrolled experiments. A recent study using 20 minutes of transcranial direct current stimulation found transient improvement of consciousness in minimally conscious state. The heterogeneous sample and unclear meaningful change weakens the study results.64

In another attempt to increase output from the thalamic nuclei, deep brain electrodes have been implanted. These patients in PVS, all after traumatic head injury, received the implantation within three months. Two series have been reported, and in one study, eight of 21 patients showed improved awareness.71 In another series, 13 of 25 cases “improved to some degree of consciousness.”10 However, proof of effect in both trauma series could not be distinguished from spontaneous recovery. Its effect in patients with a prolonged minimally conscious state remains unclear (Chapter 4).

Electrodes have also been implanted in the cervical spinal cord to improve PVS.27,36 The studies noted improvement in self-feeding and interaction with the family. In 40% of these patients regional blood flow improved and cerebral atrophy was absent in later imaging studies but mostly in patients under the age of 30. This method remains implau-sible and has not resulted in any further interest.

Acupuncture has been used in a variety of patients with acute brain injury and as a rehabilitation modality in comatose or minimally conscious patients. Usually this consists of intensive scalp, abdominal, and foot acupuncture. The basis for this treatment is Qi, rep-resenting a flow of vital energy that runs through channels called meridians. Acupuncture can regulate the flow of Qi by stimulating acupoints via pressure, needle, laser or electrical stimulation. Four randomized controlled trials and several case series reported improved outcome and more rapid awakening in over 350 cases; however, a Cochrane analysis found low methodological quality and therefore inconclusiveness.8,25,59,69

The use of alternative (non-Western traditional) medicine may come in sight early (when families demand supplemental rituals) or late (when families seek last-resort measures). Early use of religious or cultural prayers is common and easily accepted into the day-to-day care. Rarely a family demands the use of a traditional healer or substance—these requests should not be granted (an interesting discussion about this dilemma has been recently published3).

Hyperbaric oxygen therapy is based on the simple premise that this adjunctive treat-ment—100% oxygen pressurized higher than 1.0 atmospheric absolute (ATA)—improves oxygen availability, improves mitochondrial function, increases ATP production, and reduces hippocampal cell loss.17 A recent small prospective randomized phase II clinical trial


in 20 patients with traumatic brain injury documented improved outcome by the Glasgow Outcome Scale and improved physiology by microdialysis and brain tissue oxygen.53 The study protocol also added normobaric hyperoxia (100% FiO2 for one hour at 1.5 ATA fol-lowed by three hours of 100% at 1.0 ATA). Comatose patients received three treatments in the compression chamber or until they worsened or improved to follow commands. Whether hyperbaric oxygen improves re-emergence from coma is not known. The toxicity of hyper-baric oxygen treatment is generally very low but it does increase seizure probability.2 Marked tension pneumoencephalus requiring immediate cerebrospinal fluid diversion has been reported in several cases.33,44 (Prior craniotomy or prior infection with gas-forming anaero-bic organisms may be factors.) Two other studies found improved Glasgow Outcome Scale scores, better control of epilepsy, and resolution of hydrocephalus,34,60 but a larger Cochrane review in patients treated months after initial accident found insufficient evidence.6

Finally, DeFina and colleagues described 41 patients treated with a so-called “advanced care protocol” and claimed that up to 86% of patients with PVS and 100% of patients with minimally conscious state emerged from coma following this protocol. The protocol con-sisted of several phases totaling eight weeks to several months (on average three months of treatment). Phase 1 included pharmaceutical treatment that included naltrexone, car-bidopa–levodopa, bromocriptine, rivastigmine, donepezil, modafinil, desipramine, ven-lafaxine, zolpidem, amantadine, methylphenidate, dextroamphetamine, and rasagiline. These drugs were used to “potentiate neurotransmitter functions.” Phase 2 consisted of median nerve stimulation administered at the right arm for eight hours per day, seven days per week. The concept was to assist in perfusing oxygen to the brain and increasing blood–brain barrier permeability, enhancing the ability of prior medication and increas-ing the dopamine level. After five weeks, the third phase was implemented, which added nutrition, including vitamins, antioxidants, and immunonutrition. The researchers argue that the combination of these three phases could help improve awakening.19

In conclusion, there are many coma stimulation and adjunctive therapeutic approaches, but there are no data that can withstand scrutiny.

NEUROREHABILITATION

Rehabilitation centers operate on an intensive schedule, and thus criteria for inclusion have been developed. Most generally, patients are not eligible if (1) there are continuous medical concerns that may lead to an unstable situation; (2) the patient is unlikely to improve or make progress in daily therapy sessions; and (3) there is no support system after returning home. Center for Medicare and Medicaid Services (CMS) criteria are most often applied, as they determine reimbursement. In addition to the patient having


brain-related limiting neurologic impairment, CMS requires multidisciplinary therapies (at least three) and the ability to participate in and benefit from an intensive intervention (i.e., about three hours of daily therapy). CMS requires that (1) the patient has active medical problems that require physician attendance; (2) the patient has needs specific to specialized rehabilitation nursing (dysphagia, new bladder/bowel disorders, etc.); and (3) this care cannot be provided in a less intense medical environment (nursing home). The major pillars of neurorehabilitation are shown in Figure 9-2. Neurorehabilitation can only function well with a large staff that includes physiatrists, neuropsychologists, speech therapists, occupational and recreational therapists, rehabilitation nurse special-ists, social workers, and vocational case counselors. This multidisciplinary team should be carefully orchestrated, and this often requires a case manager to coordinate care. Programs usually involve activities for several hours a day, five days a week. Functional independence is best achieved if patients can enter these programs within the first six months of acute brain injury.45,66 A recent evidence-based review found substantial evi-dence for remedial interventions involving attention, memory, social communication skills, and executive function.9

Metrics in Neurorehabilitation

Rating of improvement in patients with disorders of consciousness is needed not only to better measure range of behaviors but also to assist in research on prognosis in patients with severe brain injury. It has been known that probabilistic models improve accuracy

Cognition Mobility

Mood

RehabilitationBrain Injury

Senses

MemoryConcentration

Judgment

StrengthCoordination

Gait

FluctuationImpulsivity

Apathy

VisionHearing

Special Concentration

FIGURE 9-2 Four major pillars of brain injury rehabilitation.


when compared to clinical prediction, but there continues to be uncertainty about the most meaningful and interpretable score.57,58,62 Current scales that are used in prac-tice and research studies are the Disability Rating Scale, Glasgow Outcome Scale (and the Cerebral Performance Scale), Glasgow Outcome Extended Scale, Neurobehavior Rating Scale-Revised, and, more recently, Neurologic Outcome Scale for Traumatic

TABLE 9-2 Functional independence measure (Fim™) instrument

Score Self-Care

Self-Care 1–7A. EatingB. GroomingC. BathingD. Dressing—upper bodyE. Dressing—lower bodyF. ToiletingSphincter control 1–7G. Bladder managementH. Bowel managementTransfers 1–7I. Bed, chair, wheelchairJ. ToiletK. Tub, showerLocomotion 1-7L. Walk/wheelchairM. StairsMotor Subtotal ScoreCommunication 1–7N. ComprehensionO. ExpressionSocial cognition 1–7P. Social interactionQ. Problem solvingR. MemoryCognitive Subtotal ScoreTotal FIM Score 18–126

Scores range from 1–7 (1 = worst, 7 = best) Grade: 7—Complete

Independence (Timely, Safely), 6—Modified Independence

(Device), 5—Supervision (Subject = 100%+), 4—Minimal Assist

(Subject = 75%+), 3—Moderate Assist (Subject = 50%+), 2—

Maximal Assist (Subject = 25%+), 1—Total Assist (Subject = less

than 25%). As a rough estimate, patients with FIM scores less than

40 are most commonly discharged to a skilled nursing facility.


Brain Injury.41 Outcome measures in rehabilitation most commonly are considered in relation to the ICF (International Classification of Functioning, Disability and Health) realms of impairment (how the examination is different from normal), activity limita-tions (so-called ADL and IADL), and restrictions to participation (e.g., personal, fam-ily, vocational, community roles). The NIH toolbox, PROMIS measures, AM-PAC, and TBI-QOL are examples of current measures.

Multiple functional scales have been developed, and these scales can measure per-formance at different levels of improvement (e.g., SMART).24 A validated scale is in the JFK coma recovery scale.21 This scale is skewed toward motor responses. A commonly used scale is the Functional Independence Measure (FIM; Table 9-2). This validated and adequate scale evaluates abilities in self-care but also mobility, sphincter control, and social cognition, among others. The clinical training of the rater is less important; even family members can rate the performance ability of the patient. It assesses the burden of care or amount of assistance to the patient and is a straightforward measure of activity limitations.12,15

Although the FIM is most widely used, the Disability Rating Scale has been used in research studies and comprises eight items (Table 9-3). The total scores vary from 0 to 30 (vegetative state at 22 or more and 30 death). The first three items are the Glasgow Coma Scale score (lowest number is here 0 rather than 1), and the other scores are for self-care activities and level of functioning (physically, mentally, emotionally, and socially). The interrater reliability is good, as is the comparison of ratings by family members and reha-bilitation professionals.5

Technology and New Options

New intervention options include microswitch techniques in which a touch-sensitive microswitch is fixed to the patient’s index finger, followed by visual stimulation. This technology could possibly assist patients in a minimally conscious state and facilitate communication.31

There is much interest in the use of computer-assisted technology.32 The current devel-opment of brain–computer interface training modules could allow patients with a mini-mally conscious state to become proficient in task learning.16,68 Even scalp electrodes may be able to pick up event-related potentials in EEG that would enable the patient to control a cursor or other movement. The brain–computer interface may have its best application in alert patients with devastating stroke or amyotrophic lateral sclerosis, but whether the limited attention span in minimally conscious patients is enough to enable communica-tion remains to be demonstrated. An early indication is that some sort of communication

TABLE 9-3 Disability Rating scale

Disability Rating Scale ratings to be completed within 72 hours after. Admission and within 72 hours before.

Discharge.A. EYE OPENING• (0) Spontaneous• (1) To Speech• (2) To Pain• (3) NoneB. COMMUNICATION ABILITY• (0) Oriented• (1) Confused• (2) Inappropriate• (3) Incomprehensible• (4) NoneC. MOTOR RESPONSE• (0) Obeying• (1) Localizing• (2) Withdrawing• (3) Flexing• (4) Extending• (5) NoneD. FEEDING (COGNITIVE ABILITY ONLY)• (0) Complete• (1) Partial• (2) Minimal• (3) NoneE. TOILETING (COGNITIVE ABILITY ONLY)• (0) Complete• (1) Partial• (2) Minimal• (3) NoneF. GROOMING (COGNITIVE ABILITY ONLY)• (0) Complete• (1) Partial• (2) Minimal• (3) NoneG. LEVEL OF FUNCTIONING (PHYSICAL, MENTAL, EMOTIONAL, OR SOCIAL FUNCTION)• (0) Completely Independent• (1) Independent in special environment• (2) Mildly Dependent-Limited assistance (non-resid—helper)• (3) Moderately Dependent-moderate assist (person in home)• (4) Markedly Dependent-assist all major activities, all times• (5) Totally Dependent-24-hour nursing careH. “EMPLOYABILITY” (AS A FULL-TIME WORKER, HOMEMAKER, OR STUDENT)• (0) Not Restricted• (1) Selected jobs, competitive• (2) Sheltered workshop, Non-competitive• (3) Not Employable


could be established in one patient with no clinical evidence of following a command but not in four others.38 The study also identified the challenges with EEG recording quality due to artifacts caused by respiration and ocular movements.

CONCLUSIONS

Most patients recover from coma, most are disabled and in need of rehabilitation, and most make some improvement. Rehabilitation is a complex multidisciplinary process with many variables, making testing of its efficacy difficult. Rehabilitation in the form of comprehensive team-based evaluation and intervention starts in the unit on day one. Improvements might be expected from new technology, but in patients with a severely damaged brain, functional improvement as a result of a brain–computer interface will be very challenging, and not likely to succeed. Unfortunately many “stimulation” therapies are unproven; many other therapeutic options have no proof of benefit but can cause families to go bankrupt as a result of their costs. Pharmaceutical options to enhance arousal may be the best option in many patients, but again—with most of drugs—evi-dence of efficacy is lacking.

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278

inevitably, physicians and families have to make decisions about the long-term care of patients in a prolonged comatose state. These decisions are made after multiple revisits to the state of the patient’s neurologic condition, by consensus, and in line with the patient’s values and prior expressed wishes. Contacts with families are nearly always pleasant and respectful, and such a relationship leads to a decision by con-sensus. Even in situations of disputes on the futility of care a carefully executed conference will be reconciliatory in the overwhelming proportion of cases. However, the family or family–physician relationship may become adversarial, and the course of action may even have to be decided in court. Some of these instances have become landmark medical cases.

These legal juggernauts are interesting for several reasons, and there are recogniz-able patterns. First, a conflict could arise when family members do not want to con-tinue care, yet physicians do not wish to proceed with withdrawal of care, mostly for fear of facilitating death or dying. Refusal of physicians to withdraw care, which includes withdrawal of nutrition and hydration, is now much less common since—at least in the United States—this has been regulated. More commonly in practice, family members explicitly want to continue care despite futility and a commonsense notion that outcome will be very poor. Second, it brings on a discussion about the accuracy of diagnosis and how certain physicians are in their clinical diagnosis that the patient is not aware and will not awaken. Third, and most unfortunately, it brings on the media razzmatazz. (In 2009, Time magazine published the Top 10 Comas.) These patterns permeate all major court cases, and most recently, converged in the Terri Schiavo case. This chapter summarizes the major legal cases in the United States, but the theme that is developed here is physicians’ involvement in courts and their opinions. (There is less attention paid to legal arguments.)

Law and Bioethics/ / / 10 / / /

Law and Bioethics / / 279

During these proceedings, ethical conundra come to light, and thus it is useful to also revisit the main bioethical issues surrounding comatose patients in this chapter. Some of the ethical concerns in management have been addressed in Chapters 5 and 7, and practi-cal solutions have been offered. But here, alternate views of scholars challenging accepted beliefs, religious commitments, and the most pressing current concern—organ donation after cardiac death in comatose patients—are presented.

THE COURT CASES IN THE UNITED STATES

Multiple briefs have been filed involving care of patients in prolonged unconsciousness. Summaries of six landmark cases in the United States that stand out from the rest are pre-sented, but with considerably more focus on the Terri Schiavo case. Other notable cases but with very similar subject matter are the cases of Anthony Bland29 (United Kingdom), Eluana Englaro14 (Italy), and Ineke Stinissen21 (The Netherlands).

The Quinlan Case

Karen Ann Quinlan was adopted by Joseph and Julia Quinlan (Fig. 10-1). Descriptions given by college peers revealed Karen’s self-destructive behavior, with drug and alcohol

FIGURE 10-1 Karen Ann Quinlan’s mother holding a book about her ordeal with her daughter

(with permission of Associated Press).


use at the age of 21. In 1975, after drinking at a birthday party, she was brought home and later found to be apneic. Hospital records noted out-of-hospital cardiopulmonary resus-citation for 15 to 30 minutes, and fixed pupils with decorticate posturing. Drug testing revealed the presence of benzodiazepines. When the family asked to turn off the ventila-tor, the attending neurologist, Dr. Morse, denied their request. In his opinion, disconnect-ing the ventilator could be construed as homicide because she was not brain dead. During the trial, Dr. Korein testified “the technology has now reached a point where you can in fact start to replace anything outside of the brain to maintain something that is irreversibly damaged.”2 In court, the Quinlan family noted that Karen had previously said that she did not want to be kept alive on a machine, but because no written statement could be shown this was rejected by the judge. The parents appealed to the Supreme Court of New Jersey, citing the respirator as an “extraordinary means.” The Supreme Court of New Jersey over-ruled this decision. Thus, the constitutional right to privacy could be exercised by her father, and the mechanical ventilator was discontinued. This case was remarkable because it set the stage for the development of advance directives. What made the case even more remarkable was that she was weaned off the ventilator and, despite a do-not-resuscitate order and no antibiotic treatment for infections, lived for another 10 years.

The Jobes Case

In 1980, Nancy Jobes was 16 weeks pregnant when she was admitted to the hospital for injuries from an automobile accident. Her fetus was determined to be dead and, during the operation to remove the fetus, she had an anoxic-ischemic injury to the brain that left her unconscious. She was transferred to a nursing home four months later with a tracheos-tomy and jejunostomy. Five years later, her husband and parents requested that the nurs-ing home withdraw the jejunostomy. Drs. Plum and Levy examined her and concluded that she was in a persistent vegetative state (PVS). Drs. Liss and Canlin, too, confirmed that she was in a PVS. However, Drs. Ropper and Victor testified for the nursing home and noted that on several occasions she obeyed commands (“Nancy, pick up your head”). Dr. Victor testified that ammonia under her nose resulted in a violent grimace and retrac-tion of her head. He also observed emotions in her facial gestures that he characterized as anticipation and intent when she received commands and was satisfied when congratu-lated. Dr. Ropper noted she fell “slightly outside of his operational definition of the PVS.”4

The plaintiff emphasized that Drs. Plum and Levy had observed her extensively for four days while Drs. Ropper and Victor had examined her for approximately


90 minutes. None of the experts retained by the plaintiff could elicit these volitional responses, and they interpreted the movements as startle reflexes and at random. This case was remarkable for the presence of major differences in assessment by eminently qualified experts. Justice Garibaldi allowed discontinuation of jejunos-tomy feedings. In this opinion, he favored one set of experts in neurology over other experts.3

The Brophy Case

Paul Brophy Sr., a firefighter, suffered a ruptured basilar artery aneurysm in 1983, never regained consciousness, and remained in a PVS. Almost two years later, his wife requested that the gastrostomy be removed. Dr. Koncz refused to carry out this request. In his view, this would willfully cause his death, and he was supported in his opinion by the nursing and medical staff.

His wife quoted her husband saying in response to the Quinlan case: “No way would I want to live like that, that is not living. When your ticket is punched, it is punched.” Brophy had rescued a man from a burning truck, but the man become disabled with extensive burns, Brophy had commented, “if I am ever like that just shoot me, pull the plug.” Dr. Cranford testified that Brophy was in a PVS. He also testified that only two such patients had regained conscious awareness in the past, but that “they were left in a state that some people including myself would view as worse than the vegetative state.” The Supreme Judicial Court of Massachusetts considered nutrition and hydration medical treatment, which could be declined by the patient or a substitute decision maker. A dis-sent by Judge Nolan stated:

I can think of nothing more degrading to the human person than the balance which the

court struck today in favor of death and against life. It is but another triumph for the

forces of secular humanism (modern paganism) which have now succeeded in imposing

their antilife principles at both ends of life’s spectrum. Pro dolor.5

Brophy died after support was withdrawn. The case is remarkable for its use of prior state-ments as evidence of the patient’s wishes.

The Cruzan Case

Nancy Cruzan, 25 years old (Fig. 10-2), was involved in a motor vehicle accident in 1983 and was found face-down and not breathing. She had been pulseless for approximately


ten to 15 minutes. She arrived at Freeman Hospital with multiple injuries. She remained comatose after abdominal surgery for stomach and liver lacerations. She was transferred to a nursing home but, two years, later briefly returned home for Christmas—a moment when the family realized she would remain in a vegetative state. Her father signed a “no cardiopulmonary resuscitation” form four years later.

The parents subsequently sought termination of hydration and nutrition, but the nursing home employees refused to do so without court approval.19 During the eviden-tiary hearings, Dr. Dexter testified that he could elicit an optokinetic nystagmus and found that Cruzan could fixate on his face and attend, orient to sound and maintain that orientation, and frowned to pain. In his opinion, Cruzan was in a state of akinetic mutism. Dr. Cranford, however, testified she was in a PVS. The court found that Cruzan, in a con-versation with a housemate friend, had said that she “would not want to live at least half-way normal” and granted removal of the feeding tube. The Supreme Court of Missouri reversed by a divided vote and found that these statements to her friend were not reliable. Concerning termination of nutrition, the court concluded that “no person can assume that choice for an incompetent in the absence of the formalities required under Missouri’s Living Will statutes or the clear and convincing, inherently reliable evidence absent here.” It led to a (5–4) Supreme Court decision affirming the Missouri court decision. The Cruzan family, for three years in four courts, tried to end her life support. Cruzan stayed in a PVS for eight years before her death.19 Her grave marker showed two dates, time of initial cardiac arrest (“departed”) and time of death (“at peace”), further fueling debate on a person’s existence in a PVS. In addition, the grave marker included a cartoon of an EKG tracing forming the words “thank you” before asystole (Fig. 10-2). The Cruzan

FIGURE 10-2 Nancy Cruzan before accident (provided by William Colby) and Nancy Cruzan’s

grave marker (with permission from the family).


case pointed out the opposing positions on preservation of life versus quality of life and rekindled interest in advance directives.

The Wendland Case

A landmark case of a patient in a “minimally conscious” state was that of Robert Wendland who, in 1993, while intoxicated, lost control of his truck, suffered a severe head injury, and was left comatose. He apparently regained consciousness 14 months after the accident. He was able to draw simple shapes and follow two-step commands and to write the letter R. When his gastrostomy tube became dislodged, his wife did not authorize reinsertion. Several days before his accident, he had said to his daughter that “if he could not be a provider for the family, if he could not do all the things that he enjoyed doing, just enjoying the outdoors—just basic things—feeding himself, talking, communicating . . . he would not want to live.”31 During his examination in 1997, it was found that he answered simple questions with yes and no, but when asked “do you want to die?” he gave no answer. His wife requested the removal of the feeding tube, but his mother (she said he could kiss her hand) and sister litigated to prevent it. In 2001, the California court ruled unanimously 6–0 that Wendland’s feeding tube could not be dis-continued and argued that his prior statements were neither clear and convincing nor sufficiently specific to direct his medical care. Wendland eventually died of pneumonia. The Wendland case is the first legal decision in a minimally conscious state—strictly speaking, a post hoc diagnosis (Chapter 4). The legal ramifications of the Supreme Court decision remain debated.31

The Schiavo Case

The most recent legal case involved Theresa Marie Schiavo. Early in the morning, at the age of 26 in 1990, her husband found her lifeless with agonal breathing next to their bed-room. She was defibrillated seven times but only after approximately 40 minutes was a measurable blood pressure recorded. She was admitted with fixed pupils, decerebrate posturing, and “seizing.” Bulimia and severe hypokalemia had been considered as factors to cause cardiac arrest, but the circumstances surrounding her cardiac arrest remained unclear. A $1.2 million malpractice award followed, claiming that her fertility gynecolo-gist did not recognize a very significant weight loss (to 110 pounds), bulimia, and the possibility of an electrolyte imbalance.


The award reflected the anticipated cost of long-term care. Rehabilitation was attempted and a thalamic stimulator was implanted, with no improvement. This prompted the husband, Michael Schiavo, a registered nurse by now, to consider all care futile, and he decided to respect her wishes not to be left in such a state (Fig. 10-3). The parents, however, were convinced that she was not in a PVS and that medical care should not be withdrawn. The main argument of her parents was that she was aware, probably in a minimally conscious state with an opportunity for improvement if only more aggressive rehabilitation was provided. To bolster their argument, the parents released several videos and photos of her showing her dressed to the nines. One video was also purportedly showing the tracking of a silver balloon waved in front of her. After several days of evidentiary hearings, the Florida court ruled her to be in a PVS. Seven of the eight board-certified neurologists who examined her found her to be in a PVS. The credentials of the eighth neurologist (Dr. Hammesfahr), who thought she was not in a PVS, were discredited by the trial court judge. Dr. Hammesfahr, a neurologist, also expected that vasodilator therapy—12 years after a devastating anoxic-ischemic brain injury—would be helpful and claimed he had seen results in patients with chronic brain injury.

The feeding tube was removed at the request of Michael Schiavo, who had guardian-ship. However, the Florida Supreme Court allowed Governor Jeb Bush to intervene and ordered reinstating of the feeding tube. From a legal perspective, the reversal of with-drawal of the gastrostomy was unprecedented in Florida, with its explicit right-to-die laws. In one of the last motions to a federal state judge, the attorney for the Schindler family argued that Terri Schiavo had articulated “AHHHHH” followed by screaming “WAAAAA,” loosely interpreted as “I want to live.” However, none of the multiple appeals was granted. The feeding tube was withdrawn, and Terri Schiavo died 13 days

FIGURE 10-3 Terri Schiavo and Michael Schiavo (with permission from World Picture News).


later. The Schiavo case became of major interest to right-to-life groups, which protested in front of the nursing home (Fig. 10-4). The American public, when asked on 12 national surveys and at a national exit poll on Election Day, felt that removal of the tube was an “act of mercy” (50% of respondents). One-third of the respondents believed it was murder.13

The postmortem evaluation by the chief medical examiner of Pinellas County, Florida, and a consultant neuropathologist found massive, irreversible damage of the cerebral hemispheres, consistent with the clinical diagnosis of a PVS. It was pointed out that, at autopsy, Terri Schiavo’s brain weighed only 615 g, less than half the weight of a normal brain, and over 25% less in weight than the brain of Karen Quinlan, who was in a PVS for ten years. The impressive, and so often characteristic, microscopic features included widespread cortical laminar necrosis with predominance in the parieto-occipital regions, thalami, basal ganglia, and hippocampi.47

There was an unprecedented interest among physicians of all specialties to weigh in on this case. Many physicians filed affidavits stating that she was not in a PVS. It is necessary to state that all these physicians watched the videotapes provided by the par-ents but did not examine her. Several physician members of Congress voiced through the press that they were not convinced after watching the video tapes that she was in a PVS. Specific remarks were made by surgeons, but not neurologists or neurosurgeons. Annas named it Congress at the Bedside.6 Representatives Dave Weldonn (Florida) and Phil Gingrea (Georgia) felt there was insufficient medical evidence. Congressman Joe Schwarz (Michigan), a head and neck surgeon, said, “She does have some cognitive ability.”6 Most notable were the closing remarks of Senator Bill Frist, Senate majority leader and cardiovascular surgeon, who stated that “I question it based on a review of

FIGURE 10-4 Public display of disagreement over withdrawal of support in Schiavo case. The

tape over the woman’s mouth suggests that the opinion of the right-to-life proponents has been

muted (with permission from World Picture News).


the video footage, which I spent an hour or so looking at last night in my office here at the Capitol. She certainly seems to respond to visual stimuli.”27 He subsequently sug-gested that Terri Schiavo needed an MRI or PET scan to complete a full neurologic examination. However, Congressman Dr. James McDermott (Washington) pointed out that all physicians were wrong in making a diagnosis without a physical examination.

Lessons Learned From the Court Cases

Landmark court cases began with a major disagreement that could not be solved diplomatically, and accusations and confrontation followed. This involved discord among family members, between family members and their physicians, and, less commonly, between nurses and physicians. The courts only magnified the differ-ences and often pointed out major differences between physicians. The Quinlan case launched the end-of-life movement and remains a classic legal reference. The Schiavo debacle clearly demonstrated a much deeper problem. The legal deci-sions on reinstating and removal of the feeding tube are illustrative of the long legal counter-battles (Table 10-1).

There would be a tendency to search for lessons learned. However, first, we cannot assume that a significant increase in advance directives will occur in the young individu-als who are typically struck with such a catastrophe. (The low percentage of organ donor approvals on driving licenses may be an indication.) Second, admittedly, the recognition of PVS could be difficult for many physicians outside the neurosciences, and few neurolo-gists see these patients after one year. However, withdrawal of support is perfectly justified in any catastrophic neurologic condition, and PVS does not need to be established. Third, the two opposing positions, “right-to-life” versus “right-to-die,” became quite prominent during the Schiavo debate, but we cannot assume that these parties with radically oppos-ing positions can reach a compromise. The pro-life arguments have been providing ordi-nary quality of sustenance for human life (feeding, hydration, and warmth), the presence of a constitutional right to freely exercise religion, the claim that the removal of a percuta-neous endoscopic gastrostomy (PEG) tube violates the American with Disabilities Act, and finally a sociological argument that a society will be created that disrespects human life and the disadvantaged. The right-to-die arguments include the autonomy of the per-son, the constitutional right to decline life-sustaining treatment, and the right to decline medical treatment; any action here would impose invasive treatment against the person’s wishes.


TABLE 10-1 schiavo Case: Court Decisions on Percutaneous endoscopic Gastrostomy (PeG) Feeding

1990 February 25: Terri Schiavo has a cardiac arrest leading to brain damage. Hospital later inserts

percutaneous endoscopic gastrostomy (PEG tube).

June 18: County Circuit Court appoints Michael Schiavo as Terri Schiavo’s guardian; her parents, the

Schindlers, do not object.

2000 February 11: County Circuit Court Judge George Greer rules that Terri Schiavo would have chosen to

have PEG tube removed, and orders it removed.

2001 January–April: U.S. Supreme Court Justice Anthony Kennedy refuses to stay case for a review.

April 24: PEG tube is reinserted by court order.

April 26: Schindlers file motion claiming that Michael Schiavo perjured himself. County Circuit Court

orders PEG tube be reinserted.

April 26: PEG tube is reinserted by court order.

August 7: On remand, County Circuit Court Judge Greer finds that PEG tube can be removed.

October 17: Florida Second District Court of Appeal rules that five physicians should examine Terri

Schiavo.

2002 November 22: County Circuit Court Judge Greer rules that PEG tube should be removed.

2003 June 6: Florida Second District Court of Appeal affirms County Circuit Court Judge Greer’s ruling.

August 22: Florida Supreme Court declines to review the decision.

August 30: Schindlers file federal lawsuit challenging removal of PEG tube.

October 7: Governor Jeb Bush files a brief to federal district court in support of Schindlers

October 15: PEG tube is removed by court order

October 21: Florida legislature enacts “Terri’s Law,” which allows the governor to issue a “one-time

stay in certain cases.” Governor issues executive order directing reinsertion of PEG tube and

appointing guardian ad litem.

October 21: PEG tube is reinserted by court order.

2005 January 24: U.S. Supreme Court refuses to grant review.

March 18: PEG tube is removed by court order.

March 31: Terri Schiavo dies at 9:05 a.m.

How do neurologists fare in court? The neurologist may appear as an expert witness to educate the jury on different states of unconsciousness and to emphasize quantifi-able data (such as electrophysiology and neuroimaging) while guided by practice doc-uments endorsed by major professional organizations such as the American Academy of Neurology.8 Attempts to discredit the diagnosis and review of therapeutic options in these cases that come to court are the main issues. Neurologists are subjected to tough questioning, and the plaintiff ’s critique of neurologists is summarized in Table 10-2. The differences of opinion will focus on the differences between a minimally conscious state


and PVS. New fMRI may be introduced but, without knowing its diagnostic validity, this may not resolve any issues—in fact it may introduce more ambiguity. Courts may continue to focus on the care of these patients and suggest additional interventions. Most tellingly, a UK judge accepted an expert suggestion to try the “stimulant” zolpidem for several weeks in a patient who had been in a PVS for three years before ruling to allow withdrawal of support.24 More recently, in the UK, a hospital was refused permission by a judge to withhold futile therapy (e.g., dialysis) in a deteriorating patient in a minimally conscious state.23 Each of these examples shows controversial legal determinations and the difficulty with defining futility.

Legal Aspects of Withdrawal of Support

The courts approach withdrawal of support (extubation, discontinuation of mechani-cal ventilation, discontinuation of pharmaceutical support, and termination of artificial nutrition and hydration) in different ways in different countries and even in different states in the United States. Withdrawal of artificial nutrition and hydration (a common term abbreviated “ANH”) is rarely allowed in the United Kingdom and many European countries without a court order and is not even an option in most Asian and Middle East countries. The U.S. statutes differ in their wording in three ways, with some referring to PVS, some to unconsciousness alone, and others to a terminal condition. In the United States, more than two thirds of the states uphold the rights to withdraw ANH in PVS, but restrictive statutes (banning ANH, even if an advance directive is present) are found in the District of Columbia, Kansas, and Missouri. Arizona, Kentucky, Michigan, New Hampshire, and Tennessee preclude withdrawal unless an advance directive is present, and Alabama, New York, and Ohio restrict surrogate decisions. In addition, proposed laws in several states may change the current statutes considerably. These proposals emphasize that withdrawal is allowed only if ANH cannot be administered, if ANH may

TABLE 10-2 attorneys’ Critique of neurologists in Persistent Vegetative state (PVs) Court Cases

• Arrogance to know what is unknowable• Insufficient time taken to examine patient• Lack of knowledge in the field of neurorehabilitation• No articles written on ethics or PVS or served in ethics committee• Pro euthanasia position, no respect for life• Rapid-fire commands or repetitive commands are counterproductive because patients with severe brain

injury need more time to respond.• Patients have been neglected; no stimulation programs have been initiated.


hasten death, if and only when clear and convincing evidence exists that the patient gave earlier consent to withdraw ANH. If these proposals come into effect, the consequences will be substantial and may increase court decisions in withdrawal of care.30 The American Academy of Neurology has recently revisited its position and vigorously defended the patient’s autonomy.8 Similarly, the American College of Critical Care Medicine has put forward recommendations for end-of-life care in critically ill patients which often include comatose patients.48

APPLIED ETHICS

Differences in values between family and physician may become apparent and thus cre-ate an ethical problem. There is marked diversity among cultures, and multiple schools of thought exist. In certain cultures—when it pertains to end-of-life care—mistrust of the health care system is prevalent. Some have expressed concerns that white physi-cians could be unwilling to help African Americans. Among Latinos, concerns about a language barrier are common. The prevalence of advance directives among Native Americans is low.

Spirituality remains an important factor in the management of prolonged coma. Certain cultures are more religious than others are, with some continents being predomi-nately secular. In addition, questions have been raised about the legitimacy of the diagno-sis of brain death, PVS, and the minimally conscious state.

Spirituality and Health Care

The main task for physicians in practice is to understand and acknowledge religious and cultural differences. Traditionally, hospital chaplains have assisted in discussions with families in distress and need and provided sacramental care. Multiple faith groups exist beyond the main denominations, and they all believe in the power of prayer, in the heal-ing process, and in the existence of miracles through a divine force. Some consider illness as a punishment for wrongdoing and a way to find God. All have a great respect for life, and many want to persist with the best medical care. Decisions on the level of care in comatose patients can be markedly influenced by the spiritual beliefs of the patient and the family. African Americans more commonly than white Americans believe that recov-ery is God’s will; many believe in miracles and faith healing and feel that God has the last word.11 All major religions, Christianity, Judaism, and Islam, have clearly insisted upon the sanctity of human life. However, this may not translate to personal values, and some families can be more resolute and come to terms with the severity of injury.


The Catholic Church has a clear statement by Pope John Paul II, who claimed that medical science is still unable to predict with certainty who in PVS will recover and who will not.37 He went on to say that the medical doctors do have moral duties toward per-sons without reducing their professional ethics:

A sick person in a vegetative state awaiting recovery or a natural end still has the right to basic health care, nutrition, hydration, clean linen, warmth, etc., and to the preven-tion of complications related to his confinement to bed. He also has the right to appro-priate rehabilitative care and to be monitored for clinical signs of eventual recovery.Considerations about quality of life often actually dictated by psychological, social, and economic pressures cannot take precedence over general principles.37

The Catholic Church moral principle is that it is necessary to support families who are suffering with a patient who is in prolonged coma. In one of the concluding sentences, the Pope emphasized:

It is not enough to reaffirm the general principle according to which the value of man’s

life cannot be made subordinate to any judgment of its quality expressed by other men.

It is necessary to promote the taking of positive actions as a stand against pressures to

withdraw hydration and nutrition as a way to put an end to the lives of these patients.37

The practice in the Catholic community, however, is largely unknown, and different opinions are held. Some believe that the removal of artificial hydration and nutrition is a serious violation of the right to live. Others believe it is appropriate to remove ther-apy when it is of no consequence and is futile or potentially burdensome to the patient. Christian denominations have accepted organ donation after brain death, which is seen as an expression of love for someone in desperate need. There has not been a revision of the Holy see position since.

Judaism has three elements, God, the Torah, and Israel. The Torah perspective, one of the principles in l’halacha, is that “one does not follow the rule of the majority in the case of life and death.” However, rabbis have stated that this principle may not apply to all situ-ations that are hopeless beyond a reasonable doubt. Another principle is the obligation to heal, but some rabbis have clearly stated that there is no obligation to treat the underlying illness but only to relieve the suffering of the patient. Several rabbis have expressed that a failure to provide nutrition to a patient in a PVS can be construed as similar to the act of indirect murder. Most rabbinic opinions have stated that the presence of spontaneous respiration is a sufficient clinical sign by which life or death can be determined.22 The vast


majority of Jews accept brain death, but there are exceptions (notably the Orthodox Jews in New York).

The Muslim belief is that no one is authorized to end life, and medical care should be provided even if seemingly futile. The Qur’an (Koran) teaches that anyone who concludes that treatment is not necessary would be assaulting on Allah’s authority. This is highly consistent with most religions’ conception that God is the author of life and death.28 The Qur’an20 does not allow withdrawal of care. However, a terminally ill Muslim patient can request that the treatment be discontinued based on the Islamic judicial principle of Idar Wa Idrar (no harm and no harassment). The Qur’an is clear that palliative care should include maintenance of personal hygiene and basic nutrition. Islamic law permits organ donation if all Sharia principles are fulfilled, such as “complete stoppage of all the vital functions of the brain and the doctors decide it is irreversible and the brain has started to degenerate.”28

Buddhism, Jainism, and Sikhism are important faiths that are practiced by many Asians and Indians who have emigrated to other countries. Jainism maintains that life on this earth is not finite but part of a continuous cycle of life, death, and rebirth. Sikhs believe in one God who has no form. Buddhism believes in the interconnectivity between all things in the universe and in the permanence of all created things. From a Hindu per-spective, intubation could be considered an intervention to reduce the chance of death and could interfere with Karma. Most will respect the stated wishes of the patient and will ensure a comfortable death with certain important rituals. Many of these decisions are made in a communal manner rather than individually, but there is a hierarchy of family members. The spouse is often the primary responsible person but may decide to make no firm decisions at all.

Comatose States as a Bioethical Controversy

There are dissenting voices that proclaim that most of these comatose states do not truly exist. In the clinical state presented, some scholars have critically re-evaluated brain death, PVS, and, since its introduction in 2002, the minimally conscious state. The most important arguments—none of them particularly persuasive—are reviewed here. Those who reject the concept of brain death are neither professional neurointensivists, neuro-surgeons, medical intensivists, nor transplant surgeons. It could be further argued that critics outspokenly rejecting brain death potentially undermine the good that comes from organ donation. When it comes to those waiting (and prematurely dying) for organ transplantation—a figure reaching 100,000 in the United States—these alternate views on brain death interest none.


One would imagine that clinicians closely involved with patients who worsen and become brain dead would have no problem with acceptance of this state. The transition from severe brain injury to brain death is remarkable. Certain clinical signs suddenly become evident and are often also noticed by family members. Patients are now motion-less, expressionless, and do not trigger the ventilator; blood pressure decreases to consid-erably lower values but without concomitant tachycardia; and there is only an invariant pulse fixated at 80 to 100 beats per minute. Extensive diuresis occurs simultaneously. There is no thermoregulation. The patient, dependent on a ventilator and pharmaceuti-cal agents to maintain blood pressure, has now lost all brainstem and cortical functions. Pulmonary edema emerges and, due to destruction of the parasympathetic system, car-diac arrhythmias forebode cardiac arrest. One review (from 1959 to 1988) summarizing over 1,900 patients maintained on a ventilator found terminal cardiac arrest in all cases.36 When the brain is dead, the person is dead. It is a fait accompli. Unlike the heart, lung, or kidney, the brain cannot be replaced by an organ or a device, not even a computer.

Several scholars—including physicians—have questioned this entity.9 Earlier argu-ments against the diagnosis of brain death have focused on the undesirable link between transplantation and the definition of brain death (the presence of one transplant surgeon and one transplant immunologist, in the ad hoc committee of Harvard Medical School have been cited as proof). Others felt that its definition satisfied a legal need. Stevens remarked, “More than a medical response to a technologically-induced moral problem, ‘brain death’ was an artifice of self protection . . . argument the possibility that the public would perceive a potential conflict of interest and become alarmed.”45 Veatch, a critic of the Harvard guidelines from day one and the director of the Kennedy Center for Ethics, fired back at the Harvard Committee by saying:

the task of defining death is not a trivial exercise in coining the meaning of the term.

Rather, it is an attempt to reach an understanding of the philosophical nature of

man . . . to leave such decision making in the hands of scientifically trained professionals

is a dangerous move.

Veatch’s most prominent argument has been that the loss of the cortex alone should define the death of man. The cerebral cortex in man defines the human person and not the loss of the brain’s capacity to integrate systemic organ function. The concept became known as the higher brain death formulation and would include patients with neocorti-cal destruction. However, it can be argued that no society would consider a breathing human being dead. Apnea and loss of vasomotor control of the arterial system are far more accepted as fail-safe criteria for death.


Shewmon, a pediatric neurologist, wrote, “as a convert from atheism to theism, I have particular interest in the relationships among brain, mind, body, and soul,” and followed up by saying “I have come to reject all brain-based formulations of death.” Shewmon has concluded that brain-dead patients are comatose, severely disabled living human beings with a soul and he would only accept a cessation of blood circulation for a sufficient time.

In his paper “Chronic brain death: Meta-analysis and conceptual consequences,”44 he found no evidence in the literature of physiological disintegration in brain-dead patients and actually found that they survive longer than anticipated, most notably pregnant woman, in whom the body is used as an incubator to allow fetal growth. In his opinion, the apparent ease of maintain a body’s functioning conflicts with the above-described successive organ dysfunction and cardiac arrest.43

This somatic integration theory caught on with many ethicists and invigorated the argument that patients who are brain dead are not actually dead. The literature review underlying his claim includes patients in case series and case reports. Shewmon’s argu-ment is that “it takes only a single exception to disprove a universal rule.”42 The President’s Council on Bioethics in 2008 accepted Shewmon’s argument, and many council mem-bers proposed an alternative interpretation of brain death; however, the Council also concluded that if there are no signs of consciousness and spontaneous breathing, the patient had died.12

These arguments were also of considerable interest to Catholic theologians. The Catholic Church’s position on brain death was revisited by the Pontifical Academy of Sciences in 2006 with participants from the principal regions of the world, but the group still upheld the criterion of brain death as determining the death of a human being.

To imply that brain-dead bodies are “integrated” ignores the fact they are on mechan-ical ventilators and require blood pressure support and vasopressin. This theory also ignores the multitudes of other physiological changes in other organs, including intra-vascular coagulation due to thromboplastin from the necrotic brain. Patients are immo-bile, and the vascular tone is marginally maintained with spinal reflexes: a simple bed tilt would lead to cardiovascular collapse. Nonetheless, viscera have their own pacemakers and, with the right nutrients, these bodies can be made into a cell culture system and do not require subsystems or coordination, but they do need adequate blood flow. In patients on continued care, the strict criteria for brain death examination before organ donation may not have been used, because most patients were not organ donors. Thus, another explanation for these “surviving bodies” is that sufficient medulla function has remained to stabilize the patient (the function of the medulla oblongata is notoriously poorly examined by non-neurologists).


Other arguments against brain death have been advanced notably by Evans, Byrne, Coimbra, and Potts.18,25,38 The persistence of EEG function in patients with clinical cri-teria of brain death (a highly uncommon finding, mostly evolving after anoxia and in children) and the presence of pituitary function in brain-dead patients (physiologically, the pituitary is an extracerebral organ due to external carotid artery perfusion) continue to surface as the main objections. Evans, in an open letter in 2002, agreed that there are too many anomalies, that tests may not be performed accurately due to trauma or not performed at all (apnea test), and that spinal reflexes may not be spinal at all.25 Evans sug-gested “mortal brain damage” as an alternative term.25 Byrne argued that the ad hoc com-mittee of the Harvard Medical School was not “a medical scientific method,” represented the “hubris of a few academicians” and a desire to obtain healthy living vital organs for transplantation, and included variable criteria that led to the ambiguous situation that a patient could be proclaimed “dead by one set, but not by another.”18 The main critiques against brain death by physicians involved insufficient testing of absence of brain func-tion (only demonstrable absence of blood flow could suffice), apnea testing could cause vasoconstriction and precipitate death through hypoxemia and hypercapnia, and finally there have been suggestions of recovery. Spinal reflexes could very well be true brainstem responses rather than being generated from the spinal cord. Many of these physicians and bioethicists have simply stated that brain death is coma in a dying patient but not death, and the only valid criterion is absence of circulation.35 A summary of these opinions is found in another work.50

There has been little ethical objection to the definition of PVS. Some have argued that it is very difficult to assess inconsistencies of responses and expressions of affect (moan-ing, crying, shedding tears) in PVS. Others have argued that it does not matter so much for the patient. Stone noted: “Consequently you have everything to win and nothing to lose if you gamble on staying alive: you may wake up and if you do not, unconscious life is no worse than being dead.” The argument concludes that it is your best interest to stay alive if you are comatose, and even more so if you are younger.46 This argument does not acknowledge the continuous suffering of the family nor the financial burden. A PVS remains an undignified state.

ETHICS IN ORGAN DONATION AFTER CARDIAC DEATH

After the decision has been made to withdraw all support, organ donation could be con-sidered for patients who have catastrophic brain injury but who do not fulfill the criteria of brain death. Organ donation after cardiac death, commonly abbreviated as DCD, is thus set apart from organ donation after brain death, abbreviated as DBD. In DCD, absence of


circulation determines death. These protocols are considered in comatose patients who have lost upper brainstem (pontomesencephalic) reflexes but also after primary cardio-pulmonary arrest. The assumption is that the patient will rapidly die after extubation or discontinuation of pharmaceutical agents. The diagnosis of cardiac arrest is made in the operating room, followed by organ-preserving measures such as in situ perfusion of the kidneys or cold flush, requiring a femoral catheter. Experience with DCD protocols has been reported from centers in the United States (Pittsburgh, Philadelphia, and Madison) and Europe (Netherlands, Spain, and United Kingdom, but not in Germany and Austria) showing an increase in organ retrieval using these protocols.15

There are two main arguments against the implementation of these DCD protocols. First, predicting cardiac arrest after withdrawal may be difficult, and it is not uncom-mon for the patient to live and need to return to the intensive care unit. The exact time needed after cardiac arrest to determine irreversibility and permanence is not known, and there are variable time intervals in current protocols (5 to 10 minutes). The obser-vation of resumption of cardiac rhythm after minutes of arrest creates uncertainties on when to pronounce death. Second, some have argued that the decision to withdraw support could be driven by a desire to donate organs in a climate of high demand. In the most extreme form of objection, critics have argued that persons are “killed for their organs.”39

Autoresuscitation (return of spontaneous circulation) has been termed the “Lazarus phenomenon” (different from the “Lazarus sign”; see Chapter 5). Multiple cases with this phenomenon have been described after the discontinuation of cardiopulmonary resuscitation, with a time interval mostly within 10 minutes. Explanations offered include delayed action of intravenous epinephrine, hyperkalemia, and hyperinflation (high atrial pressures during ventilation and when ventilatory support is discontinued increased venous return after gasping of the patient).32

The situation may be different in withdrawal of support in comatose patients with a catastrophic brain injury who do not fulfill the criteria of brain death but who have vari-able injury to the brainstem. A preliminary study in 12 patients after the withdrawal of support in catastrophic brain injury found that no autoresuscitation existed when the patient was monitored for at least ten minutes after asystole.49 Another study in 37 patients with catastrophic neurologic injury, who underwent donation after cardiac death (DCD) with a mean time of extubation to circulatory arrest of 22 minutes, found no episodes of autoresuscitation after five minutes of observation. No autoresuscitation was found in the first two minutes of asystole.41

Other potential ethical concerns are conflicts of interest.17,33,35 The decision to withdraw intensive care support should be separate from the decision to donate organs. The decision


to withdraw support should be based only on the presence of a hopeless situation and after a shared decision with family members that continuation of care would not be in the patient’s interest. After this decision is made, organ procurement coordinators meet with the family to discuss a DCD pathway. The concerns with children are unique, and a policy statement—supporting DCD with appropriate constraints—by the American Academy of Pediatrics has recently been published.1 This statement followed a controversial use of DCD (and heart transplantation) with a waiting period of 75 seconds.16 The policy reinforced a waiting period between two and five minutes. Another major controversy is uncontrolled donation after circulatory death. In this protocol, patients with out-of-hospital cardiac arrest and after an unsuccessful CPR effort (30 minutes) are declared dead after a no-touch period of five minutes, followed by in situ cooling or normothermic extracorporeal membrane oxygen-ation. Here the irreversibility of circulatory function is in question, and the use of invasive measures to preserve organs before consent often done by the same team responsible for resuscitation. These controversies have been recently discussed.9,40

It remains to be seen whether these DCD protocols will have a significant impact on donor retrieval, and the number of patients has remained small. A consensus pro-tocol has been proposed in the United States to increase the number of eligible cases, and recommendations have been published.10 A recent survey showed major concerns with different groups of health care providers. These concerns included uncertain criteria for cardiac death, questionable quality of organs, the “slippery slope” between DCD and euthanasia, protocols driven by utilitarian and financial reasons, a possible decline in the diagnosis of brain death, the inability of physicians to assess prognosis, and erosion of public support and fear of negative publicity.7,26,34

CONCLUSIONS

Unfortunately, the aforementioned legal cases are surrounded by misinformation and reluc-tance to understand the implications of these comatose states. Nevertheless, many legal cases are settled in court without much attention. Exposure to the media may solicit physi-cian opinions, and these cases may easily become a spectacle. Bioethical issues surface under these circumstances. The physician involved with the care of comatose patients should ulti-mately understand and respect different values while maintaining optimal professionalism.

REFERENCES

1. Ethical controversies in organ donation after circulatory death. Pediatrics 2013;131:1021–1026.2. In the matter of Karen Quinlan, an alleged incompetent, LEXSEE 355 A.2D 647 671(Supreme Court of

New Jersey 1976).


3. In the matter of Nancy Ellen Jobes, Chancery Division—Morris—County Docket No. C-4971-85E (Superior Court of New Jersey 1986).

4. In the matter of Nancy Ellen Jobes NOS A–108, A–109, LEXSEE 529 A.2D 434 436(Supreme Court of New Jersey 1987).

5. Patricia E. Brophy v. New England Sinai Hospital, Inc., LEXSEE 497 N.E.2D 626 634(Supreme Judicial Court of Massachusetts 1986).

6. Annas GJ. “Culture of life” politics at the bedside—the case of Terri Schiavo. N Engl J Med 2005;352:1710–1715.

7. Aulisio MP, Devita M, Luebke D. Taking values seriously: Ethical challenges in organ donation and transplantation for critical care professionals. Crit Care Med 2007;35:S95–101.

8. Bacon D, Williams MA, Gordon J. Position statement on laws and regulations concerning life-sustaining treatment, including artificial nutrition and hydration, for patients lacking decision-making capacity. Neurology 2007;68:1097–1100.

9. Bernat JL. Controversies in defining and determining death in critical care. Nat Rev Neurol 2013;9:164–173.

10. Bernat JL, D’Alessandro AM, Port FK, et al. Report of a national conference on donation after cardiac death. Am J Transplant 2006;6:281–291.

11. Best M. A spiritual perspective: Why do African Americans resist end-of-life decisions? Chaplaincy Today 2003;19:7–9.

12. Bioethics, The President’s Council on. Controversies in the Determination of Death: A White Paper of the President’s Council on Bioethics. Washington, DC, 2008.

13. Blendon RJ, Benson JM, Herrmann MJ. The American public and the Terri Schiavo case. Arch Intern Med 2005;165:2580–2584.

14. Bonito V, Primavera A, Borghi L, Mori M, Defanti CA. The discontinuation of life support measures in patients in a permanent vegetative state. Neurol Sci 2002;23:131–139.

15. Bos MA. Ethical and legal issues in non-heart-beating organ donation. Transplantation 2005;79: 1143–1147.

16. Boucek MM, Mashburn C, Dunn SM, et al. Pediatric heart transplantation after declaration of cardiocir-culatory death. N Engl J Med 2008;359:709–714.

17. Bradley JA, Pettigrew GJ, Watson CJ. Time to death after withdrawal of treatment in donation after cir-culatory death (DCD) donors. Curr Opin Organ Transplant 2013;18:133–139.

18. Byrne PA, Weaver WF. Brain Death Is Not Death. New York: Kluwer Academic/Plenum Publishers, 2004.19. Colby W. Long Goodbye: The Deaths of Nancy Cruzan. Carlsbad, CA: Hay House; 2002.20. Daar AS, al Khitamy AB. Bioethics for clinicians: 21. Islamic bioethics. CMAJ 2001;164:60–63.21. de Beaufort I. Patients in a persistent vegetative state—a Dutch perspective. N Engl J Med 2005;352:

2373–2375.22. Dorff EN. Applying traditional Jewish law to PVS. NeuroRehabilitation 2004;19:277–283.23. Dyer C. Judge was wrong to insist doctors should give “burdensome” treatment to minimally conscious

patient, court rules. BMJ 2013;346:f1455.24. Dyer C. Woman in persistent vegetative state can die, rules judge. BMJ 2006;333:1238.25. Evans DW. Brain death. Brain death is a recent invention. BMJ 2002;325:598.26. Fost N. Reconsidering the dead donor rule: is it important that organ donors be dead? Kennedy Inst

Ethics J 2004;14:249–260.27. Frist B. Frist Disputes Fla. Doctors’ Diagnosis of Schiavo. Washington, DC: Washington Post; 2005.28. Hedayat KM. The possibility of a universal declaration of biomedical ethics. J Med Ethics 2007;33:17–20.29. Howe J. The persistent vegetative state, treatment withdrawal, and the Hillsborough disaster: Airedale

NHS Trust v Bland. Pract Neurol 2006;6:238–246.30. Larriviere D, Bonnie RJ. Terminating artificial nutrition and hydration in persistent vegetative state

patients: current and proposed state laws. Neurology 2006;66:1624–1628.31. Lo B, Dornbrand L, Wolf LE, Groman M. The Wendland case—withdrawing life support from incom-

petent patients who are not terminally ill. N Engl J Med 2002;346:1489–1493.


32. Maleck WH, Piper SN, Triem J, Boldt J, Zittel FU. Unexpected return of spontaneous circulation after cessation of resuscitation (Lazarus phenomenon). Resuscitation 1998;39:125–128.

33. Manara AR, Murphy PG, O’Callaghan G. Donation after circulatory death. Br J Anaesth 2012;108 Suppl 1:i108–121.

34. Mandell MS, Zamudio S, Seem D, et al. National evaluation of healthcare provider attitudes toward organ donation after cardiac death. Crit Care Med 2006;34:2952–2958.

35. Miller FG, Truog RD. Death, Dying, and Organ Transplantation: Reconstructing Medical Ethics at the End of Life. Oxford University Press, 2011.

36. Pallis C. Brainstem death. In: Braakman R, ed. Handbook of Clinical Neurology: Head Injury. Vol 13. Amsterdam: Elsevier Science Publisher BV, 1990:441–496.

37. Pope John Paul II. Life-sustaining treatments and vegetative state: scientific advances and ethical dilem-mas. Issues Law Med 2004;20:167–170.

38. Potts M, Evans DW. Does it matter that organ donors are not dead? Ethical and policy implications. J Medl Ethics 2005;31:406–409.

39. Robertson JA. The dead donor rule. Hastings Cent Rep 1999;29:6–14.40. Rodriguez-Arias D, Deballon IO. Protocols for uncontrolled donation after circulatory death. Lancet

2012;379:1275–1276.41. Sheth KN, Nutter T, Stein DM, Scalea TM, Bernat JL. Autoresuscitation after asystole in patients being

considered for organ donation. Crit Care Med 2012;40:158–161.42. Shewmon DA. Brain death: a valid theme with invalid variations, blurred by semantic ambiguity. In: White

RJ, Angstwurm H, I CdP, eds. Working Group on the Determination of Brain Death and its Relationship to Human Death. Vatican City: (Scripta Varia 83) Pontifical Academy of Sciences, 1992:23–51.

43. Shewmon DA. “Brainstem death,” “brain death” and death: a critical re-evaluation of the purported equivalence. Issues Law Med 1998;14:125–145.

44. Shewmon DA. Chronic “brain death”: meta-analysis and conceptual consequences. Neurology 1998;51:1538–1545.

45. Stevens ML. Redefining death in America, 1968. Caduceus 1995;11:207–219.46. Stone J. Advance directives, autonomy and unintended death. Bioethics 1994;8:223–246.47. Thogmartin JR. Medical Examiner District Six, Pasco and Pinellas Counties, Report of Autopsy, June

13, 2005.48. Truog RD, Campbell ML, Curtis JR, et al. Recommendations for end-of-life care in the intensive

care unit: a consensus statement by the American College of Critical Care Medicine. Crit Care Med 2008;36:953–963.

49. Wijdicks EFM, Diringer MN. Electrocardiographic activity after terminal cardiac arrest in neurocatas-trophes. Neurology 2004;62:673–674.

50. Wijdicks EFM. Brain Death, 2nd ed. Oxford University Press, 2011.

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INTRODUCTION

Families, with all their doubts and uncertainties, face a difficult situation when a loved one is in a coma. Most have little to relate to, and some seek information elsewhere. Family members often first go to the Internet, only to discover that few sites contain relevant and unambiguous information. Many hospitals have an information center that provides educational material.

This chapter views coma from the family’s perspective and discusses how fami-lies—and the public in general—receive information about coma through the media. Newspapers and local or national television broadcasts are the main media outlets, in addition to websites.6,33

How does the public become informed about coma, and how could the media and other sources influence the public’s perception of coma? Is there a potential influence on a credulous public? How do common forms of entertainment portray coma?

NEWS WRITING ON COMA

Physicians and journalists have two entirely different professional cultures, and the chasm between the professions is considerable.6,9,32,33 Most physicians are reserved and restrained about revealing information; in contrast, in the highly competitive journal-ism industry reporters are driven to write compelling stories and have to meet deadlines. William Osler warned physicians “not to dally with the Delilah of the press” (Delilah begged Samson to reveal his strength and then betrayed him). In Osler’s view, the press could potentially undermine a physician’s reputation and diminish the confidence of his or her colleagues.20 Without doubt, some physicians like to offer their opinions and do not

media and Popular Culture/ / / 11 / / /


object to being cast in the role of a spokesperson. Commentators must be available and must respond to the reporter quickly (return calls to the journalist are typically requested within hours of the request) and must not mind being quoted and mentioned as experts. However, it may be impossible for journalists to recognize experts who have conflicts of interest that could bias their response. Frankly, true “experts” should be media-shy and appropriately restrained.

Surely, reporting on coma can be newsworthy and certainly has journalistic appeal. Severe brain injury may occur against a background of medical errors, abuse, alleged police brutality, or assault. Journalists may have problems sorting through the vast amount of information available and may at worst resort to “tabloidization.” Catchy headlines about “miraculous” awakenings from coma may foster certain expectations on the part of the public, especially when the article includes phrases like “doctors are shocked,” “spectacu-lar and never seen before,” or “doctors cannot explain.” Therefore, for example, writing about just an “awakening” without examining the true dimensions of the problems facing comatose patients is potentially disturbing.34 Although it remains unclear how much the public carefully judges single sensational cases, the message that readers may draw from the presentation of comatose states and awakening may be distorted. This lack of clarity in reporting has been recognized,17 and a better practice model has been proposed by the Association of Health Care Journalists.26

National newspapers, major weekly periodicals, and also medical societies have professional medical writers. Their task is to prepare a news release and interview the author of the study and related peers. There is a considerable effort to present oppos-ing views, often using direct quotations that are typically verified by the interviewee. Adopting a neutral and nuanced stance toward recent news is warranted, particularly when the scientific finding has not been corroborated.18,21 When dealing with break-ing news, the facts may not yet be known, and it is the duty of physicians, particularly neurologists, to clarify, explain, and most importantly, caution. More recently, monthly periodicals have appeared that offer in-depth coverage of neurologic conditions includ-ing coma, neuroethics, and other policies, and the editors are neurologists in practice (for instance, Neurology Today is the official publication of the American Academy of Neurology). This ensures a consistent high level of quality, but unfortunately the distri-bution is only among physicians, although abstracts may appear in the media or on the Internet. Separate sections on health appear regularly in major national newspapers and are often co-written by physicians (e.g., “Health” in The New York Times). These articles reflect a wide spectrum of views in good measure; however, again it is not clear whether these columns attract the attention of the general public aside from more educated read-ers or academics.

media and Popular Culture / / 301

THE NEWSPAPER AND COVERAGE OF COMA

The daily newspaper remains an important source of information, and its ready availabil-ity on the Internet might only increase exposure. Newspapers print newsworthy informa-tion on comatose patients in three major domains: findings on new clinical or laboratory research,4 awakening from coma, and legal proceedings surrounding end-of-life decisions. Research in coma is sparse, but new developments could immediately attract attention, particularly if the findings contradict current tenets in neurology.

Most of the news on coma is potentially shocking. Failure to correctly diagnose brain death is news and hard to pass up by reporters (Fig. 11-1). This situation is of course exceedingly rare, but these cases do reach the media and often get television coverage (see the section about television below).

FIGURE 11-1 Near-miss diagnosis of brain death. After declaration of brain death, one of the

nurses discovers a strong gag reflex and an organ donation procedure is aborted. The story

reads, “The apparent close call is the second in recent months to raise questions about whether,

amid a national organ shortage, doctors might be compromising the care of prospective donors.

Law enforcement authorities in San Luis Obispo County are investigating whether a transplant

surgeon tried to hasten the death of a 26-year-old patient last year by ordering high volumes of

pain medication.” The article continues: “he just came in and threw the paper on my dad’s legs

and said `we got two signatures we’re pulling the plug’ . . . that is hospital policy’.” (From the Los Angeles Times, with permission.)


There have recently been reports concerning “miracle awakenings” and unexpected awareness in patients in a persistent vegetative state (PVS). (Reporters often compare these cases to Rip Van Winkle, the fabled Dutchman who fell asleep under a tree and awoke several years later.) The most interesting recent coverage involved the story of an unfortunate, severely brain-injured man Terry Wallis. He remained comatose ini-tially but then improved gradually. More exceptionally, Wallis started to speak after 19 years of grunts. Newspaper reporters and bloggers covered the story extensively, using eye-catching wording: “Miracle in Arkansas,”2 “Comatose man’s brain rewired itself, doc-tors say; While fibers were severed, nerve cells stayed intact allowing later recovery,”19 and “A man lay in coma-like state, his brain was busy rebuilding.”15 Some newspaper stories remained cautious, but the widespread coverage, including a TV documentary,1 left the impression that the diagnosis of PVS can be misleading. (Terry Wallis was most likely in a minimally conscious state but had not been examined by a neurologist before his dramatic improvement.)

Another patient, Sarah Scantlin, from Hutchinson, Kansas, suddenly “awakened from coma after 20 years.” Her doctor said that “she could react to following things with her eyes.” During a therapy session, she said “okay” and then began to utter simple sentences.3

In early 2005, a Buffalo firefighter apparently started to speak after he was treated with “a new drug regimen that would take 6 months to become effective.” Donald Herbert sus-tained a head injury from a roof cave-in and a lack of oxygen after rushing into a burning apartment.30 He remained in a coma for 2½ months, then apparently regained conscious-ness, but was left with speech and vision problems.

Gary Dockary, from Tennessee, recovered over a period of several days after seven years of “coma or communicating at a lower level.”29 He had a gunshot wound to the left forehead, damaging the left frontal temporal area. Although there was dramatic improve-ment initially, he regressed to his prior state before he died.

David Mack recovered after 20 months in a PVS. A CT scan did not show any pro-gressive atrophy. He regained consciousness after 22 months, although there is more evi-dence that it was after 15 months.31

For members of the public, it is difficult to understand the medical facts, especially when they are also exposed to headlines that suggest that patients are more aware than they normally should be. For the physician, obviously, the accuracy of these reports should be questioned, but it remains difficult to verify these cases and obtain sufficient informa-tion. A systematic review of these cases would be useful, but the amassed documents are likely fragmentary and difficult to interpret. Common features of these patients are that they are not in a PVS, but in variable states of severe impairment with marked impairment


of mobility, mute but responding. What is most interesting is that, in many cases, a fairly dramatic improvement in communication skills occurs over a period of hours or days, but then—if we believe the media coverage—patients often typically relapse into the previ-ous state. Not uncommonly, dopamine agonists or antidepressants have been introduced prior to clinical improvement, suggesting the possibility of neurotransmitter modula-tion in some patients in a minimally conscious state. These cases may represent recovery (meaning that the diagnosis is correct and there is a true exceptional improvement) or discovery (in which the diagnosis is incorrect and changed after a better examination).

Until recently the news coverage of comatose patients had remained unexamined. Our review of newspapers of each state in the United States, over a 5-year period, found that coma is an infrequent news story; we identified a total of 340 stories with “coma” in the headline.37 Therefore, it is perhaps not likely that the public’s perception is influenced by coverage of coma in newspapers. Most of those stories involved violence, accidents, and drug overdose that was not evident by reading the headline alone. One of ten reports involved drug-induced coma initiated by the physician to reduce intracranial pressure (Fig. 11-2). A common theme in newspaper articles on coma was that physicians displayed no hope while the family disagreed, or family members were disagreeing among themselves over whether to withdraw support. However, it is evident that when coma is a topic, the editors of major U.S. newspapers select stories that involve young persons involved in vio-lence or trauma. The general impression left by the daily newspaper is thus different from the reality in the hospital (e.g., a recent study in the ICU found that coma is mostly due to drug intoxication, stroke, cardiopulmonary resuscitation, and shock27). Coverage of coma in U.S. newspapers is more reflective of young individuals in a rehabilitation center rather than severely injured elderly patients in an ICU and thus offers a more positive outlook. As expected, the term “brain death” is often used colloquially and is poorly defined and

FIGURE 11-2 Recent headline on lone survivor of a mine disaster. Although not apparent from

the headline, the article indicates a “medically-induced coma.” (From The New York Times, with

permission.)


differentiated from other comatose states; frequently death after withdrawal of support is considered a final event (“Brain death woman dies after withdrawal of life support”).8

A recent comprehensive analysis of the newspaper coverage of coma including the Schiavo case in two local and two general newspapers (St. Petersburg Times, The Tampa Tribune, The Washington Post, The New York Times) revealed over 1,000 articles between 1990 and 2005; there were major inaccuracies in diagnosis and a gap between expert opinions and lay perspectives.24 Letters to the editor also provided some insight into the terminology used by the public; the letters frequently included “death by starvation,” “murder,” or “deprivation of food and water.”25 Newspapers also published a plethora of cartoons, mostly ridiculing policymakers, during the Schiavo case. Some showed insight into the difficult family dynamics (Fig. 11-3).

TELEVISION AND COMA

Recovery from coma is rarely breaking news on networks.22,23 Dignitaries may receive attention, and lesser-known individuals may also get caught up in a major news story. Occasionally, survivors of a major catastrophe (e.g., mine accident, traffic accident) may get additional attention. In addition, major TV networks employ medical correspondents

FIGURE 11-3 Cartoon published during the height of the Schiavo case with permission of Chip

Bok and Creators Syndicate, Inc.


and may frame recent discoveries into brief documentaries. Finally, advertisements may use the depiction of coma as an amusing means to sell their product. A recent Porsche advertisement that was aired on national TV used awakening from prolonged coma to bring out the surprise on seeing a new car model.

In 2008, the “Today Show” on NBC aired a segment called “Back from the dead” about Zach Dunlap, who had a “one-in-a-million break” and recovered after having been “diagnosed brain dead.” The case, as presented, is of a patient who was declared dead after his nuclear brain scan showed no uptake. Nursing staff soon thereafter noted he was with-drawing to pain stimuli. He recovered after a long rehabilitation period. Dunlap’s case was the focus of international attention. The medical record has not been reviewed, and there has been uncertainty if Dunlap even was considered a donor. The Organ Bank of Texas released a statement that in essence said the patient was not brain dead at the time of consideration. Another poorly documented case appeared on TV in Darwin, Australia, in 2011, where Gloria Cruz woke three days after her ventilator was turned off (“Husband celebrates miracle as ‘brain dead’ wife wakes up in hospital”).

A dramatic documentary, called “Pigen der ikke ville dø ” (the girl that wouldn’t die), involved the Aarhus University Hospital in Denmark aired in 2012. It started out as a documentary about organ donation, but then to the surprise of the filmmakers the story developed a Hitchcockian twist. The attending neurosurgeon had told the parents of a 19-year-old girl with a traumatic brain injury that she would not recover (“No, there is no hope”), but she “miraculously” awakened after withdrawal of support, became eligible for rehabilitation and recovered substantially. She was never diagnosed brain dead, but she was considered fatally injured and organ donation was discussed prematurely in the event she would die. The documentary also included colleague neurosurgeons who felt that after reviewing the medical records the patient was “not as bad” as presented. This TV documentary caused a stir in the European countries where it was aired.

Most of the depictions of coma are seen in TV serials. Daytime soap operas often depict coma and recovery. A recent review of Web-posted storylines of daytime soaps such as General Hospital, The Young and the Restless, The Bold and the Beautiful, and Passions found that the depictions of recovery from coma were unrealistic.5 Characters were in a coma for only approximately two weeks, 89% made a full recovery, and only 4% died, significantly lower than expected when compared with data from scientific publications.

There has been an increase in serial medical dramas on U.S. television. ER is an exam-ple of what has been called “medicine as a pop culture icon.”7 It depicts an emergency room that provides ideal health care, although it carefully avoids ridicule and displays con-siderable compassion. ER has portrayed coma, most of it drug-induced coma with a good recovery, and one episode dealt with brain death and organ donation. The script is accurate


and most likely reflects the comprehensive medical advice that the writers have obtained. However, more recently, there has been a noticeable deterioration in the accuracy of how coma is depicted in TV series. The popular series House, MD—watched by an estimated 25 million viewers, according to Nielsen Media Research—recently aired “Son of a coma guy”28: a patient who had been in a PVS for 10 years suddenly awakened after Dr. House injected L-dopa, immediately sat up in bed, and asked for a steak. In one episode of “Grey’s Anatomy” —another top-rated series—a patient who had been in a PVS for 16 years was admitted from a nursing home after falling out of bed. The medical team noted no atrophy on the CT and believed he was in a minimally conscious state. They suggested to the upset family that an “amphetamine drip” should be started; it awakened him within hours. He became fully lucid (“how long have I been out?”)13; he was laughing and a bit amused that he might be a major embarrassment for his family. In The Drew Carey Show, Drew Carey slipped into a coma after an accident.12 While his family was considering withdrawal of support, Drew was in a dream-like state, being fed by beautiful women pulling off slices from a pizza tree and drinking from a beer fountain. It remains unclear what message, if “message” is the right word, the writers wanted to convey in this episode.

Serious TV documentaries on coma are nearly nonexistent. A recent documentary entitled Coma showed a surreal abundance of pity, sorrow, and loneliness in head injury survivors in a rehabilitation center, but lacked a reasoned analysis of the causes that led to coma and what to expect after recovery from coma.35

THE INTERNET AND COMA

The influence of the World Wide Web is uncertain, the accuracy of the material is unex-amined, and there is much miscellany. Family members often seek clarification of medical terminology from the Internet. Several websites provide information on rehabilitation after traumatic head injury. Other sites provide support and an emotional outlet (www.braintalk.org).

The use of websites to pay tribute to patients or to follow improvement after a major brain injury is increasing. The themes are “triumph over tragedy” (www.brookebecker. com) and “from paralysis to power” (www.katesjourney.com). These inspirational web-sites emphasize not only unexpected recoveries but also physicians’ errors. Photos of patients in hospital beds are contrasted with photos showing remarkable recoveries. The Terri Schiavo case has also been documented fully on the family’s website (www.terrisfight.org). Not only photos and video clips of her parents approaching her but also a hospital dismissal summary with medical details have been posted. The video clips of her examination were particularly successful in convincing some physicians and

www.braintalk.org

www.braintalk.org

www.brookebecker. com

www.brookebecker. com

www.katesjourney.com

www.terrisfight.org

www.terrisfight.org


politicians that she was not in PVS (Chapter 8). The site (renamed the “Terri Schindler Foundation”) contains links to “remarkable cases” of recovery from a severe disability. Indirectly, Terri Schiavo’s family puts forth the notion that she was disabled and needed appropriate rehabilitation.

Finally, since 2002, www.waiting.com has been providing information about coma, among other topics. After a video introduction by attorney Gordon Johnson, Jr., the site offers a plethora of medical information and multiple links, including legal issues. The site, maintained by the Brain Injury Law Group, claims it has an educa-tional purpose.

Little reliable information about coma is available, and there is a lack of dependable sources. Easy access to medical practice parameters may help families to understand the complexity of decision making and prognostication. Social media has greatly expanded over the years, but its role in educating the public on brain injury remains insufficiently examined.

CINEMA AND COMA

Coma is a useful plot device, and screenwriters use it for various reasons: to depict a dream-like state with actual nightmares, to enable a change in personality, to show revenge after recovery from coma, to show relief when a patient awakens against all odds, or simply to remove a character from the plot. Films depicting coma are predominantly thrillers, with motor vehicle accidents, gunshot wounds, or violence causing brain injury. Unconsciousness can also be a major theme of a movie (e.g., Critical Care), and even the title of a movie (e.g., Coma). The progressive stupor in a child with adrenoleukodystro-phy was dramatically represented in the movie Lorenzo’s Oil.14 Cinema (especially given the wide distribution of DVDs) may become one of the most influential of all the arts, so the depiction of neurologic disorders must be accurate. Neurologic advice, much like that from historians and scientists for other films, is indispensable to present an accurate depiction of coma.16

Unfortunately, the representation of comatose states in contemporary cinema is inac-curate in most instances.36 Rarely does the character have a tracheotomy (despite being comatose for months), contractures, or a feeding tube. Rather, coma is depicted as a sleep-like state; the characters all have a quiet, pleasant look. PVS has been represented in a few movies, most remarkably showing beautiful actresses asleep in Habla con Ella (Talk to Her). Not showing the muscle atrophy, decubitus ulcers, bladder and bowel inconti-nence, and feeding tube may be a conscious decision by screenwriters to maximize enter-tainment, but it is a disservice to the viewer. Moreover, in Habla con Ella, the physician

www.waiting.com


suggests that awakening after 14 years has been noted and uses a magazine article showing a miracle awakening to convince the friend of the comatose bullfighter to continue care.

The most notable misrepresentations are the miraculous awakenings from coma. Sudden awakening from coma follows a characteristic pattern in the movies: patients in coma for several years awaken within seconds and are lucid, without apparent cog-nitive deficit. In many, awakenings are provoked by a stimulus (e.g., a mosquito bite). Awakening either is sudden, sitting upright in bed, or may be associated with marked restlessness and agitation. Sudden movement of a hand, reaching and squeezing a family member, is another theme (Rocky II). The success of rehabilitation is emphasized after many years in coma (Dead Zone, Habla con Ella), trivializing the catastrophic injury.

The attending physician is often portrayed with little compassion (Table 11-1). Consistent with earlier studies,10,11 physicians are displayed as paternalistic and egotisti-cal. Patients in PVS are often referred to by physicians as “vegetables”; some screenwrit-ers have taken it a step further by talking about “the garden” (nursing home).

The general viewer is capable of identifying these inaccuracies, but a survey of key scenes suggested that an unacceptable number of viewers (36%) have difficulty point-ing out these misleading scenes.32 Nonetheless, screenplays depicting coma can be factual, and there are several examples (Dreamlife of Angels, Reversal of Fortune, Miami Vice, and Fracture). Most screenwriters, however, go for uncompromising, fantastical entertainment.

TABLE 11-1 Physician Dialogue Lines in motion Pictures about Coma

Movie LineRegarding Henry Mrs. Turner, your husband is incredibly lucky. The bullet wound to the head caused

minimal damage. See, it hit the right frontal lobe. That’s the only part of the brain that

has redundant systems. I mean, if you’re going to get shot in the head . . . that’s the way

to do it.Lying in Wait He is no longer in a coma. He is in what we call a persistent vegetative state.

He cannot speak. The tests prove that, but you never know. One day Keith may sit up and

recite the Gettysburg Address.Paparazzi Now, let’s talk about this guy here. His vitals are good, but comas are a tricky thing. We

just have to wait.Habla con Ella Man: So that means there is hope? Doctor: No. I repeat, scientifically, no. But if you

choose to believe go ahead.Blind Horizon Well, 50% total recovery, 35% partial, and 15% you plant him in the ground and watch

him grow.Critical Care I have lettuce in my refrigerator that has a better chance of becoming conscious than this

guy.

From reference 36 with permission.


CONCLUSIONS

We can only scratch the surface here, but what is apparent is a very troubling situation. Sources of information for the public may involve newspapers, local TV, the Internet, and the movies. Without being unnecessarily hostile to the press, one can argue that the representation of comatose states in the media is concerning. Seldom do reporters shape the information in a useful way and correctly convey the major consequences of coma and rehabilitation to the public. There are only a few instances of an admirable combi-nation of reportage and essay. The credibility of newspaper reports can be increased by specifically mentioning coma associated with sedating drugs initiated by the physician. Journalists should make the extra call to a physician rather than relying on police reports. Screenwriters often make a mockery of coma and awakenings, creating scripts that are decidedly unflattering to the medical profession. It is uncertain whether that can change.

Coma is a consequence of a brain injury that often leads to a severe disability and agony to family members. There should be a sensible depiction in media outlets and an attempt to frame it correctly. Journalists, screenwriters, TV commentators, and corre-spondents all have a responsibility to be cautious. Audience members may be quite per-ceptive but are still are unsure where to draw the line between fact and wishful thinking.

REFERENCES

1. The man who slept 19 years. Discovery Health Channel 2005.2. Brantley M. Miracle in Arkansas. Arkansas Times 2006.3. Brown DL. The Awakening: Sarah Scantlin’s 20-year journey from comatose to silence to breakthrough.

Washington Post 2005.4. Burns RB, Moskowitz MA, Osband MA, Kazis LE. Newspaper reporting of the medical literature. J Gen

Intern Med 1995;10:19–24.5. Casarett D, Fishman JM, MacMoran HJ, Pickard A, Asch DA. Epidemiology and prognosis of coma in

daytime television dramas. BMJ 2005;331:1537–1539.6. Cohen L, Morgan PP. Medical dramas and the press: who benefits from the coverage? CMAJ

1988;139:657–661.7. Cohen MR, Shafer A. Images and Healers: A Visual History of Scientific Medicine. Durham, NC: Duke

University Press, 2004.8. Daoust A, Racine E. Depictions of ‘brain death’ in the media: medical and ethical implications. J Med

Ethics 2013 April 12 [E-pub before print].9. DeVries WC. The physician, the media, and the ‘spectacular’ case. JAMA 1988;259:886–890.

10. Flores G. Mad scientists, compassionate healers, and greedy egotists: the portrayal of physicians in the movies. J Natl Med Assoc 2002;94:635–658.

11. Golden G. The physician at the movies: Master and Commander. Pharos Alpha Omega Alpha Honor Med Soc 2005;68:51.

12. Helford B. Drew’s in a coma.2001.13. Horton P. Thanks for the memories.2005.


14. Hudson Jones A. Medicine and the movies: Lorenzo’s Oil at century’s end. Ann Intern Med 2000;133: 567–571.

15. Kaplan K. As man lay in coma-like state, his brain was busy rebuilding. Los Angeles Times 2006.16. Knight J. Science in the movies: Hollywood or bust. Nature 2004;430:720–722.17. Lantz JC, Lanier WL. Observations from the Mayo Clinic National Conference on Medicine and the

Media. Mayo Clin Proc 2002;77:1306–1311.18. Larsson A, Oxman AD, Carling C, Herrin J. Medical messages in the media—barriers and solutions to

improving medical journalism. Health Expect 2003;6:323–331.19. Marchione M. Comatose man’s brain rewired itself, doctors say. While fibers were severed, nerve cells

stayed intact allowing later recovery. Baltimore Sun 2006.20. Osler W. Aequanimitas with Other Addresses: Internal Medicine as a Vocation. Philadelphia, PA: Blakiston

Son and Co., 1905.21. Picard A. How can we improve medical reporting? Let me count the ways. Int J Health Serv 2005;35:

603–605.22. Pribble JM, Goldstein KM, Fowler EF, et al. Medical news for the public to use? What’s on local TV

news. Am J Manag Care 2006;12:170–176.23. Pribble JM, Goldstein KM, Majersik JJ, et al. Stroke information reported on local television news: a

national perspective. Stroke 2006;37:1556–1557.24. Racine E, Amaram R, Seidler M, Karczewska M, Illes J. Media coverage of the persistent vegetative state

and end-of-life decision-making. Neurology 2008;71:1027–1032.25. Racine E, Karczewska M, Seidler M, Amaram R, Illes J. How the public responded to the Schiavo con-

troversy: evidence from letters to editors. J Med Ethics 2010;36:571–573.26. Schwitzer G. A statement of principles for health care journalists. Am J Bioeth 2004;4:W9–13.27. Senouci K, Guerrini P, Diene E, et al. A survey on patients admitted in severe coma: implications for

brain death identification and organ donation. Intensive Care Med 2004;30:38–44.28. Shore D. Son of a coma guy.2006.29. Smothers R. Injured in ‘88, officer awakens in ‘96. The New York Times 1996.30. Staba D. Illness claims a firefighter whose awakening made headlines. The New York Times 2006.31. UPI. David Mack who emerged from long coma in ‘81 dies. The New York Times 1986.32. Wahl OF. Stop the presses: journalistic treatment of mental illness. In: Friedman LD, ed. Cultural Sutures,

Medicine and Media. Durham, NC: Duke University Press, 2004.33. Wang Z, Gantz W. Health content in local television news. Health Commun 2007;21:213–221.34. Wijdicks EFM. Minimally conscious state vs. persistent vegetative state: the case of Terry (Wallis) vs. the

case of Terri (Schiavo). Mayo Clin Proc 2006;81:1155–1158.35. Wijdicks EFM. Why the new HBO documentary, ‘COMA,’ is disappointing. Neurology Today

2007;7:28–29.36. Wijdicks EFM, Wijdicks CA. The portrayal of coma in contemporary motion pictures. Neurology

2006;66:1300–1303.37. Wijdicks EFM, Wijdicks MF. Coverage of coma in headlines of US newspapers from 2001 through 2005.

Mayo Clin Proc 2006;81:1332–1336.

/ / / / / / / / / / / / / / / / / / PART TWO / / | / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / /

THE CLINICAL APPROACH TO THE COMATOSE PATIENT

313

Coma has many causes, and each clinical presentation has unique characteristics. Comatose patients present in the field, in the emergency department, in the ICU, in the recovery room, or on the ward. Often there is one particular overriding clue or at least some hierarchy in multifactorial situations. Therefore, a one-factor expla-nation model is needed to understand clinical circumstances caused by all sorts of triggers. When the cause is likely or established, more information is warranted—in par-ticular, how best to manage the patient and what clinical course is likely. Early prognos-tication is avoided, but in patients with catastrophic injury, limitations of interventions are recognized.

Diagnostic evaluation and patient management are discussed during rounds, at the bedside, during phone calls from the emergency department or outside the hospi-tal. Therefore, each following vignette is introduced as a dialogue (“A Conversation”) between a resident (R) and neurologist or neurosurgeon (N) or as an interaction between staff (Fig. 12-1). After this introduction of the case, an explanation of the cause of coma follows. Each clinical vignette reflects current understanding of the discussed disorder and has a table with attributed causes of coma. It includes the presumed localization in structural coma and alternative explanations in coma associated with acute physiological brain dysfunction or toxins. Given a certain cause, its purpose is not only to explain why and how patients are comatose, but also how we can best support the patient, reverse the condition, or make decisions on palliative care. Each vignette ends with a key observation and essential references.

These 100 clinical vignettes should provide the essential pieces of information to understand the mechanisms of coma.

An Introduction to 100 Vignettes/ / / 12 / / /

314 / / The ComATose PATIenT

FIGURE 12-1 The conversations.

315

A CONVERSATION

AN EXPLANATION

Traumatic brain injury is seldom an isolated injury. The arrival of a blood-covered, poly-trauma patient requires certain priorities. After securing the airway, oxygen administra-tion, venous access, and fluid resuscitation, the attending physician should classify the type and severity of injury. In the early stage of assessment, care must be taken to define (1) the presence of multisystem injury, (2) the type of brain injury and need for neuro-surgical intervention, and (3) the presence of a coagulopathy.10,16 The “routine” imaging

Comatose and Traumatic Brain Injury

/ / /13 / / /


of a patient with “severe” trauma—both arbitrary qualifiers—is usually predicated on a high injury severity score (ISS; Table 13-1). This score correlates closely with mortal-ity and outcome, but, although established, the designations are subject to individual choices. In a patient with an ISS of more than 20, the injury is considered severe enough to justify more imaging studies, including CT of the chest, abdomen, pelvis, and in par-ticular cervical and thoracic spine that should include multislice, 2.5-mm scanning with sagittal reconstruction. In our patient example, multiple injuries were present (Fig. 13-1).

A recent study at a trauma center found that 38% of patients with blunt trauma had an unexpected finding on body CT scans, although these injuries did not all lead to a change in treatment (Fig. 13-2).13 In other studies—obviously depending on the severity of injury—patients with traumatic brain injury not uncommonly had a clinically significant abnormality elsewhere (e.g., ureteropelvic junction injury, diaphragmatic injury, pneu-mothorax, and thoracolumbar fractures).1,8 Multiple organ injury is expected and com-mon in bomb blast injuries. Survivors are injured by flying debris or from a “blast wind” ejection. CT scans of the brain may show typical contusions, but also more frequently a comminuted maxillary sinus fracture due to penetrating trauma or burst fractures of the spine.6 In the most severe cases extracorporeal membrane oxygenation (ECMO) has helped in saving lives.1

TABLE 13-1 Injury severity score (Iss)

Region AIS

Head and neck 1–6Face 1–6Chest 1–6Abdomen 1–6Extremities 1–6External 1–6Injury Severity Score

The ISS is an anatomical scoring system that provides an

overall score for patients with multiple injuries. Each injury

is assigned an abbreviated injury scale (AIS) score and

is allocated to one of six body regions (head, face, chest,

abdomen, extremities [including pelvis], and external) (AIS

score: 1 = minor, 2 = moderate, 3 = serious, 4 = severe, 5 = critical,

6 = unsurvivable). Only the highest AIS score in each body region

is used. The three most severely injured body regions have their

score squared and added together to produce the ISS score. With

an injury and AIS of 6, ISS automatically defaults to 75.

Comatose and Traumatic Brain Injury / / 317

The causes of coma in traumatic brain injury are shown in Table 13-2. Decreased con-sciousness in a polytraumatized patient can be due to the additional effect of alcohol and drugs but is more likely directly due to the severity of the impact. Hemorrhagic contu-sions may expand and shift the brainstem. Cerebral edema may occur after diffuse axonal injury or even after evacuation of a contusional lesion and suddenly increase intracranial pressure (ICP). Traumatic brain injury with marked anoxia (found head down) or isch-emia (marked blood loss or near exsanguination) may be the cause of persistent coma. Traumatic dissection of the carotid or vertebral artery may be more common than recog-nized and would require a CT angiogram or MRI in order to diagnose it.

(A) (B)

FIGURE 13-1 (A) Chest x-ray. Widening of the superior mediastinum, left pneumothorax, exten-

sive subcutaneous emphysema of the left chest wall. (B) CT scan shows massive soft tissue

swelling and traumatic subarachnoid hemorrhage.

0

20

40

60

80

Pati

ent

(no.

)

100

Rib/ste

rnal

fractu

res

Pulmon

ary

contu

sions

Hemot

horax

/

pneu

mot

horax

Med

iastin

al

hemato

ma

Free

fluid

Splenic

lacer

ation

Liver l

acer

ation

Retrop

erito

neal

inju

ry

Pelvic/

lum

bar

fractu

re

FIGURE 13-2 Injury profile of patients with unexpected CT findings (n = 173). Some patients had

more than one finding. From Self et al.13


The main findings on CT scan and MRI are shown in Figure 13-3. CT scan of the brain can demonstrate shear lesions and hemorrhagic contusions, but also primary brain-stem injury (Chapter 15) and extracerebral hematomas (Chapters 17 and 18) Initially, CT scan may not bring out anoxic-ischemic injury or diffuse axonal injury. Hemorrhagic contusions could appear hours after the first admission CT scan, thus warranting serial

TABLE 13-2 Causes of Coma in Traumatic Brain Injury

• Diffuse axonal injury• Cerebral edema• Expanding hemorrhagic temporal lobe contusion• Anoxic-ischemic injury associated with shock and upper airway collapse• Drug overdose or alcohol intoxication• Cerebral infarcts with carotid or vertebral artery dissection

(A) (B)

(C) (D)

FIGURE 13-3 CT scans and MR examples of traumatic brain injury (A) Bilateral mixed-density

contusional lesions in temporal lobes. (B) Traumatic subarachnoid blood. (C) Severe injury to

corpus callosum. (D) Additional anoxic injury after subdural hematoma.


CT scanning in any patient with a severe traumatic head injury. Traumatic subarachnoid hemorrhage favors the convexity but may be bilaterally present in the sylvian fissures. Intraparenchymal contusions have a proclivity for the anterior temporal lobe and infe-rior frontal lobe and tend to present in multiple locations. MRI (including gradient echo sequence) may demonstrate lesions in the corpus callosum not detected by CT scan. Lesions in the corpus callosum and subcortical white matter indicate considerable shear injury. Brain edema may be prominent, and reduced ADC values on DWI MRI corre-spond with a cellular form of edema and not vasogenic edema.11

A TREATMENT PLAN AND PROGNOSIS

The early management of traumatic brain injury is control of ICP and maintenance of cerebral perfusion pressure. Despite a recent South American clinical trial showing no additional benefit of ICP monitoring in patients already aggressively treated on the basis of CT and clinical examination, most neurosurgeons still have a low threshold for placing an ICP monitor (Chapter 7).3 Adequate sedation and analgesia (e.g., combination of pro-pofol and fentanyl) may be needed to initially control ICP. Mechanical ventilation aiming at Paco2 30 to 35 mm Hg with PEEP levels at 10 cm H2O or less is desirable. The head is elevated at 30 degrees and in a neutral, not rotated, position. Hyperosmotic solutions are preferred, and in refractory cases, barbiturates or indomethacin may be helpful to deter-mine a possible effect on ICP, but whether monitoring of ICP improves outcome is not known and unlikely.3 The management of the patient with mild hypothermia is unclear, but early rapid rewarming is discouraged.

It is important to determine the significance of a parenchymal mass lesion. Comatose patients with frontotemporal contusions that are greater than 2 cm or a midline shift more than 5 mm and any patient who has a lesion greater than 5 cm should be considered for a craniotomy. This implies subtemporal decompression with temporal lobectomy in some cases.2 Decompressive craniotomy can control intractable ICP but does not improve out-come.7,14,17 Bifrontal decompressive craniectomy within 48 hours of injury can be consid-ered in patients with diffuse cerebral edema and evidence of increased ICP refractory to interventions.

Hypercapnia and hypocapnia are both common in patients with severe traumatic brain injury. Patients who, on arrival, have a normal arterial Pco2 have a better outcome than patients who are outside the normal range.4 Early tracheostomy in intubated patients with traumatic brain injury decreases morbidity and markedly increases patient comfort. It reduces ventilator days and also decreases the rate of ventilator-associated infections.

Another specific management issue is seizure management in patients who experi-ence a seizure within 24 hours of injury; treatment has traditionally included phenytoin.


The value of seizure prophylaxis in nonpenetrating head injury is unclear, and it is likely not useful beyond the first week of injury. The growing experience with levetiracetam may result in replacement of phenytoin. Not only is its safety profile better, but there is also evidence that it has additional neuroprotective properties.18 There are emerging data on the potential value of continuous video-EEG monitoring, but it has not found univer-sal application and is costly.

Multiple outcome prediction models have been published. There is a consensus that poor outcome is likely in patients with closed head injury and age above 60 years, absence of postresuscitation motor response, one or two nonreactive pupils 24 hours after injury, or loss of upper brainstem reflexes (pupils, cornea, and oculocephalic responses).5,18 The recent results of the IMPACT study (outcome based on Glasgow outcome score at 6 months in patients older than 14 years) identified the following prognosticators for a poor outcome: increasing levels of glucose, increased prothrombin time, decreasing levels of hemoglobin, hypotension, hypoxemia, hypothermia followed by early rewarm-ing, increasing age (particularly after 30 years), and CT characteristics of increased ICP (effaced basal cisterns, brain tissue shift of more than 5 mm from midline in combination with traumatic subarachnoid hemorrhage).12 MRI, at least in children and adolescents, found that the presence of multiple (seven or more) hemorrhagic lesions on MRI pre-dicted poor outcome.15

However, with this type of brain injury we never know for certain and prognostica-tion is hard, very hard, and perhaps simply impossible. The outcome is determined by many factors, and there are often factors that cannot be put into a scale, score, or model. It seems unjustified to make early hard predictions in patients with intact brainstem reflexes. Moreover, there is concern about the reliability of outcome assessment of the Glasgow outcome scale in traumatic head injury trials, and this could invalidate some of the identified prognostic factors.9 Most recovery occurs within 6 months, but significant steps may occur later, particularly in younger patients.

A CONCLUDING NOTE

Traumatic brain injury can be a single injury, but there are other injuries in most patients. Pulmonary injury may lead to rapid changes in oxygenation and hypercarbia, which can affect outcome. In patients who need sedation or neuromuscular blocking agents, ICP monitoring is needed to show the development of new contusional masses and subdural or epidural hematomas. When contusions emerge, they may cause mass effect and a sud-den rise in ICP, and surgical removal is warranted. Decompressive craniectomy alone is an option to control ICP in patients developing medically refractory brain edema.


REFERENCES

1. Biderman P, Einav S, Fainblut M, Stein M, Singer P, Medalion B. Extracorporeal life support in patients with multiple injuries and severe respiratory failure: a single-center experience? J Trauma Acute Care Surg. 2013;75:907–12.

2. Bullock MR, Chesnut R, Ghajar J, et al. Surgical management of traumatic parenchymal lesions. Neurosurgery 2006;58:S25–46.

3. Chesnut RM, Temkin N, Carney N, et al. A trial of intracranial-pressure monitoring in traumatic brain injury. N Engl J Med 2012;367:2471–2481.

4. Davis DP, Serrano JA, Vilke GM, et al. The predictive value of field versus arrival Glasgow Coma Scale score and TRISS calculations in moderate-to-severe traumatic brain injury. J Trauma 2006;60:985–990.

5. Gill M, Windemuth R, Steele R, Green SM. A comparison of the Glasgow Coma Scale score to simplified alternative scores for the prediction of traumatic brain injury outcomes. Ann Emerg Med 2005;45:37–42.

6. Hare SS, Goddard I, Ward P, Naraghi A, Dick EA. The radiological management of bomb blast injury. Clin Radiol 2007;62:1–9.

7. Honeybul S, Ho KM, Lind CR, Gillett GR. The future of decompressive craniectomy for diffuse traumatic brain injury. J Neurotrauma 2011;28:2199–2200.

8. Keel M, Trentz O. Pathophysiology of polytrauma. Injury 2005;36:691–709.9. Maas AI, Roozenbeek B, Manley GT. Clinical trials in traumatic brain injury: past experience and cur-

rent developments. Neurotherapeutics 2010;7:115–126.10. Maegele M, Lefering R, Yucel N, et al. Early coagulopathy in multiple injury: an analysis from the

German Trauma Registry on 8724 patients. Injury 2007;38:298–304.11. Marmarou A, Signoretti S, Fatouros PP, et al. Predominance of cellular edema in traumatic brain swelling

in patients with severe head injuries. J Neurosurg 2006;104:720–730.12. Murray GD, Butcher I, McHugh GS, et al. Multivariable prognostic analysis in traumatic brain

injury: results from the IMPACT study. J Neurotrauma 2007;24:329–337.13. Self ML, Blake AM, Whitley M, Nadalo L, Dunn E. The benefit of routine thoracic, abdominal,

and pelvic computed tomography to evaluate trauma patients with closed head injuries. Am J Surg 2003;186:609–613.

14. Timmons SD, Ullman JS, Eisenberg HM. Craniectomy in diffuse traumatic brain injury. N Engl J Med 2011;365:373; author reply 376.

15. Tong KA, Ashwal S, Holshouser BA, et al. Diffuse axonal injury in children: clinical correlation with hemorrhagic lesions. Ann Neurol 2004;56:36–50.

16. Voggenreiter G, Aufmkolk M, Majetschak M, et al. Efficiency of chest computed tomography in critically ill patients with multiple traumas. Crit Care Med 2000;28:1033–1039.

17. Walcott BP, Nahed BV, Sheth SA, et al. Bilateral hemicraniectomy in non-penetrating traumatic brain injury. J Neurotrauma 2012;29:1879–1885.

18. Wang H, Gao J, Lassiter TF, et al. Levetiracetam is neuroprotective in murine models of closed head injury and subarachnoid hemorrhage. Neurocrit Care 2006;5:71–78.

322

A CONVERSATION

AN EXPLANATION

When a bullet passes through the brain, a temporary cavity emerges due to its veloc-ity at close range. This cavity is a result of outward acceleration of tissue adjacent to the track and is dependent on the energy and shape of the bullet. The primary track shows axonal destruction with axonal fragments not only bordering the track but also neuro-nal changes up to 20 mm from the track-13 The velocity of the projectile is an impor-tant determinant in destruction and associated released energy, and thus there are major

Comatose and Gunshot Wounds/ / / 14 / / /

Comatose and Gunshot Wounds / / 323

differences between handguns, rifles, and military-grade weapons. Most gunshot wounds are homicides or suicides, and, less often, accidental injury.4 It is the leading cause of pen-etrating head injury in the United States.3,10 Explosive injury is more common than gun-shot wounds in contemporary combat situations.5

The causes of coma in a gunshot wound are shown in Table 14-1. Coma associated with a penetrating gunshot wound to the head results from injury to several lobes of the brain (Fig. 14-1), intraventricular hemorrhage, an expanding hematoma, or rapidly devel-oping brain edema. In some patients, the diencephalic structures and mesencephalon are destroyed. The track may enter into the posterior fossa, further extending the injury, and exit occipitally. Involvement of major vascular structures may occur.15


Arrival to a major medical center is important, but very few comatose patients have a chance of survival beyond 12 hours after injury.11 Destruction of the diencephalon, dif-fuse cerebral edema, or a laceration of a major cerebral vessel leading to massive cerebral hematoma all implicitly point to a poor outcome. Gunshot through the oropharynx may lacerate the vertebral artery.6 Migration of bullet fragments may occur, including emboli-zation to pulmonary arteries.9

Many neurosurgeons apply a protocol that combines assessment of consciousness on admission, the presence or absence of brainstem responses, and the presence of a hema-toma with mass effect on CT scan.7,8,12,14 The presence of pneumocephalus, epidural or subdural hematomas, or subarachnoid hemorrhage does not necessarily indicate a poor prognosis. Suggestions for management are shown in Figure 14-2. In this algorithm, coma and the presence of brainstem reflexes, including pupillary reflexes, are decisive elements. Patient who are stuporous and localizing should undergo debridement. This debridement consists of removal of necrotic tissue, accessible bone and bullet fragments, and evacuation of hematoma. In approximately 50% of patients, surgical intervention might be necessary, but it remains unclear whether deep débridement is advantageous in these patients.7 Fixed pupils, multilobar hematoma, and coma leads to death or per-sistent vegetative state in all cases.14 In a recently large Brazilian study of civilian gunshot

TABLE 14-1 Causes of Coma in Gunshot Wounds

• Brainstem injury (gun placed in mouth)• Hematoma with brainstem shift• Massive bihemispheric hematoma (gun placed on temple)• Diffuse cerebral edema


FIGURE 14-1 Left: gunshot injury with massive swelling and parenchymal hematoma along the

track with occipital exit wound. Right: gunshot injury crossing midline (temporal to temporal)

Comatose and Gunshot Wounds / / 325

wounds, age, coma at presentation, pupil abnormalities, presence of intracerebral hema-toma, and also respiratory infection were important factors.2 Removal of bullet material lodged deep inside the brain or ventricles is rarely successful.

An intracranial pressure (ICP) monitor can be placed, followed by treatment of ICP surges with conventional measures. However, many patients with gunshot wounds to the head are in extremis and progress to brain death, and ICP treatment is rarely suc-cessful. Patients with a penetrating head injury may develop a considerable consumptive coagulopathy that may need fresh frozen plasma or Factor VII or prothrombin complex concentrate.1

A CONCLUDING NOTE

Pupillary light response, depth of coma, and presence of a bihemispheric parenchymal hematoma are important initial factors that should be taken into account before pro-ceeding with a neurosurgical intervention. Gunshot wounds to the head could result in prolonged coma due to diencephalic destruction and in many patients result in a high mortality due to development of diffuse cerebral edema.

REFERENCES

1. Aiyagari V, Menendez JA, Diringer MN. Treatment of severe coagulopathy after gunshot injury to the head using recombinant activated factor VII. J Crit Care 2005;20:176–179.

2. Ambrosi PB, Valenca MM, Azevedo-Filho H. Prognostic factors in civilian gunshot wounds to the head: a series of 110 surgical patients and brief literature review. Neurosurg Rev 2012;35:429–435.

Penetrating gunshot injury of the head

GCS 3 fixed pupils GCS 3 reactive pupils or GCS 3

No surgery CT scan

Significant hematoma

No Yes

SurgeryGCS 6GCS 3, 4, or 5

SurgeryNo surgery

FIGURE 14-2 Neurosurgical options in gunshot injury to the brain. From Martins et al.,12 with

permission. GCS: Glasgow Coma Scale


3. Aryan HE, Jandial R, Bennett RL, et al. Gunshot wounds to the head: gang- and non-gang-related inju-ries and outcomes. Brain Inj 2005;19:505–510.

4. Balci Y, Canogullari G, Ulupinar E. Characterization of the gunshot suicides. J Forensic Leg Med 2007;14:203–208.

5. Belmont PJ, Jr., McCriskin BJ, Sieg RN, Burks R, Schoenfeld AJ. Combat wounds in Iraq and Afghanistan from 2005 to 2009. J Trauma Acute Care Surg 2012;73:3–12.

6. Cohen JE, Rajz G, Itshayek E, Umansky F, Gomori JM. Endovascular management of exsanguinating vertebral artery transection. Surg Neurol 2005;64:331–334.

7. Cosar A, Gonul E, Kurt E, et al. Craniocerebral gunshot wounds: results of less aggressive surgery and complications. Minim Invasive Neurosurg 2005;48:113–118.

8. Gonul E, Erdogan E, Tasar M, et al. Penetrating orbitocranial gunshot injuries. Surg Neurol 2005;63:24–30; discussion 31.

9. Hughes BD, Vender JR. Delayed lead pulmonary emboli after a gunshot wound to the head. Case report. J Neurosurg 2006;105:233–234.

10. Kriet JD, Stanley RB, Jr., Grady MS. Self-inflicted submental and transoral gunshot wounds that produce nonfatal brain injuries: management and prognosis. J Neurosurg 2005;102:1029–1032.

11. MacLeod JB, Cohn SM, Johnson EW, McKenney MG. Trauma deaths in the first hour: are they all unsal-vageable injuries? Am J Surg 2007;193:195–199.

12. Martins RS, Siqueira MG, Santos MT, Zanon-Collange N, Moraes OJ. Prognostic factors and treatment of penetrating gunshot wounds to the head. Surg Neurol 2003;60:98–104.

13. Oehmichen M, Meissner C, Konig HG, Gehl HB. Gunshot injuries to the head and brain caused by low-velocity handguns and rifles. A review. Forensic Sci Int 2004;146:111–120.

14. Polin RS, Shaffrey ME, Phillips CD, Germanson T, Jane JA. Multivariate analysis and prediction of out-come following penetrating head injury. Neurosurg Clin North Am 1995;6:689–699.

15. Vascik JM, Tew JM, Jr. Foreign body embolization of the middle cerebral artery: review of the literature and guidelines for management. Neurosurgery 1982;11:532–536.

327

A CONVERSATION

AN EXPLANATION

Primary brainstem injury is divided into penetrating and nonpenetrating injuries. The penetrating injuries are typically fatal, although several fortunate patients have been described with good recovery. In those instances, injury involved non-missile brainstem injury, and penetration may be caused by a metallic hook, screwdriver, or any other blunt object.1 Such injuries will lead to localizing neurologic signs but rarely coma and can cause facial paralysis, hemiparesis, dysarthric speech, and intranuclear ophthalmoplegia.2,3

Comatose and Traumatic Brainstem Lesion

/ / / 15 / / /


Other penetrating injuries of the brainstem include nail-gun and crossbow bolt acci-dents.6 The injury is usually through the orbital apex, through the superior orbital fissure, and then into the upper brainstem.

The causes of coma in traumatic brainstem injury are shown in Table 15-1. Nonpenetrating traumatic brainstem injury is the result of a rotation of the hemispheres in the anterior–posterior plane with the brainstem fixed in place.8 Shearing forces and torque cause severing of the perforating arteries and thus hemorrhages. It is likely due to a different mechanism than Duret hemorrhages (associated with increased intracranial pressure) or tearing associated with brainstem displacement (due to a mass causing a central or lateral force). It has been argued that hyperextension of the neck may stretch perforating arteries to the brainstem.9 The lesion can be anterior to the fourth ventricle and aqueduct, and this explains the occurrence of medial longitudinal fasciculus injury.2,7 The rotational forces may also converge on the diencephalon and upper brainstem. As an isolated lesion, brain injury is rare, and it is far more commonly seen with other shearing lesions. The brainstem may be damaged against the tentorium.


Treatment is largely supportive. Some of these comatose patients may have only retained medullary function, which provides adequate blood pressure and a respiratory drive, and these patients can potentially be weaned off the ventilator after tracheostomy. Posterior and bilateral brainstem lesions are poor prognostic signs.4 Nonpenetrating injury with primary brainstem injury has a much worse prognosis than other types of traumatic brain injury. These comatose patients have significant pontomesencephalic neuronal injury, and survival is not expected.5,10–13 The vast majority of comatose patients die without awakening, which is explained by a permanently injured reticular formation (Fig. 15-1).

A CONCLUDING NOTE

Traumatic brainstem injury may be the primary reason for coma in traumatic brain injury, due to the significant force, and is more often combined with other shear lesions at other

TABLE 15-1 Causes of Coma in Traumatic Brainstem Lesion

• Dorsal pontine-mesencephalon lesion• Multiple associated hemispheric shear lesions• Associated lobar contusions with mass effect• Associated extradural or subdural hematoma with mass effect

Comatose and Traumatic Brainstem Lesion / / 329

locations. The outcome is largely determined by the size of the lesion. Comatose patients usually have lost most brainstem reflexes except for medulla oblongata pressor centers maintaining circulatory stability. In less severely affected cases, recovery is possible, but a residual deficit is expected.

REFERENCES

1. de Andrade AF, de Almeida AN, Muoio VM, Marino R, Jr. Penetrating screwdriver injury to the brain-stem. Case illustration. J Neurosurg 2006;104:853.

2. Gray OM, Forbes RB, Morrow JI. Primary isolated brainstem injury producing internuclear ophthal-moplegia. Br J Neurosurg 2001;15:432–434.

FIGURE 15-1 Serial CT scan images in a patient with a traumatic brain injury showing multiple

small shear lesions, predominantly in the dorsal part of the brainstem.


3. Hashimoto T, Nakamura N, Richard KE, Frowein RA. Primary brain stem lesions caused by closed head injuries. Neurosurg Rev 1993;16:291–298.

4. Hilario A, Ramos A, Millan JM, et al. Severe traumatic head injury: prognostic value of brain stem inju-ries detected at MRI. AJNR Am J Neuroradiol 2012;33:1925–1931.

5. Khoshyomn S, Penar PL, Nagle K, Braff SP. Survival after severe penetrating non-missile brainstem injury: case report. J Trauma 2004;56:1131–1134.

6. Quinn LM, Egan RA, Shults WT. Transorbital penetrating brainstem injuries. Arch Ophthalmol 2006;124:915–916.

7. Randhawa S, Shah VA, Kardon RH, Lee AG. Neurological picture. An internuclear ophthalmoplegia with ipsilateral abduction deficit: half and half syndrome. J Neurol Neurosurg Psychiatry 2007;78:309.

8. Ropper AH, Gorson KC. Clinical practice. Concussion. N Engl J Med 2007;356:166–172.9. Sato M, Kodama N, Yamaguchi K. Post-traumatic brain stem distortion: a case report. Surg Neurol

1999;51:613–616.10. Wedekind C, Lippert-Gruner M. Long-term outcome in severe traumatic brain injury is significantly

influenced by brainstem involvement. Brain Inj 2005;19:681–684.11. Wijdicks EF, Atkinson JL, Okazaki H. Isolated medulla oblongata function after severe traumatic brain

injury. J Neurol Neurosurg Psychiatry 2001;70:127–129.12. Woischneck D, Klein S, Reissberg S, et al. Prognosis of brain stem lesion in children with head injury.

Childs Nerv Syst 2003;19:174–178.13. Zuccarello M, Fiore DL, Trincia G, et al. Traumatic primary brain stem haemorrhage. A clinical and

experimental study. Acta Neurochir (Wien) 1983;67:103–113.

331

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AN EXPLANATION

There are clinical and autopsy criteria for the diagnosis of shaken-baby or shaken-impact syndrome.2,7,13,16,21 Shaken-impact syndrome is usually caused by males, often the bio-logical father, the mother’s boyfriend, or a childcare provider such as a nanny or babysit-ter. The major suspect is usually the one who finds the baby at the time of presentation. However, none of the clinical signs are specific, and all are open to interpretation and controversy.3,5,15,17,18,22 There has been controversy in explaining the pathophysiology (Chapter 6). More recently, a provocative study, known as the Geddes Hypothesis, found

Comatose and shaken-Impact syndrome

/ / / 16 / / /


that subdural and retinal hemorrhages were not caused by traumatic shearing of the sub-dural veins and retinal vessels but by cerebral hypoxemia and raised intracranial pressure from brain swelling, suggesting that little trauma rather than repetitive shaking would need to be involved to cause these symptoms. Whether a specific rotational force is nec-essary to produce such a syndrome has been questioned.6,12

The clinical recognition of a patient with shaken-baby or shaken-impact syndrome is difficult, and it must be viewed in a much broader social context. Characteristically, it is an infant found not breathing, resuscitated, and brought in comatose10,14 (Table 16-1). Most of the time, the young child will have no obvious external injury. Scalp swelling can be seen with a bulging anterior fontanel, together with bruises, welts, or burns.14 On examination, retinal hemorrhages are apparent that can be predominantly in the periph-eral portion of the retina and can even be unilateral (Figure 16-1). Without dilatation of the pupil, these abnormalities are not easily visualized with funduscopy.1 A perimacular retinal fold is often present. The macula is attached to the vitreous retinal blood vessels and retina and therefore is easily severed due to traction.9,20 One study found that optic sheath hemorrhages were significantly more often found in shaken-baby syndrome than in accidental blunt head injury.23 Hematomas may even extend to the orbital tissue and can sometimes only be detected after autopsy and en bloc resection of the orbit.23 The skeletal survey may be able to detect prior fractures, but skeletal injury is absent in more than half of the abused children.19 Accidental trauma can also produce fractures, but diaphyseal fractures are more commonly found in shaken-impact syndrome.11

The causes of coma in shaken-impact syndrome are shown in Table 16-2. It is less likely due to mass effect of an extradural or subdural hematoma and more often due to diffuse cerebral swelling. Most often, coma (or brain death) is a consequence of devastat-ing anoxic-ischemic injury associated with respiratory arrest. The CT scan of the brain may show a subdural hematoma or marked hypodensities, also known as the “black brain”4 (Fig. 16-1). This pertains to extensive loss of the gray–white matter differentia-tion, with relative sparing of the basal ganglia and posterior fossa. (The sparing of the posterior fossa is also known as the “reversal sign.”8) MRI is more helpful in documenting subdural hematoma and the presence of diffuse encephalomalacia. Subdural hematoma

TABLE 16-1 Clinical signs of shaken-Impact syndrome

• Found comatose with agonal breathing• Full fontanel• Brain swelling and subdural hematomas on CT scan• Posterior arc rib fractures• Grab-type bruising on arm

Comatose and shaken-Impact syndrome / / 333

is usually in the parieto-occipital convexity (Chapter 6). Gradient-echo imaging may reveal the presence of blood products.

Alternative explanations for shaken-impact syndrome include coagulopathies such as hemophilia and hypoprothrombinemia caused by vitamin K deficiency. Important blood tests should include platelet count, prothrombin time, activated partial thromboplastin and bleeding times; abnormal values could point to an alternative explanation.

TABLE 16-2 Causes of Coma in shaken-Impact syndrome

• Anoxic-ischemic laminar cortical necrosis• Bilateral subdural hematomas• Diffuse axonal brain injury• Diffuse cerebral swelling

FIGURE 16-1 Massive retinal hemorrhages and typical “black brain” associated with

shaken-impact syndrome.



Surgical intervention to remove the subdural hematoma is rarely successful, and place-ment of an intracranial pressure (ICP) monitor often documents a normal ICP. Babies presenting with acute respiratory failure after resuscitation and cerebral edema on imag-ing have a poor outcome. If they do survive, the vast majority will have serious long-term morbidity.

A CONCLUDING NOTE

Physicians should recognize that sudden respiratory failure followed by cardiopulmonary resuscitation in a baby or child less than 2 years old could point toward shaken-impact syndrome. Early involvement of a social worker may be helpful to revisit the social envi-ronment. Alternative diagnoses should be considered, and a full coagulation panel should be obtained.

REFERENCES

1. Arlotti SA, Forbes BJ, Dias MS, Bonsall DJ. Unilateral retinal hemorrhages in shaken baby syndrome. J AAPOS 2007;11:175–178.

2. Christian CW, Block R. Abusive head trauma in infants and children. Pediatrics 2009;123:1409–1411.3. Donohoe M. Evidence-based medicine and shaken baby syndrome: part I: literature review, 1966–1998.

Am J Forensic Med Pathol 2003;24:239–242.4. Duhaime AC, Bilaniuk L, Zimmerman R. The “big black brain”: Radiographic changes after severe

inflicted head injury in infancy. J Neurotrauma 1993;10 (Suppl 1):S59.5. Duhaime AC, Christian CW, Rorke LB, Zimmerman RA. Nonaccidental head injury in infants—the

“shaken-baby syndrome.” N Engl J Med 1998;338:1822–1829.6. Geddes JF, Hackshaw AK, Vowles GH, Nickols CD, Whitwell HL. Neuropathology of inflicted head

injury in children. I. Patterns of brain damage. Brain 2001;124:1290–1298.7. Gerber P, Coffman K. Nonaccidental head trauma in infants. Childs Nerv Syst 2007;23:499–507.8. Han BK, Towbin RB, De Courten-Myers G, McLaurin RL, Ball WS, Jr. Reversal sign on CT: effect of

anoxic/ischemic cerebral injury in children. AJR Am J Roentgenol 1990;154:361–368.9. Hylton C, Goldberg MF. Images in clinical medicine. Circumpapillary retinal ridge in the shaken-baby

syndrome. N Engl J Med 2004;351:170.10. King WJ, MacKay M, Sirnick A. Shaken baby syndrome in Canada: clinical characteristics and outcomes

of hospital cases. CMAJ 2003;168:155–159.11. Kleinman PK, Blackbourne BD, Marks SC, Karellas A, Belanger PL. Radiologic contributions to the

investigation and prosecution of cases of fatal infant abuse. N Engl J Med 1989;320:507–511.12. Lancon JA, Haines DE, Parent AD. Anatomy of the shaken baby syndrome. Anat Rec 1998;253:13–18.13. Laurent-Vannier A, Nathanson M, Quiriau F, et al. A public hearing. “Shaken baby syndrome: guidelines

on establishing a robust diagnosis and the procedures to be adopted by healthcare and social services staff.” Scoping report. Ann Phys Rehabil Med 2011;54:533–599.

14. Le Fanu J. Shaken baby syndrome. Arch Dis Child 2006;91:715.15. Miller M, Leestma J, Barnes P, et al. A sojourn in the abyss: hypothesis, theory, and established truth in

infant head injury. Pediatrics 2004;114:326.

Comatose and shaken-Impact syndrome / / 335

16. Oehmichen M, Meissner C, Saternus KS. Fall or shaken: traumatic brain injury in children caused by falls or abuse at home—a review on biomechanics and diagnosis. Neuropediatrics 2005;36:240–245.

17. Tilak GS, Pollock AN. Missed opportunities in fatal child abuse. Pediatr Emerg Care 2013;29:685–768.18. Richards PG, Bertocci GE, Bonshek RE, et al. Shaken baby syndrome. Arch Dis Child 2006;91:205–206.19. Rorke LB. Neuropathology. In: Ludwig S, Kornberg A, eds. Child Abuse: A Medical Reference, 2nd ed.

New York: Churchill Livingstone, 1992:403–421.20. Schloff S, Mullaney PB, Armstrong DC, et al. Retinal findings in children with intracranial hemorrhage.

Ophthalmology 2002;109:1472–1476.21. Stewart TC, Polgar D, Gilliland J, et al. Shaken baby syndrome and a triple-dose strategy for its preven-

tion. J Trauma 2011;71:1801–1807.22. Uscinski R. Shaken baby syndrome: fundamental questions. Br J Neurosurg 2002;16:217–219.23. Wygnanski-Jaffe T, Levin AV, Shafiq A, et al. Postmortem orbital findings in shaken baby syndrome. Am

J Ophthalmol 2006;142:233–240.

336

A CONVERSATION

AN EXPLANATION

As a direct result of injury to the middle meningeal artery (situated beneath the pterion), most epidural hematomas are located in the parietotemporal area.3 Uncommon localiza-tions are in the posterior fossa and vertex, and these are areas that may not be clearly imaged on CT or hardly noticed due to the multiplicity of line artifacts.1,8 Most acute epidural hematomas are above the tentorium, and they may present in different ways. In 25% to 50% of cases, patients may present initially comatose to the emergency depart-ment.11 In the remaining patients, an asymptomatic interval exists in which the patient

Comatose and Acute epidural hematoma

/ / / 17 / / /

Comatose and Acute epidural hematoma / / 337

remains conscious after the impact, but then rapidly deteriorates. There is often a sudden onset of coma with development of a fixed unilateral pupil that rapidly progresses into bilateral fixed pupils. The presence of an epidural hematoma in the vertex may be far more difficult to recognize and perhaps has a more rapid evolution with headaches followed by a significant decline in consciousness in a matter of hours.

The causes of coma in acute epidural hematoma are shown in Table 17-1. The degree of brainstem displacement and compression is a major mechanism of coma, but other brain contusions may be present. Acute hydrocephalus has been described as cause of coma in patients with an epidural hematoma in the posterior fossa, although lateral brain-stem shift is a more likely mechanism. Complex partial epilepsy in supratentorial epidural hematoma may emerge in patients after surgical evacuation and is a possible reason for not fully awakening.

On CT scan, an epidural hematoma is noted as a mixed-density or a hyperlucent area and, as in this case (Fig. 17-1), indicates continuous bleeding.5,9,10 Epidural hematomas are sometimes associated with free air, which points to a mastoid or sinus fracture. In the acute

TABLE 17-1 Causes of Coma in Acute epidural hematoma

• Lateral brainstem displacement• Associated lobar contusions• Recurrent hemorrhage after craniotomy• Acute obstructive hydrocephalus (posterior fossa)• Complex partial status epilepticus

(A)

(B)

FIGURE 17-1 (A) Epidural hematoma with hyperlucent area. (B) Adequate evacuation of epidural

hematoma but a new epidural hematoma on the other side.


phase, MR imaging of epidural hematoma is isointense on T1 and hyper- or hypodense on T2. When it becomes subacute, the intensity changes to hyperintense on T1.


Neurosurgical evacuation is key. Subgroups of patients who do not benefit from emer-gency neurosurgery have not been identified. Although the presence of fixed pupils and associated intracranial hemorrhages may intuitively indicate poor outcome, data are not available to justify foregoing surgical evacuation. Long-term morbidity and mortality in children are linked to lack of promptness of evacuation.3 In addition, prognosis is deter-mined by other factors. Initial volume (>50 cc) and obliteration of the basal cisterns are important poor prognosticating CT signs.12 Brain tissue shift of more than 5 mm (mea-sured at the location of the septum pellucidum) is also a CT prognosticator for poor out-come.12 Clinically, the presence of bilateral fixed pupils is associated with poor outcome in half of the patients despite evacuation of the hematoma. In older studies, the degree of coma has been identified as an important factor determining outcome at 6 months. Mortality is about 10% if the patient is stuporous but about 74% when comatose with abnormal motor responses.4 Indications for surgery are volume greater than 30 cm3 but also any comatose patient, particularly if anisocoria or new focal signs emerge.2

Outcome in posterior fossa epidural hematoma is determined by associated supra-tentorial lesions.6 Some series have reported excellent recovery in the majority of cases.7

A CONCLUDING NOTE

Acute epidural hematoma is generally a highly unstable lesion with a potential for expan-sion. Serial CT scanning is needed. Additional contusions or even a second epidural hematoma may develop.11 In such instances, patients may become unconscious, lucid after craniotomy, and then unconscious again.

REFERENCES

1. Bozbuga M, Izgi N, Polat G, Gurel I. Posterior fossa epidural hematomas: observations on a series of 73 cases. Neurosurg Rev 1999;22:34–40.

2. Bullock MR, Chesnut R, Ghajar J, et al. Surgical management of acute epidural hematomas. Neurosurgery 2006;58:S7–15.

3. Ciurea AV, Kapsalaki EZ, Coman TC, et al. Supratentorial epidural hematoma of traumatic etiology in infants. Childs Nerv Syst 2007;23:335–341.

4. Gennarelli TA, Spielman GM, Langfitt TW, et al. Influence of the type of intracranial lesion on outcome from severe head injury. J Neurosurg 1982;56:26–32.

Comatose and Acute epidural hematoma / / 339

5. Inamasu J, Hori S, Aoki K, et al. CT scans essential after posttraumatic loss of consciousness. Am J Emerg Med 2000;18:810–811.

6. Jang JW, Lee JK, Seo BR, Kim SH. Traumatic epidural hematoma of the posterior cranial fossa. Br J Neurosurg 2011;25:55–61.

7. Karasu A, Sabanci PA, Izgi N, et al. Traumatic epidural hematomas of the posterior cranial fossa. Surg Neurol 2008;69:247–251.

8. Miller DJ, Steinmetz M, McCutcheon IE. Vertex epidural hematoma: surgical versus conservative management: two case reports and review of the literature. Neurosurgery 1999;45:621–624; discussion 624–625.

9. Oertel M, Kelly DF, McArthur D, et al. Progressive hemorrhage after head trauma: predictors and con-sequences of the evolving injury. J Neurosurg 2002;96:109–116.

10. Rocchi G, Caroli E, Raco A, Salvati M, Delfini R. Traumatic epidural hematoma in children. J Child Neurol 2005;20:569–572.

11. Swartz KR, Fee DB, Dempsey RJ. Blossoming traumatic epidural hematoma. J Emerg Med 2003;25:451–452.

12. van den Brink WA, Zwienenberg M, Zandee SM, et al. The prognostic importance of the volume of traumatic epidural and subdural haematomas revisited. Acta Neurochir (Wien) 1999;141:509–514.

340

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AN EXPLANATION

Emergency transfer of a patient with an acute subdural hematoma to a center with neu-rosurgical intervention allows emergency treatment. Acute subdural hematoma is mostly caused from a fall or assault and less commonly a motor vehicle accident.5 Acute or chronic subdural hematomas, particularly when bilateral, occur after trivial trauma in patients with anticoagulation and more or less spontaneously in the setting of cerebro-spinal fluid (CSF) hypotension due to a spinal CSF leak (Chapter 49).11 An acute subdu-ral hematoma is clinically recognized as an impaired level of consciousness after a “lucid

Comatose and Acute subdural hematoma

/ / / 18 / / /

Comatose and Acute subdural hematoma / / 341

interval.” This delay of clinical manifestations has been questioned, and many patients deteriorate from onset and may eventually present with signs of brain tissue shift. On CT scan, acute subdural hematoma has a crescent shape, is hyperdense, and most notably demonstrates its mass effect by compressing the ventricles (Fig. 18-1). On FLAIR MRI, acute subdural hematomas are hyperintense to CSF.

The causes of coma in acute subdural hematoma are shown in Table 18-1. With a significant trauma likely, subdural hematoma might not be the only brain injury, and additional intracranial or extracranial injuries might be found.1 A prospective study of 33 patients with surgical evacuation of subdural hematoma found that 50% had addi-tional evidence of brain tissue injury underlying the evacuated subdural hematoma.3

FIGURE 18-1 CT scan of a patient with acute subdural hematoma and marked tissue shift (note

displacement of septum pellucidum and pineal gland). The enlarged tip of the temporal lobe is

also dramatically shifted and almost midline.


Failure to awaken after surgical removal may also be attributed to an expanding contusion (Fig. 18-2). Subarachnoid hemorrhage may be present and may indicate the presence of a ruptured intracranial carotid aneurysm.7,14,16 Alcohol intoxication—and not so much the subdural hematoma itself—may cause a marked decline in consciousness. The degree of brainstem shift and intrinsic brainstem injury determines the depth of coma and recovery after evacuation. Failure to improve after surgical evacuation may also be due to the devel-opment of a hematoma at a remote site (cerebellum, hemispheric). Venous hypertension has been implicated as a mechanism.4,10


Indication for surgery is determined by the level of consciousness, presence of shift and brainstem displacement, and, if available, increasing intracranial pressure.2,5,6,11 Useful recommendations for surgery have been published.2 Any patient who has neurologic deterioration would need evacuation of an acute subdural hematoma.12 Many neurosur-geons would evacuate an acute subdural hematoma with a thickness more than 10 mm

TABLE 18-1 Causes of Coma in Acute subdural hematoma

• Mass effect and lateral brain tissue shift and brainstem displacement• Expanding hemispheric contusion• Alcohol intoxication• Rupture of cerebral aneurysm (rare)• Remote hematoma after evacuation (rare)

FIGURE 18-2 Evacuation of subdural hematoma; patient failed to awaken. Note the new contra-

lateral contusion on repeat CT scan with shift to the opposite side.

Comatose and Acute subdural hematoma / / 343

(this size is approximately the same as the skull thickness) or a midline shift of more than 5 mm on CT scan.2 The decision to operate in comatose patients with large subdural hematomas is arbitrary and determined by neurologic findings. Contrast extravasation markedly predicted hematoma growth—similar as in cerebral hematomas.9 Little or no improvement is expected in patients with large hematomas when both pupils and cornea reflexes are lost and motor response is extensor posturing or worse. A patient group may be identified in which there is no benefit of surgery. These patients have massive mid-line shift and early brainstem hemorrhages and have lost upper brainstem reflexes (pupil reflexes, corneal reflexes, and oculocephalic reflexes).13,15,17 The postoperative phase may be complicated by seizures, and some patients have a prolonged recovery.8

A CONCLUDING NOTE

An acute subdural hematoma with a thickness greater than 10 mm or a midline shift of more than 5 mm on CT scan requires evacuation even if the pupils are fixed to light. The decision to operate in comatose patients with large subdural hematomas and absent upper brainstem reflexes remains questionable, with little benefit expected. Associated contusional lesions may contribute to impaired consciousness and may not be initially apparent on CT scan.

REFERENCES

1. Abe M, Udono H, Tabuchi K, et al. Analysis of ischemic brain damage in cases of acute subdural hema-tomas. Surg Neurol 2003;59:464–472.

2. Bullock MR, Chesnut R, Ghajar J, et al. Surgical management of acute subdural hematomas. Neurosurgery 2006;58:S16–24.

3. Hlatky R, Valadka AB, Goodman JC, Robertson CS. Evolution of brain tissue injury after evacuation of acute traumatic subdural hematomas. Neurosurgery 2004;55:1318–1323; discussion 1324.

4. Hyam JA, Turner J, Peterson D. Cerebellar haemorrhage after repeated burr hole evacuation for chronic subdural hematoma. J Clin Neurosci 2007;14:83–86.

5. Koc RK, Akdemir H, Oktem IS, Meral M, Menku A. Acute subdural hematoma: outcome and outcome prediction. Neurosurg Rev 1997;20:239–244.

6. Maas AI, Steyerberg EW, Butcher I, et al. Prognostic value of computerized tomography scan character-istics in traumatic brain injury: results from the IMPACT study. J Neurotrauma 2007;24:303–314.

7. Marbacher S, Fandino J, Lukes A. Acute subdural hematoma from ruptured cerebral aneurysm. Acta Neurochir (Wien) 2010;152:501–507.

8. Rabinstein AA, Chung SY, Rudzinski LA, Lanzino G. Seizures after evacuation of subdural hemato-mas: incidence, risk factors, and functional impact. J Neurosurg 2010;112:455–460.

9. Romero JM, Kelly HR, Delgado Almandoz JE, et al. Contrast extravasation on CT angiography predicts hematoma expansion and mortality in acute traumatic subdural hemorrhage. AJNR Am J Neuroradiol 2013;34:1528–1534.

10. Sato M, Nakano M, Asari J, Watanabe K. Intracerebral haemorrhage during surgery for chronic subdural haematoma. J Clin Neurosci 2007;14:81–83.

11. Schievink WI, Moser FG, Pikul BK. Reversal of coma with an injection of glue. Lancet 2007;369:1402.


12. Servadei F, Nasi MT, Cremonini AM, et al. Importance of a reliable admission Glasgow Coma Scale score for determining the need for evacuation of posttraumatic subdural hematomas: a prospective study of 65 patients. J Trauma 1998;44:868–873.

13. Servadei F, Nasi MT, Giuliani G, et al. CT prognostic factors in acute subdural hematomas: the value of the ‘worst’ CT scan. Br J Neurosurg 2000;14:110–116.

14. Shepherd D, Kapurch J, Datar S, Lanzino G, Wijdicks EF. Sphenoid and subdural hemorrhage as a pre-senting sign of ruptured clinoid aneurysm. Neurocrit Care 2013 (Epub July 27).

15. Uzan M, Yentur E, Hanci M, et al. Is it possible to recover from uncal herniation? Analysis of 71 head injured cases. J Neurosurg Sci 1998;42:89–94.

16. Westermaier T, Eriskat J, Kunze E, et al. Clinical features, treatment, and prognosis of patients with acute subdural hematomas presenting in critical condition. Neurosurgery 2007;61:482–487; discussion 487–488.

17. Wijdicks EFM. Uncal herniation in acute subdural hematoma: point of no return. Arch Neurol 2002;59:305.

345

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AN EXPLANATION

There has been emerging evidence for an increase in anticoagulation-associated intra-cerebral hemorrhage, which is largely due to increased use of warfarin.6 One risk factor for warfarin-related intracerebral hematoma is the presence of leukoaraiosis on CT scan. It has been speculated that leukoaraiosis in elderly patients may imply cerebral amyloid angiopathy and therefore increases the odds.21

Comatose and Cerebral hematoma

/ / / 19 / / /


Comatose patients with intracerebral hematoma often have been on oral anticoagula-tion or dual antiplatelet therapy that allows massive growth of the hematoma and thus more mass effect.

The causes of coma in cerebral hematoma are shown in Table 19-1. Each location may have a different mechanism of causing coma. The initial destruction of diencephalon structures is often the main reason for coma in thalamic hematomas. Consciousness is immediately lost in a large destructive thalamic hematoma that dissects into the mesen-cephalon (Fig. 19-1). Enlargement of a lobar hematoma is another mechanism and may cause more brainstem displacement (Fig. 19-2). One cause of enlargement of a cerebral hematoma is increasing cerebral edema. Perihematoma edema starts very early, within the first hours after onset, and may continue for at least three to four days and may have a delayed onset. The cause of edema surrounding the hematoma is a combination of factors that includes clot retraction with extrusion of serum but also activation of the coagulation cascade with production of thrombin and finally red blood cell lysis (Chapter 6).

A second cause of enlargement is expansion of the hematoma with more mass effect.10 This occurs in approximately 30% of the patients within the first hour but is less commonly observed after four hours. Enlargement of the hematoma is not related to baseline blood pressure, or pulse pressure (systolic–diastolic pressure) corrected for heart rate.11 The loca-tion of the hematoma may matter, with less frequently observed expansion in lobar hema-tomas. More commonly, enlargement of cerebral hematoma is related to the prior use of aspirin or warfarin. However, expansion of the warfarin-associated hematoma may not be halted by rapid correction of increased international normalized ratio (INR).12

CT characteristics of cerebral hematomas associated with anticoagulation include fluid–clot levels (“footprints”)5 (Fig. 19-3) and less edema than expected surrounding the hematoma due to less red blood cell lysis releasing hemoglobin. CT scan may show midline shift, intraventricular expansion, or massive destruction of the thalamus. Lobar hematoma would need to be differentiated from hemorrhagic infarct or venous occlusive disease.


Expansion of the hematoma affects outcome.9 One study calculated that for “each 1-mL increase in baseline intracerebral hemorrhage volume, the hazard ratio of dying

TABLE 19-1 Causes of Coma in Cerebral hematoma

• Large-volume hematoma with brainstem displacement• Destruction of diencephalon• Hemoventricle with acute hydrocephalus• Multiple lobar hematomas

Comatose and Cerebral hematoma / / 347

increased by 1% and survivors are 6% more likely to worsen by one point on the modi-fied Rankin scale.”3 Warfarin-associated intracerebral hemorrhages are often fatal. This is mostly a consequence of continuous bleeding allowing increasing volume or rupture into ventricles. There is a wide variation of opinions among experts on how to treat anticoagulation-associated hematomas.1 Essential in management of patients with warfarin-associated intracerebral hemorrhages is early correction of increased

FIGURE 19-1 Destructive thalamus hematoma with extension into mesencephalon.


FIGURE 19-2 Putaminal hematoma with compression of the thalamus and lateral brainstem shift.

FIGURE 19-3 Enlarging hematoma in anticoagulated patient. Note multiple fluid levels

(“footprints”).


INR with fresh frozen plasma (FFP) and vitamin K.1 Recombinant activated factor VII may be more effective in correcting INR.22 However, the usefulness of recombinant activated factor VII in patients who are comatose with massive intracranial destruc-tive hemorrhage is highly questionable. The concern with recombinant activated factor VII relates also to the number of thromboembolic events in treated patients.4,7,8,13,14,22 A recent study found that thromboembolic events are mostly arterial and involve not only acute myocardial infarction but also emboli to femoral, hepatic, pulmonary, renal, splenic, and iliac arteries.18 Deep venous thrombosis and pulmonary emboli have also been noted. Nonetheless, recombinant activated factor VII or other drugs (e.g., pro-thrombin complex) are far more effective than FFP and vitamin K. Reversal of warfarin is typically initiated in a patient with INR above 1.4.2,16 Reversal may involve the use of FFP and intravenous vitamin K (10 mg, typically), but recombinant factor VIIa or pro-thrombin complex concentrate is preferred. Current guidelines recommend, next to vitamin K 10 mg intravenously, infusion of four-factor prothrombin complex concen-trate (PCC) in combination with FFP or recombinant human factor VIIa.17 Benefits of PCC are shorter time to normalize INR (usually <30 minutes), little volume of infu-sion, and administration of all vitamin K-dependent coagulation factors. PCC lasts lon-ger than recombinant factor VIIa and less additional FFP is needed. The exact dose of PCC or factor VII is not known, but most studies have shown that factor VIIa with an additional dose of 10 to 50 mcg/kg was effective in reversing anticoagulation-associated intracranial hemorrhage.

Surgical evacuation of the cerebral hematoma should be considered. However, most randomized trials showed no improvement in outcome in patients with deep gan-glionic hemorrhages who were surgically treated and neurologically stable. A subgroup analysis of the Surgical Trial in Intracerebral Hemorrhage (STICH) trial suggested that patients with lobar hematomas (reaching within 1 cm of the cortical surface) had a pos-sible benefit of early surgery. The STICH trial also clearly defined that outcome was not affected by surgery in patients who presented in coma;15 in fact, in comatose patients, early surgery increased the risk of poor outcome by 8%. The STICH II trial, however, did not show any benefit of surgery in outcome in patients who had a lobar hematoma but could increase survival in patients with superficial hematoma and no intraventricu-lar hematoma. 16

However, the approach is different with worsening patients with rapidly expand-ing lobar hematoma: these patients could benefit from early evacuation, which may lead to improved outcome in 20% of patients. This also applies to patients with anticoagulation-associated cerebral hematomas.19,20


A CONCLUDING NOTE

Anticoagulation-associated cerebral hematoma should be managed with rapid correc-tion of increased INR using FFP and vitamin K, but PCC or recombinant activated fac-tor VIIa is a more effective option.11 Surgical evacuation of a cerebral lobar hematoma remains a viable option when mass effect exists. Persistent coma in cerebral hematoma can be attributed to direct destruction of the thalamus, brainstem shift, or marked intra-ventricular hematoma.

REFERENCES

1. Aguilar MI, Hart RG, Kase CS, et al. Treatment of warfarin-associated intracerebral hemorrhage: litera-ture review and expert opinion. Mayo Clin Proc 2007;82:82–92.

2. Andrews CM, Jauch EC, Hemphill JC, 3rd, Smith WS, Weingart SD. Emergency neurological life sup-port: intracerebral hemorrhage. Neurocrit Care 2012;17 Suppl 1:S37–46.

3. Davis SM, Broderick J, Hennerici M, et al. Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology 2006;66:1175–1181.

4. Deveras RA, Kessler CM. Reversal of warfarin-induced excessive anticoagulation with recombinant human factor VIIa concentrate. Ann Intern Med 2002;137:884–888.

5. Ecker RD, Wijdicks EF. Footprints of coagulopathy. J Neurol Neurosurg Psychiatry 2002;73:534.6. Flaherty ML, Kissela B, Woo D, et al. The increasing incidence of anticoagulant-associated intracerebral

hemorrhage. Neurology 2007;68:116–121.7. Flaherty ML, Woo D, Haverbusch M, et al. Potential applicability of recombinant factor VIIa for intrace-

rebral hemorrhage. Stroke 2005;36:2660–2664.8. Freeman WD, Brott TG, Barrett KM, et al. Recombinant factor VIIa for rapid reversal of warfarin antico-

agulation in acute intracranial hemorrhage. Mayo Clin Proc 2004;79:1495–1500.9. Gebel JM, Jr., Jauch EC, Brott TG, et al. Relative edema volume is a predictor of outcome in patients with

hyperacute spontaneous intracerebral hemorrhage. Stroke 2002;33:2636–2641.10. Huttner HB, Schellinger PD, Hartmann M, et al. Hematoma growth and outcome in treated neurocriti-

cal care patients with intracerebral hemorrhage related to oral anticoagulant therapy: comparison of acute treatment strategies using vitamin K, fresh frozen plasma, and prothrombin complex concentrates. Stroke 2006;37:1465–1470.

11. James RF, Palys V, Lomboy JR, Lamm JR Jr, Simon SD. The role of anticoagulants, antiplatelet agents, and their reversal strategies in the management of intracerebral hemorrhage. Neurosurg Focus 2013;34:E6.

12. Lee SB, Manno EM, Layton KF, Wijdicks EF. Progression of warfarin-associated intracerebral hemor-rhage after INR normalization with FFP. Neurology 2006;67:1272–1274.

13. Mayer SA. Ultra-early hemostatic therapy for intracerebral hemorrhage. Stroke 2003;34:224–229.14. Mayer SA, Brun NC, Begtrup K, et al. Recombinant activated factor VII for acute intracerebral hemor-

rhage. N Engl J Med 2005;352:777–785.15. Mendelow AD, Gregson BA, Fernandes HM, et al. Early surgery versus initial conservative treatment in

patients with spontaneous supratentorial intracerebral hematomas in the International Surgical Trial in Intracerebral Hemorrhage (STICH): a randomised trial. Lancet 2005;365:387–397.

16. Mendelow AD, Gregson BA, Rowan EN, et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral hematomas (STICH II): a randomized trial. Lancet 2013;382:397–408.

17. Morgenstern LB, Hemphill JC, 3rd, Anderson C, et al. Guidelines for the management of spontane-ous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2010;41:2108–2129.


18. O’Connell KA, Wood JJ, Wise RP, Lozier JN, Braun MM. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA 2006;295:293–298.

19. Rabinstein AA, Atkinson JL, Wijdicks EFM. Emergency craniotomy in patients worsening due to expanded cerebral hematoma: to what purpose? Neurology 2002;58:1367–1372.

20. Rabinstein AA, Wijdicks EFM. Determinants of outcome in anticoagulation-associated cerebral hema-toma requiring emergency evacuation. Arch Neurol 2007;64:203–206.

21. Smith EE, Rosand J, Knudsen KA, Hylek EM, Greenberg SM. Leukoaraiosis is associated with warfarin-related hemorrhage following ischemic stroke. Neurology 2002;59:193–197.

22. Sorensen B, Johansen P, Nielsen GL, Sorensen JC, Ingerslev J. Reversal of the International Normalized Ratio with recombinant activated factor VII in central nervous system bleeding during warfarin throm-boprophylaxis: clinical and biochemical aspects. Blood Coagul Fibrinolysis 2003;14:469–477.

352

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AN EXPLANATION

Intraventricular hemorrhage is common in aneurysmal subarachnoid hemorrhage after a rebleed and is common in enlarging ganglionic hemorrhages. In both instances there is worsening in level of consciousness and emerging coma. Primary intraventric-ular hemorrhage—blood only in the ventricular system and as a consequence acute h ydrocephalus—is an unusual cause of intracranial hemorrhage and accounts for only

Comatose and Intraventricular hemorrhage

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Comatose and Intraventricular hemorrhage / / 353

2% to 3% of all cerebral hemorrhages.6,8 Often, when closely scrutinized, the intraven-tricular hemorrhage is associated with a caudate or thalamic hemorrhage. The original source of the hemorrhage sometimes becomes clear after an MRI is performed.

The cause of primary intraventricular hemorrhage is typically unknown, and postmor-tem studies have often found no explanation. A dural arteriovenous fistula or arteriovenous malformation may be found on the cerebral angiogram. In this setting hemorrhage has been explained by progressive dilatation of the pressurized subependymal veins that drain into the malformation. Prior hypertension is commonly found in primary intraventric-ular hemorrhage and suggests a similar mechanism of arterial rupture as in ganglionic hemorrhage.

Intraventricular hemorrhage is likely hemorrhage under arterial pressure and decom-presses downstream ineffectively, acutely enlarging the entire system and damaging the periventricular neuronal structures. The severity of intraventricular hemorrhage can be assessed semi-quantitatively by grading each involved ventricle. A simple scale that is often used is the Graeb scale, and it has been validated (Table 20-1).4 If all ventricles are filled and expanded, the presentation is particularly severe and the outcome has been historically considered poor.2

Approximately 30% of patients present in coma with extensor responses, but many do present with stupor and no other localizing signs. Coma is explained by acute hydro-cephalus stretching the surrounding structures, or it could be due to thalamic hemor-rhage destroying much of the diencephalon. In addition, there can be dorsal brainstem compression from an acutely enlarged fourth ventricle and aqueduct. In patients who become comatose while a ventriculostomy is in place, clotting off the ventriculostomy can often be implicated and may not necessarily be reflected by further enlargement of the ventricular system. The causes of coma in intraventricular hemorrhage are shown in Table 20-2.

TABLE 20-1 Graeb scale

Lateral ventricles (each one scored separately) 1 = trace of blood or mild bleeding 2 = less than half of the ventricle filled with blood 3 = more than half of the ventricle filled with blood 4 = ventricle filled with blood and expandedThird and fourth ventricle 1 = blood present, ventricle size normal 2 = ventricle filled with blood and expanded



Placement of a ventriculostomy will reduce intracranial pressure but does not clear intra-ventricular hemorrhage very well (Fig. 20-1). Therefore, thrombolytic agents injected into the catheter may improve clearance; indeed, if 1 mg every 8 hours of tPA is administered, clearance of blood much improves. Thus, extraventricular drainage (EVD) is essential and should require measuring of the opening pressure followed by continuous drainage.1 Many neurosurgeons place a ventriculostomy at a 0- to 5-mm Hg level to allow further drainage. In addition, antibiotic-impregnated catheters can be used to reduce infection risk. Whether minimally invasive neurosurgery is beneficial is uncertain, but endoscopic removal of clots from the ventricles has been quite successful—at least by neuroradiology criteria—but whether it improves outcome is not established. Outcome may be deter-mined by inability to improve obstructive hydrocephalus and inability to reduce the mass effect of intraventricular blood clot. The blood clot into the ventricles may also cause an inflammatory reaction with periventricular edema and possibly chronic hydrocephalus.

Some have suggested the following approach. Intraventricular thrombolysis is admin-istered after 4 mL of cerebrospinal fluid (CSF) is removed, followed by injection of 1 mL rt-PA (1 mg/mL solution), followed by flushing with 3 mL normal saline. The EVD

TABLE 20-2 Causes of Coma in Intraventricular hemorrhage

• Acute hydrocephalus• Extension into the thalamus• Dorsal brainstem compression from enlarged fourth ventricle• Clotting off external ventriculostomy

FIGURE 20-1 Primary intraventricular hemorrhage (note casted ventricular system).

Comatose and Intraventricular hemorrhage / / 355

system should be clamped for one hour if the intracranial pressure (ICP) is normal; if the ICP is increased more than 20 mm Hg, the EVD system should be left open.5,7,9 This procedure is repeated three times a day until the third and fourth ventricles have cleared completely on CT scan.3 Intraventricular thrombolysis is contraindicated in any patient with a marked coagulopathy and in patients with a nonoccluded ruptured aneurysm. Overshunting may not improve drainage, and it is unclear whether this will reduce per-manent CSF shunts in patients.10 Outcome is also determined by the rapidity of clinical improvement after ventriculostomy. Patients may have extensor responses on admission but may follow commands the next day.

A CONCLUDING NOTE

Intraventricular hemorrhage causes coma through massive hydrocephalus. Ventri culostomy with thrombolysis allows clearance of the blood clot and improvement of ventricular size.

REFERENCES

1. Dey M, Jaffe J, Stadnik A, Awad IA. External ventricular drainage for intraventricular hemorrhage. Curr Neurol Neurosci Rep 2012;12:24–33.

2. Gaab MR. Intracerebral hemorrhage (ICH) and intraventricular hemorrhage (IVH): improvement of bad prognosis by minimally invasive neurosurgery. World Neurosurg 2011;75:206–208.

3. Gaberel T, Magheru C, Emery E. Management of non-traumatic intraventricular hemorrhage. Neurosurg Rev 2012;35:485–494; discussion 494–485.

4. Graeb DA, Robertson WD, Lapointe JS, Nugent RA, Harrison PB. Computed tomographic diagnosis of intraventricular hemorrhage. Etiology and prognosis. Radiology 1982;143:91–96.

5. Hanley DF. Intraventricular hemorrhage: severity factor and treatment target in spontaneous intracere-bral hemorrhage. Stroke 2009;40:1533–1538.

6. Little JR, Blomquist GA, Jr., Ethier R. Intraventricular hemorrhage in adults. Surg Neurol 1977;8:143–149.7. Morgan T, Awad I, Keyl P, Lane K, Hanley D. Preliminary report of the clot lysis evaluating acceler-

ated resolution of intraventricular hemorrhage (CLEAR–IVH) clinical trial. Acta Neurochir Suppl 2008;105:217–220.

8. Naff NJ. Intraventricular hemorrhage in adults. Curr Treat Options Neurol 1999;1:173–178.9. Staykov D, Bardutzky J, Huttner HB, Schwab S. Intraventricular fibrinolysis for intracerebral hemorrhage

with severe ventricular involvement. Neurocrit Care 2011;15:194–209.10. Ziai WC, Torbey MT, Naff NJ, et al. Frequency of sustained intracranial pressure elevation during treat-

ment of severe intraventricular hemorrhage. Cerebrovasc Dis 2009;27:403–410.

356

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AN EXPLANATION

Pontine hemorrhages are a far less common location of cerebral hematoma. Clinical suspicion may be triggered when patients fall (or more likely slump) over, followed by extensor posturing or “convulsions.” Internuclear ophthalmoplegia, pinpoint pupils, and posturing are often diagnostic.8 With extension of the pontine hemorrhage to the mesen-cephalon, pupils may be in a mid-position (rather than small). Ocular bobbing is a local-izing sign, although its mechanism is not known.9 Sixth nerve palsy may be found.8 The

Comatose and Pontine Hemorrhage

/ / / 21 / / /

Comatose and Pontine Hemorrhage / / 357

sudden decline in consciousness causes immediate upper airway obstruction, and many patients are intubated with an agonal gasping breathing pattern.

The causes of coma in pontine hemorrhage are shown in Table 21-1. The ascending reticular activating system is in the tegmentum area, and thus even small localized lesions may cause coma. Complete destruction of all pontine structures occurs more often in patients with poorly controlled hypertension. The hematoma may also dissect upward through the mesencephalon and destroy the thalamic nuclei. Sudden enlargement of the fourth ventricle due to extension into the ventricles may also be a contributing factor, but its magnitude is unclear. An acutely placed ventriculostomy has been unsuccessful in changing level of consciousness.

CT scan can demonstrate CT patterns with hematomas in the tegmentum (Fig. 21-1) or central pons (Fig. 21-2), or with extension to mesencephalon and thalamus.2,11


In-hospital mortality in patients with destructive pontine hematoma approaches 70%, and withdrawal of support—knowing the injury is causing a very poor outcome—is a

TABLE 21-1 Causes of Coma in Pontine Hemorrhage

• Total pons destruction• Tegmental pontine hematoma• Extension to mesencephalon and thalamus• Fourth ventricle rupture and enlargement

FIGURE 21-1 Tegmental pontine hemorrhage in a patient with acutely impaired consciousness

(note that eyes are deviated away from the hemorrhage).

358 / / THe ComaTose PaTienT

major reason.7 Poor prognostic factors are initial presence of autonomic dysregulation with hyperthermia, hypertension, and tachycardia, and are indicative of a more severe injury.3–5,11 Poor outcome is anticipated in patients with a hematoma volume more than 4 mL and ventral hemorrhage.10 It is unlikely that fine-needle stereotactic aspiration will affect outcome. The outcome is poor if mechanical ventilation is needed and extension to the upper mesencephalic-thalamic region is documented on CT scan.10 In patients who recover, a cerebral angiogram may be needed to detect a pontine arteriovenous malfor-mation, but an underlying lesion is more common in small lesions and younger patients. MRI may document a cavernoma, and early resection (within 21 days) may lead to improvement.1,6

A CONCLUDING NOTE

Gaze preference to the same side of a hemiparesis followed by a decline in consciousness may point to a tegmental pontine hemorrhage. Primary pontine hemorrhages can be one of the most destructive cerebral hematomas. Ocular bobbing and extensor posturing may point toward the diagnosis in a suddenly comatose patient with marked hypertension or other dysautonomic features.

REFERENCES

1. Bruneau M, Bijlenga P, Reverdin A, et al. Early surgery for brainstem cavernomas. Acta Neurochir (Wien) 2006;148:405–414.

FIGURE 21-2 Destructive pontine hemorrhage.

Comatose and Pontine Hemorrhage / / 359

2. Chung CS, Park CH. Primary pontine hemorrhage: a new CT classification. Neurology 1992;42:830–834.3. Del Brutto OH, Campos X. Validation of intracerebral hemorrhage scores for patients with pontine

hemorrhage. Neurology 2004;62:515–516.4. Jang JH, Song YG, Kim YZ. Predictors of 30-day mortality and 90-day functional recovery after primary

pontine hemorrhage. J Korean Med Sci 2011;26:100–107.5. Murata Y, Yamaguchi S, Kajikawa H, et al. Relationship between the clinical manifestations, computed

tomographic findings and the outcome in 80 patients with primary pontine hemorrhage. J Neurol Sci 1999;167:107–111.

6. Pandey P, Westbroek EM, Gooderham PA et al. Cavernous malformation of brainstem,thalamus and basal ganglia: a series of 176 patients. Neurosurgery 2013;72:573–589.

7. Rabinstein AA, Tisch SH, McClelland RL, Wijdicks EFM. Cause is the main predictor of outcome in patients with pontine hemorrhage. Cerebrovasc Dis 2004;17:66–71.

8. Sherman SC, Saadatmand B. Pontine hemorrhage and isolated abducens nerve palsy. Am J Emerg Med 2007;25:104–105.

9. Weisberg LA. Primary pontine haemorrhage: clinical and computed tomographic correlations. J Neurol Neurosurg Psychiatry 1986;49:346–352.

10. Wessels T, Moller-Hartmann W, Noth J, Klotzsch C. CT findings and clinical features as markers for patient outcome in primary pontine hemorrhage. AJNR Am J Neuroradiol 2004;25:257–260.

11. Wijdicks EFM, St Louis E. Clinical profiles predictive of outcome in pontine hemorrhage. Neurology 1997;49:1342–1346.

360

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AN EXPLANATION

Unlike most instances of supratentorial cerebral hematoma, a cerebellar hematoma is a neurosurgical emergency. The abrupt presence of a large clot in an already very tight anatomical space is immediately consequential, and patients with a cerebellar hema-toma frequently deteriorate. Cerebellar hematoma may be due to prior poorly controlled hypertension, arteriovenous malformation, a first presentation of metastatic cancer,4 or,

Comatose and Cerebellar Hemorrhage

/ / / 22 / / /

Comatose and Cerebellar Hemorrhage / / 361

more rarely, a consequence of removal of supratentorial hematoma.3 Cerebellar hema-toma is more common in patients on anticoagulation.9

Patients present with acute vertigo and rapid decline in consciousness; pupils are spared, but pontine reflexes (corneal and oculovestibular responses) are abnor-mal, together with abnormal motor response. Expansion of the hematoma may occur within 24 hours.4 In one study, 46% of patients deteriorated with a decreasing level of consciousness, a new presentation of brainstem sign, or worsening motor response to pain.3 The causes of coma in cerebellar hematoma are shown in Table 22-1. The cause of coma in patients with cerebellar hematoma is explained by brainstem distortion and compression, much less likely due to acute hydrocephalus as a result of fourth ventricle distortion. A cerebellar hematoma can be contiguous with the fourth ventricle, enlarg-ing it and putting pressure on the dorsal pontine structures (Fig. 22-1). Compression of the brainstem can be at the mesencephalon level due to upward displacement of cer-ebellar tissue, but mostly compression occurs due to direct effect at the midportion of the pons. An acute cerebellar hematoma may cause rapid pontine-medullary compres-sion, apnea, and cardiac arrest. In those patients, failure to awaken after removal of the cerebellar hematoma may be more related to diffuse anoxic-ischemic injury. Clinical signs that predicted neurologic deterioration were not only small poorly reactive pupils, abnormal corneal reflexes, or oculocephalic reflexes but also CT scan findings. Warning signs of deterioration on CT scan are a hemorrhage extended to the vermis, a hematoma size more than 3 cm, the presence of brainstem distortion, intraventricu-lar hemorrhage, upward tissue displacement as evidenced by distortion of the quadri-geminal cistern, and the presence of an acute hydrocephalus (“tight posterior fossa”) (Chapter 6; Fig. 22-2).


Very few patients improve after a ventriculostomy if there is persistent brainstem com-pression from the cerebellar hematoma.8 Third ventriculostomy alone has been suc-cessfully tried but not in comatose patients.7 Therefore, decompressive suboccipital

TABLE 22-1 Causes of Coma in Cerebellar Hemorrhage

• Brainstem-pons compression (lateral cerebellar tissue shift)• Mesencephalon compression (upward brain tissue shift)• Acute hydrocephalus• Global anoxic-ischemic injury due to respiratory arrest


craniotomy is needed in comatose patients.11 A recent study suggested that the fourth ventricle appearance might be useful in determining whether observation, ventriculos-tomy, or evacuation of the hematoma is warranted. This protocol erroneously empha-sizes ventriculostomy as a first measure, and this may theoretically cause further upward shift and worsening of the patient.5 In very few patients, observation alone is justified and can only be considered if there is normal fourth ventricle size and the patient is alert. The decision to remove the cerebellar hematoma is at the discretion of the neuro-surgeon, and most would not hesitate to remove a cerebellar hematoma if there is any evidence of tight posterior fossa, size more than 3 cm, obliteration of the prepontine cistern, development of acute hydrocephalus, or medial extension of the hematoma, or when a hemorrhage has occurred in a metastasis (Fig. 22-3). Some neurosurgeons have attempted CT-guided fibrinolysis or endoscopic removal.6,12 The size of the hematoma

FIGURE 22-1 Cerebellar hematoma contiguous with an enlarged fourth ventricle filled with blood.


and age of the patient may play a role in decision making.1,10,13 It is a fact that the out-come in deteriorating patients is much worse than in patients without deterioration, and this again suggests that early intervention is needed. Long-term outcome in survivors can be favorable.2

A CONCLUDING NOTE

Both clinical and CT scan features are helpful in making the decision to evacuate a cere-bellar hematoma. Clinical findings that indicate brainstem compression, such as the pres-ence of abnormal cornea reflex or emergence of runs of bradycardia with hypertension, are all alarming signs for further compression. The presence of a so-called “tight posterior fossa” on CT scan with signs of fourth ventricle distortion, upward herniation, distortion

FIGURE 22-2. Massive cerebellar hematoma with CT features of a “tight posterior fossa.”


of the quadrigeminal cistern, and the presence of acute hydrocephalus is an important guide to decide whether or not to proceed with neurosurgical evacuation.

REFERENCES

1. Da Pian R, Bazzan A, Pasqualin A. Surgical versus medical treatment of spontaneous posterior fossa haematomas: a cooperative study on 205 cases. Neurol Res 1984;6:145–151.

2. Dolderer S, Kallenberg K, Aschoff A, Schwab S, Schwarz S. Long-term outcome after spontaneous cer-ebellar haemorrhage. Eur Neurol 2004;52:112–119.

3. Hyam JA, Turner J, Peterson D. Cerebellar hemorrhage after repeated burr hole evacuation for chronic subdural haematoma. J Clin Neurosci 2007;14:83–86.

4. Kanner AA, Suh JH, Siomin VE, et al. Posterior fossa metastases: aggressive treatment improves survival. Stereotact Funct Neurosurg 2003;81:18–23.

5. Kirollos RW, Tyagi AK, Ross SA, van Hille PT, Marks PV. Management of spontaneous cerebellar hema-tomas: a prospective treatment protocol. Neurosurgery 2001;49:1378–1386; discussion 1386–1377.

6. Mohadjer M, Eggert R, May J, Mayfrank L. CT-guided stereotactic fibrinolysis of spontaneous and hypertensive cerebellar hemorrhage: long–term results. J Neurosurg 1990;73:217–222.

7. Roux FE, Boetto S, Tremoulet M. Third ventriculocisternostomy in cerebellar haematomas. Acta Neurochir (Wien) 2002;144:337–342.

8. St Louis EK, Wijdicks EF, Li H. Predicting neurologic deterioration in patients with cerebellar hemato-mas. Neurology 1998;51:1364–1369.

9. Toyoda K, Okada Y, Ibayashi S, et al. Antithrombotic therapy and predilection for cerebellar hemor-rhage. Cerebrovasc Dis 2007;23:109–116.

10. Wijdicks EF, St Louis EK, Atkinson JD, Li H. Clinician’s biases toward surgery in cerebellar hemato-mas: an analysis of decision-making in 94 patients. Cerebrovasc Dis 2000;10:93–96.

No

No

No

No

Yes

Yes

Yes

Yes

Cerebellar hematoma

Coma or impairedconsciousness

MiosisAbnormal corneal

reflexes

No

CT: "Tightposterior fossa"

CT: Hemorrhage inmetastasis

Observe

Clot evacuation

Clot evacuation

Clot evacuation

Clot evacuation

FIGURE 22-3 Suggestions to surgically manage cerebellar hemorrhage. CT, computed tomogra-

phy indicated computed tomography of the brain.


11. Witsch J, Neugebauer H, Zweckberger K, Juttler E. Primary cerebellar hemorrhage: complications, treat-ment and outcome. Clin Neurol Neurosurg 2013;115:863–869.

12. Yamamoto T, Nakao Y, Mori K, Maeda M. Endoscopic hematoma evacuation for hypertensive cerebellar hemorrhage. Minim Invasive Neurosurg 2006;49:173–178.

13. Yanaka K, Matsumaru Y, Nose T. Management of spontaneous cerebellar hematomas: a prospective treatment protocol. Neurosurgery 2002;51:524–525.

366

A CONVERSATION

AN EXPLANATION

At the time of rupture, aneurysmal subarachnoid hemorrhage (SAH) causes coma in 20% to 30% of patients.1 In “poor grade” patients, neurologic findings may include exten-sor posturing and loss of upper brainstem reflexes, and further progression may occur in hours from the ictus. A wide light-fixed pupil may indicate oculomotor palsy from a ruptured posterior communicating aneurysm or lateral brainstem displacement from a hematoma in the temporal or frontal lobe. Pinpoint pupils may indicate the presence of an acute hydrocephalus with ventricles often filled with blood.

Comatose and aneurysmal subarachnoid Hemorrhage

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Comatose and aneurysmal subarachnoid Hemorrhage / / 367

The causes of coma after aneurysmal SAH are shown in Table 23-1. Typically, a sudden rise in intracranial pressure at the moment of rupture reduces cerebral perfusion globally in both hemispheres and results in marked ischemic changes. Intraventricular extension of the hemorrhage and hydrocephalus may be a cause of coma, and thus improvement may be seen after ventriculostomy. Intracerebral hematoma with lateral or central brain-stem shift (particularly with rupture of a middle cerebral artery aneurysm) is a less com-mon explanation for coma after SAH. Rupture of a basilar artery aneurysm directly into the pons is equally rare but fatal. (Infarction in the pons from ischemia after clipping or coiling is more common.) A recently recognized abnormality in SAH is the presence of global cerebral edema after SAH. It may be present initially but also after cardiopulmo-nary resuscitation soon after the ictus and therefore points to a severe anoxic-ischemic injury. These CT patterns are mostly seen in patients who are comatose after SAH with a large amount of blood on CT scan.2 However, there have been reports of reversibility of diffuse cerebral edema.9

Nonconvulsive status epilepticus may be a reason for unexplained coma after SAH. One study found nonconvulsive status epilepticus in 8% of patients with SAH, includ-ing patients treated prophylactically with antiepileptic drugs.4 Nonconvulsive status epi-lepticus was seen more often in comatose patients with an SAH, in older patients after placement of a ventriculostomy, and with cerebral edema on CT scan.4 However, despite electroencephalographic resolution, antiepileptic drugs did not result in improvement in most patients.4 This may therefore indicate that nonconvulsive status epilepticus is a marker of significant brain injury after SAH and not necessarily a treatable complication.3

CT and MRI are helpful diagnostic tests. CT scan is highly sensitive and will demon-strate blood in basal cisterns and ventricles in all comatose patients. Acute hydrocephalus may be an additional feature (Fig. 23-1). Diffuse cerebral edema on CT indicates a far more severe impact (Fig. 23-2). MRI in SAH has recently been able to demonstrate the initial impact of increased intracranial pressure associated with decreased cerebral blood flow or even temporarily arrested cerebral blood flow (Fig. 23-3). MR can also be use-ful in deteriorating patients and can document the ravaging effects of delayed cerebral

TABLE 23-1 Causes of Coma in aneurysmal subarachnoid Hemorrhage

• Diffuse ischemic global cortical injury• Early cerebral edema• Acute hydrocephalus• Hematoma in the temporal lobe and brainstem shift (ruptured middle cerebral artery aneurysm)• Hematoma in the pons (ruptured basilar artery aneurysm)• Nonconvulsive status epilepticus


FIGURE 23-1 Diffuse SAH with all cisterns and fissures filled with clot. Intraventricular hemor-

rhage and acute hydrocephalus is present.

FIGURE 23-2 Diffuse cerebral edema as a result of diffuse ischemic injury at ictus.


ischemia due to cerebral vasospasm. Serial CT scans can show subsequent appearance of new blood at new sites, and an example of two rebleeds within one day in a patient with a basilar artery aneurysm is shown in Figure 23-4.


Early surgical repair or endovascular treatment (coil placement) of a recently ruptured cerebral aneurysm is needed to prevent rebleeding.6,10 Ventriculostomy in acute hydro-cephalus may be needed. However, early placement of a ventriculostomy, evacuation of an associated hematoma, early coil placement, and aggressive fluid management have

FIGURE 23-3 Example of damaging effect to the brain after SAH. MRI (FLAIR and DWI) showing

diffuse ischemic injury in a comatose patient with SAH MR imaging on day 4 after the rupture

and no evidence of cerebral vasospasm on cerebral angiogram.


not consistently resulted in a better outcome in patients presenting comatose after an SAH. The outcome may be determined at the time of impact.13,17 Timing of World Federation of Neurologic Surgeons (WFNS) grading matters, with much better associa-tion of outcome with postresuscitation assessment.5 Nonetheless, about 50% of patients without a cerebral hematoma or acute hydrocephalus improve to better clinical grades.14 Moreover, cardiopulmonary resuscitation due to aneurysmal rupture is not necessarily a poor prognosticating sign.16 Therefore, patients comatose after SAH should receive full support.11,12 Early coil embolization in poor-grade SAH has been advocated, with a good clinical outcome in 30% of patients.15,18 Similar results have been described with urgent clipping of the aneurysm.8 This aggressive approach of early repair of a ruptured aneu-rysm can also be considered in older patients with good results.

A CONCLUDING NOTE

The outcome of comatose patients with SAH is uncertain. Within the first days of rup-ture, there are multiple causes of coma in aneurysmal SAH. Each may have a specific treatment (e.g., ventriculostomy or evacuation of a lobar hematoma). Early repair of the aneurysm in comatose patients after SAH may lead to a good outcome in a third of the patients.7

REFERENCES

1. Al-Shahi R, White PM, Davenport RJ, Lindsay KW. Subarachnoid hemorrhage. BMJ 2006;333:235–240.2. Claassen J, Carhuapoma JR, Kreiter KT, et al. Global cerebral edema after subarachnoid hemorrhage: fre-

quency, predictors, and impact on outcome. Stroke 2002;33:1225–1232.3. Claassen J, Taccone FS, Horn P, et al. Recommendations on the use of EEG monitoring in critically ill

patients: consensus statement from the neurointensive care section of the ESICM. Intensive Care Med 2013;39:1337–1351.

FIGURE 23-4 Serial CT scans showing rebleeding on each new CT scan from a ruptured basilar

aneurysm before patient could be treated endovascularly.


4. Dennis LJ, Claassen J, Hirsch LJ, et al. Nonconvulsive status epilepticus after subarachnoid hemorrhage. Neurosurgery 2002;51:1136–1143; discussion 1144.

5. Giraldo EA, Mandrekar JN, Rubin MN, et al. Timing of clinical grade assessment and poor outcome in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg 2012;117:15–19.

6. Hellingman CA, van den Bergh WM, Beijer IS, et al. Risk of rebleeding after treatment of acute hydro-cephalus in patients with aneurysmal subarachnoid hemorrhage. Stroke 2007;38:96–99.

7. Klein AM, Howell K, Straube A, Pfefferkorn T, Bender A. Rehabilitation outcome of patients with severe and prolonged disorders of consciousness after aneurysmal subarachnoid hemorrhage (aSAH). Clin Neurol Neurosurg 2013;115:2136–2141.

8. Laidlaw JD, Siu KH. Poor-grade aneurysmal subarachnoid hemorrhage: outcome after treatment with urgent surgery. Neurosurgery 2003;53:1275–1280.

9. McLaughlin N, Bojanowski MW. Reversibility of extensive hemispheric cytotoxic cerebral edema fol-lowing subarachnoid hemorrhage. Neurocrit Care 2006;4:143–146.

10. Naidech AM, Janjua N, Kreiter KT, et al. Predictors and impact of aneurysm rebleeding after subarach-noid hemorrhage. Arch Neurol 2005;62:410–416.

11. Naval NS, Chang T, Caserta F, et al. Improved aneurysmal subarachnoid hemorrhage outcomes: a com-parison of 2 decades at an academic center. J Crit Care 2013;28:182–188.

12. Rabinstein AA, Lanzino G, Wijdicks EFM. Multidisciplinary management and emerging therapeutic strategies in aneurysmal subarachnoid haemorrhage. Lancet Neurol 2010;9:504–519.

13. Rosengart AJ, Schultheiss KE, Tolentino J, Macdonald RL. Prognostic factors for outcome in patients with aneurysmal subarachnoid hemorrhage. Stroke 2007;38:2315–2321.

14. Sasaki T, Sato M, Oinuma M, et al. Management of poor-grade patients with aneurysmal subarachnoid hemorrhage in the acute stage: Importance of close monitoring for neurological grade changes. Surg Neurol 2004;62:531–535; discussion 535–537.

15. Suzuki S, Jahan R, Duckwiler GR, et al. Contribution of endovascular therapy to the management of poor-grade aneurysmal subarachnoid hemorrhage: Clinical and angiographic outcomes. J Neurosurg 2006;105:664–670.

16. Toussaint LG, 3rd, Friedman JA, Wijdicks EFM, et al. Survival of cardiac arrest after aneurysmal sub-arachnoid hemorrhage. Neurosurgery 2005;57:25–31; discussion 25–31.

17. van den Berg R, Foumani M, Schroder RD, et al. Predictors of outcome in World Federation of Neurologic Surgeons grade V aneurysmal subarachnoid hemorrhage patients. Crit Care Med 2011;39:2722–2727.

18. Weir RU, Marcellus ML, Do HM, Steinberg GK, Marks MP. Aneurysmal subarachnoid hemorrhage in patients with Hunt and Hess grade 4 or 5: treatment using the Guglielmi detachable coil system. AJNR Am J Neuroradiol 2003;24:585–590.

372

A CONVERSATION

AN EXPLANATION

Cerebral venous thrombosis (CVT) remains a diagnostic challenge owing to its protean clinical and radiological presentation.17 The diagnosis of CVT is frequently delayed in patients who have a headache alone (as a consequence of intracranial hypertension) and perhaps also because of a failure to recognize papilledema.8 CVT accounts for less than 2% of cases of nontraumatic intracranial hemorrhage. Conversely, intracranial hemor-rhage has been reported in 20% to 40% of patients with CVT.1,20 The risk of hemorrhage is related to the extent of cerebral venous thrombosis.24 While most hemorrhages associated

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/ / / 24 / / /

Comatose and Cerebral Venous Thrombosis / / 373

with CVT are small, patchy, or merely petechial foci in larger hypodense areas,1 enlarge-ment of lobar hemorrhagic infarction has been observed.1,19,21 Another manifestation is a cortical localized subarachnoid hemorrhage;16 this is likely due to rupture of dilated cortical veins. Focal seizures or complex partial status epilepticus are common presenting symptoms, with aphasia or hemiparesis as accompanying signs.

The causes of coma in CVT are shown in Table 24-1. Complex partial status epilepti-cus may occur in more localized lesions, and that in itself can explain impaired conscious-ness, such as in this vignette (Fig. 24-1). Involvement of the sagittal sinus may result in multiple hemispheric infarcts.

Emergency evacuation may be needed for some patients with a temporal lobe hema-toma, and the diagnosis may become clear only after removal of the hematoma and review of microscopic pathology (Fig. 24-2). Deep cerebral vein involvement may cause bilateral thalamic infarcts. Decompressive craniectomy is considered in selected patients.18

Findings on CT may be highly variable, and up to 20% of CT scans are normal in the setting of established CVT.1 The more specific “cord” (see Fig. 24-2), “dense triangle,” or “delta” signs (all representing clot in cerebral venous circulation) are relatively infre-quent, with delta signs, for example, seen only in 20% to 30% of patients with superior

TABLE 24-1 Causes of Coma in Cerebral Venous Thrombosis

• Multiple hemorrhagic infarcts (sagittal sinus)• Bithalamic hemorrhagic infarcts (deep cerebral vein)• Temporal lobe hematoma (vein of Labbé)• Complex partial status epilepticus (cortical veins)

FIGURE 24-1 MRI and MR venogram in a patient with a sagittal sinus thrombosis and complex

partial status epilepticus.


sagittal sinus thrombosis.1,19 Gadolinium-enhanced three-dimensional MR venography has remarkably facilitated the diagnosis and documents incomplete filling of the cerebral venous system.13,15,21

Laboratory tests could be helpful, and D-dimer levels are nonspecifically elevated in serum in many patients with an acute CVT. Other coagulopathies should be sought and include rare thrombophilias such as protein C and protein S deficiencies, antithrom-bin deficiency, or prothrombin gene mutation 20210 GA.12 Use of oral contraceptives remains a major trigger3 (Table 24-2).


Anticoagulation with intravenous heparin is widely accepted as a treatment in nonhem-orrhagic CVT.2,6,7,22 Alternatively, more selective endovascular delivery of a thrombo-lytic drug (usually tPA) has been safely and effectively employed.4,5,11 Experience with clot retrieval devices is also reported and may become the first approach in deteriorat-ing patients even before anticoagulation.19 In cases of CVT complicated by hemorrhage

FIGURE 24-2 Precipitous decline in a patient with thrombosed vein of Labbé and transverse sinus.

Hyperdensity along the patient’s left transverse sinus: “cord sign” (arrowheads). Cerebral venous

thrombosis was confirmed by postoperative MR venogram (absence of signal in the patient’s left

transverse-sigmoid venous system). L = vein of Labbé; T = transverse sinus; S = sigmoid sinus.


before treatment, immediate intravenous heparinization may still be viewed as first-line treatment.2,7,23 Compared with systemic thrombolytic administration, selective endo-vascular delivery of thrombolytic agents is safer, with fewer secondary hemorrhages.4,5,11 Treating CVT with mechanical thrombectomy is dependent on the ability to navigate an appropriate device to the thrombosed intracranial venous territory from a peripheral access.4

TABLE 24-2 Conditions associated with Cerebral Venous Thrombosis

GENETIC PROTHROMBOTIC CONDITIONSAntithrombin deficiencyProtein C and protein S deficienciesFactor V Leiden mutationProthrombin mutationHomocysteinemiaACQUIRED PROTHROMBOTIC STATESCancerNephrotic syndromeAntiphospholipid antibodiesPregnancyPuerperiumINFECTIONSOtitis, mastoiditis, sinusitisMeningitisINFLAMMATORY DISEASESystemic lupus erythematosusGranulomatosis with polyangiitisSarcoidosisInflammatory bowel diseaseBehçet syndromeHEMATOLOGIC CONDITIONSPolycythemiaThrombocythemiaLeukemiaAnemia (severe)DRUGSOral contraceptivesAsparaginaseMISCELLANEOUSTraumatic brain injurySurgical injury to sinuses or catheterization of the jugular veinLumbar punctureDehydration, especially in children



Standard practice is intravenous heparin followed by warfarin for 6 to 12 months or indefinitely when a thrombophilia is present.2,7 Seizures require treatment, but only leve-tiracetam and lamotrigine have no serious interactions with warfarin, so they should be considered first.

Recurrence of CVT is very uncommon, but the recurrence may also involve other locations such as deep venous thrombosis in the legs.10,14 Outcome is worse with involve-ment of the deep cerebral veins, right-side involvement (typically the larger sinus), and coma at presentation.9

A CONCLUDING NOTE

CVT may cause coma through several mechanisms. It may be due to complex partial seizures, an expanding lobar hematoma, or multiple hemispheric infarcts. Emergency evacuation may be needed in patients with a temporal lobe hemorrhagic infarct with mass effect.

REFERENCES

1. Ameri A, Bousser MG. Cerebral venous thrombosis. Neurol Clin 1992;10:87–111.2. Bousser MG. Cerebral venous thrombosis: nothing, heparin, or local thrombolysis? Stroke

1999;30:481–483.3. Bousser MG, Crassard I. Cerebral venous thrombosis, pregnancy and oral contraceptives. Thromb Res

2012;130 Suppl 1:S19–22.4. Chahlavi A, Steinmetz MP, Masaryk TJ, Rasmussen PA. A transcranial approach for direct mechanical

thrombectomy of dural sinus thrombosis. Report of two cases. J Neurosurg 2004;101:347–351.5. Chow K, Gobin YP, Saver J, et al. Endovascular treatment of dural sinus thrombosis with rheolytic

thrombectomy and intra-arterial thrombolysis. Stroke 2000;31:1420–1425.6. Coutinho JM, de Bruijn SF, deVeber G, Stam J. Anticoagulation for cerebral venous sinus thrombosis.

Stroke 2012;43:e41–e42.7. Einhaupl K, Bousser MG, de Bruijn SF, et al. EFNS guideline on the treatment of cerebral venous and

sinus thrombosis. Eur J Neurol 2006;13:553–559.8. Ferro JM, Lopes MG, Rosas MJ, Fontes J. Delay in hospital admission of patients with cerebral vein and

dural sinus thrombosis. Cerebrovasc Dis 2005;19:152–156.9. Girot M, Ferro JM, Canhao P, et al. Predictors of outcome in patients with cerebral venous thrombosis

and intracerebral hemorrhage. Stroke 2007;38:337–342.10. Gosk-Bierska I, Wysokinski W, Brown RD, Jr., et al. Cerebral venous sinus thrombosis: Incidence of

venous thrombosis recurrence and survival. Neurology 2006;67:814–819.11. Horowitz M, Purdy P, Unwin H, et al. Treatment of dural sinus thrombosis using selective catheteriza-

tion and urokinase. Ann Neurol 1995;38:58–67.12. Kosinski CM, Mull M, Schwarz M, et al. Do normal D-dimer levels reliably exclude cerebral sinus throm-

bosis? Stroke 2004;35:2820–2825.13. Majoie CB, van Straten M, Venema HW, den Heeten GJ. Multisection CT venography of the dural sinuses

and cerebral veins by using matched mask bone elimination. AJNR Am J Neuroradiol 2004;25:787–791.


14. Maqueda VM, Thijs V. Risk of thromboembolism after cerebral venous thrombosis. Eur J Neurol 2006;13:302–305.

15. Mullins ME, Grant PE, Wang B, Gonzalez RG, Schaefer PW. Parenchymal abnormalities associated with cerebral venous sinus thrombosis: assessment with diffusion–weighted MR imaging. AJNR Am J Neuroradiol 2004;25:1666–1675.

16. Oppenheim C, Domigo V, Gauvrit JY, et al. Subarachnoid hemorrhage as the initial presentation of dural sinus thrombosis. AJNR Am J Neuroradiol 2005;26:614–617.

17. Piazza G. Cerebral venous thrombosis. Circulation 2012;125:1704–1709.18. Rajan Vivakaran TT, Srinivas D, Kulkarni GB, Somanna S. The role of decompressive craniectomy in

cerebral venous sinus thrombosis. J Neurosurg 2012;117:738–744.19. Raychev R, Tateshima S, Rastogi S et al. Successful treatment of extensive cerebral venous sinus throm-

bosis using a combined approach with Penumbra aspiration system and Solitaire FR retrieval device. J. Neurointerv. Surg 2013. Epub ahead of print.

20. Singh T, Chakera T. Dural sinus thrombosis presenting as unilateral lobar haematomas with mass effect: an easily misdiagnosed cause of cerebral haemorrhage. Australas Radiol 2002;46:351–365.

21. Stam J. Thrombosis of the cerebral veins and sinuses. N Engl J Med 2005;352:1791–1798.22. Stefini R, Latronico N, Cornali C, Rasulo F, Bollati A. Emergent decompressive craniectomy in patients

with fixed dilated pupils due to cerebral venous and dural sinus thrombosis: report of three cases. Neurosurgery 1999;45:626–629; discussion 629–630.

23. Wingerchuk DM, Wijdicks EFM, Fulgham JR. Cerebral venous thrombosis complicated by hemorrhagic infarction: factors affecting the initiation and safety of anticoagulation. Cerebrovasc Dis 1998;8:25–30.

24. Zubkov AY, McBane RD, Brown RD, Rabinstein AA. Brain lesions in cerebral venous sinus thrombosis. Stroke 2009;40:1509–1511.

378

A CONVERSATION

AN EXPLANATION

Patients with a hemispheric infarct have profound neurologic deficits such as gaze deviation, global aphasia, hemineglect, or hemiplegia and thus a high score on the National Institute of Health Stroke scale (NIHSS). Apraxia of eyelid opening (or cere-bral ptosis) is a typical feature in patients with a nondominant hemispheric infarct and a heralding sign of herniation.1 Large cerebral infarcts involve the middle cere-bral territory and often adjacent anterior cerebral artery territory. Predisposing factors have been identified in patients who go on to develop brain swelling. The severity of

Comatose and Hemispheric stroke

/ / / 25 / / /

Comatose and Hemispheric stroke / / 379

swelling may be related to age, with less compensatory mechanism in elderly patients.24 There is evidence that patients with early abnormality of cerebral autoregulation are at higher risk of brain swelling.7 Abnormal cerebral autoregulation may promote further infarction, usually in an area with marginal blood pressure.7 Women are also more likely to have early deterioration from hemispheric stroke, but this propensity has not been understood.12,15 The causes of coma in hemispheric stroke are shown in Table 25-1.

Worsening responsiveness in hemispheric infarct is related to the development of brain swelling and displacement of the brainstem. Increased intracranial pres-sure is a late phenomenon, and brainstem distortion, both in horizontal or verti-cal directions, is the main component of impaired consciousness and may develop slowly. Deterioration from swelling typically occurs within 36 to 60 hours; therefore, frequent CT scan intervals are necessary to document further radiological deterio-ration. Rapid (less than 24 hours) brain edema has been described and has been attributed to reperfusion.10 In some patients, hemorrhagic conversion, particularly in areas of the thalamoperforators, can cause sudden worsening from central brainstem displacement. Bilateral occlusion of the middle cerebral artery may present with sud-den coma and a bihemispheric syndrome, most often in patients with atrial fibrilla-tion not protected by anticoagulation.11 (Chapter 26)

CT and MRI both can identify the seriousness of the cerebral infarct. DWI volume of more than 80 ml within 6 hours of onset predicts a fulminant course.25 Early CT scan may show a hypodensity and hyperintensity in the middle cerebral artery (MCA) indicating a proximal occlusion. MRI may further show the territory of involvement (Fig. 25-1). Deterioration from swelling is most common when ischemia expands beyond the MCA territory (anterior cerebral artery, posterior cerebral artery, and anterior choroidal artery). Involvement of the anterior choroidal artery infarcts the uncus and therefore fur-ther enlarges the swollen tissue mass (Fig. 25-2).


Medical treatment is limited in scope and effectiveness.6,8,14,16,19,22 Treatment involves maintenance of normovolemia, normoglycemia (glucose less than 150 mmol/L),8 and

TABLE 25-1 Causes of Coma in Hemispheric stroke

• Lateral brainstem displacement from acute swelling (reperfusion edema)• Central brainstem displacement from gradual swelling• Hemorrhagic conversion and increasing mass effect• Multiterritorial infarction (bilateral middle cerebral artery or carotid artery occlusions)


avoidance of hypertensive surges. It is completely uncertain if these measures minimize hemorrhagic conversion, reduce edema, and maintain perfusion through collateral arter-ies. Craniectomy to allow decompression of the swollen infarct has been advocated. Mannitol (20% solution, 0.5 g/kg) or use of hypertonic saline every four to six hours (3%, 30 mL) can be considered in patients who worsen from brain tissue shift but is only helpful as a bridge to decompressive surgery.6 However, there is no evidence that early repeated use of osmotic agents prevents further deterioration.14 Hyperventilation or bar-biturates are not effective. A trial of high-dose dexamethasone did not improve outcome in patients with cerebral infarction.16 Therapeutic hypothermia is unproven.19

The factors that predict prognosis after decompressive hemicraniectomy have recently been identified, but this procedure is likely less effective in patients older than 60 years.17 Decompressive hemicraniectomy can be considered in patients with a high risk of fatal swelling2,3,5,9 and often in patients with a carotid artery occlusion4,10,13,25 (thrombotic or dissection). The presence of additional territorial involvement on CT scan or hemor-rhagic conversion of a large cerebral infarct also increases the odds.15,18 Decompressive hemicraniectomy involves removal of a large bone flap and duraplasty.20,21 The timing of surgery is unclear. Therefore, it is possible that decompressive hemicraniectomy will result in good outcome in patients who may not necessarily need a decompressive crani-ectomy and otherwise would recover without any further clinical intervention. A recent pooled analysis of three uncompleted trials suggested a benefit of craniectomy within 48 hours of onset. There was a significant reduction of mortality but much less reduction of severe morbidity.23 Recommendations for medical and surgical management by the American Heart Association and American Stroke Association have been published.25

FIGURE 25-1 Early CT findings of partial MCA territory effacement but no mass effect. MRI taken

hours after the CT shows a much larger involvement and the size predicts deterioration.

Comatose and Hemispheric stroke / / 381

A CONCLUDING NOTE

Brainstem displacement from massive swelling, hemorrhagic conversion, or acute reperfu-sion edema is the main mechanism of coma in patients with hemispheric infarct. Further deterioration is more likely when there is additional territorial involvement in patients with occlusive disease of the MCA. Decompressive hemicraniectomy—resulting in recoil of the

FIGURE 25-2 Serial CT scans in deteriorated patients from swollen MCA infarcts. From left to

right: initial CT, CT at nadir, and CT at follow-up evaluation. First row: MCA infarction; second

row: additional anterior cerebral artery infarct; third row: additional posterior cerebral artery

infarct; fourth row: additional anterior choroidal artery infarction. From Maramattom et al.15 with

permission.


shifted brainstem—is the only possible therapeutic option in patients with cerebral swell-ing from hemispheric infarcts. Patients survive, but with a moderate to severe handicap.

REFERENCES

1. Blacker DJ, Wijdicks EF. Delayed complete bilateral ptosis associated with massive infarction of the right hemisphere. Mayo Clin Proc 2003;78:836–839.

2. Brown MM. Surgical decompression of patients with large middle cerebral artery infarcts is effective: not proven. Stroke 2003;34:2305–2306.

3. Carter BS, Ogilvy CS, Candia GJ, Rosas HD, Buonanno F. One-year outcome after decompressive sur-gery for massive nondominant hemispheric infarction. Neurosurgery 1997;40:1168–1175.

4. Cruz–Flores S, Berge E, Whittle IR. Surgical decompression for cerebral oedema in acute ischaemic stroke. Cochrane Database of Systematic Reviews 2012;1:CD003435.

5. Demchuk A, Krieger D. Large middle cerebral artery infarction. Neurology 1998;51:1514–1515.6. Demchuk AM, Krieger DW. Mass effect with cerebral infarction. Curr Treat Options Neurol 1999;1:189–199.7. Dohmen C, Bosche B, Graf R, et al. Identification and clinical impact of impaired cerebrovascular auto-

regulation in patients with malignant middle cerebral artery infarction. Stroke 2007;38:56–61.8. Garg R, Chaudhuri A, Munschauer F, Dandona P. Hyperglycemia, insulin, and acute ischemic stroke: a

mechanistic justification for a trial of insulin infusion therapy. Stroke 2006;37:267–273.9. Gupta R, Connolly ES, Mayer S, Elkind MS. Hemicraniectomy for massive middle cerebral artery terri-

tory infarction: a systematic review. Stroke 2004;35:539–543.10. Hacke W, Schwab S, Horn M, et al. ‘Malignant’ middle cerebral artery territory infarction: clinical course

and prognostic signs. Arch Neurol 1996;53:309–315.11. Hu WT, Wijdicks EFM. Sudden coma due to acute bilateral M1 occlusion. Mayo Clin Proc 2007;82:1155.12. Jaramillo A, Gongora-Rivera F, Labreuche J, Hauw JJ, Amarenco P. Predictors for malignant middle cere-

bral artery infarctions: a postmortem analysis. Neurology 2006;66:815–820.13. Kimberly WT, Sheth KN. Approach to severe hemispheric stroke. Neurology 2011;76:S50–56.14. Manno EM, Adams RE, Derdeyn CP, Powers WJ, Diringer MN. The effects of mannitol on cerebral

edema after large hemispheric cerebral infarct. Neurology 1999;52:583–587.15. Maramattom BV, Bahn MM, Wijdicks EF. Which patient fares worse after early deterioration due to

swelling from hemispheric stroke? Neurology 2004;63:2142–2145.16. Norris JW. Steroids may have a role in stroke therapy. Stroke 2004;35:228–229.17. Rabinstein AA, Mueller-Kronast N, Maramattom BV, et al. Factors predicting prognosis after decom-

pressive hemicraniectomy for hemispheric infarction. Neurology 2006;67:891–893.18. Robertson SC, Lennarson P, Hasan DM, Traynelis VC. Clinical course and surgical management of mas-

sive cerebral infarction. Neurosurgery 2004;55:55–61.19. Schwab S, Georgiadis D, Berrouschot J, et al. Feasibility and safety of moderate hypothermia after mas-

sive hemispheric infarction. Stroke 2001;32:2033–2035.20. Schwab S, Hacke W. Surgical decompression of patients with large middle cerebral artery infarcts is

effective. Stroke 2003;34:2304–2305.21. Steiner T, Ringleb P, Hacke W. Treatment options for large hemispheric stroke. Neurology

2001;57:S61–68.22. Subramaniam S, Hill MD. Massive cerebral infarction. Neurologist 2005;11:150–160.23. Vahedi K, Hofmeijer J, Juettler E, et al. Early decompressive surgery in malignant infarction of the middle

cerebral artery: a pooled analysis of three randomised controlled trials. Lancet Neurol 2007;6:215–222.24. Wijdicks EFM, Diringer MN. Middle cerebral artery territory infarction and early brain swelling: pro-

gression and effect of age on outcome. Mayo Clin Proc 1998;73:829–836.25. Wijdicks EFM, Sheth KN, Carter BS, et al. Recommendations for the management of cerebral and cer-

ebellar infarction with swelling. Stroke 2014: Epub ahead of print.

383

A CONVERSATION

AN EXPLANATION

Sudden coma due to bihemispheric ischemic injury from acute arterial occlusions is rare, but there are several case reports.1–3 The presentation remains difficult to recognize because the CT scan can initially be normal and a hyperdense middle cerebral artery (MCA) sign is rarely seen bilaterally. In some patients, a CTA or cerebral angiogram will surprisingly document bilateral M1 segment occlusions. In some instances, there is prior

Comatose and Bihemispheric stroke

/ / / 26 / / /


symptomatic carotid artery or MCA occlusion, resulting in a stroke followed by an occlu-sion on the opposite side (Fig. 26-1).

Patients present with a hemispheric syndrome and no gaze deviation, although eyes may briefly deviate toward the new stroke or in a vertical direction. Patients are mute and develop extensor posturing, closely mimicking acute basilar artery occlusion except for the lack of brainstem findings. Spontaneous eye movements such as roving or ping-pong movements are common. It has a different presentation than any other acute stroke, which typically involves one single cerebral hemisphere.

Clinical recognition is difficult but the absence of brainstem findings, prior hemi-spheric stroke, and no other localizing signs in a patient with major risk factors for recur-rent embolization (e.g., atrial fibrillation) should point toward this possible scenario. Causes of coma in bihemispheric stroke are shown in Table 26-1. Due to bilateral projec-tions of the ascending reticular formation to the cortex, bilateral injury is necessary.


In young individuals, acute endovascular treatment could recanalize an MCA occlusion. Bilateral carotid occlusions are notoriously difficult to open or stent, and a good outcome

FIGURE 26-1 Bilateral ischemic stroke (prior infarct with newly emerging cerebral infarct).

TABLE 26-1 Causes of Coma in Bihemispheric stroke

• Acute MCA occlusion with prior stroke opposite side• Bihemispheric ischemic injury• Diffuse cerebral edema• Lateral or central brainstem displacement

Comatose and Bihemispheric stroke / / 385

even after successful recanalization cannot be expected in a patient presenting comatose. In some patients, once the cerebral infarcts starts swelling there is no effective interven-tion. Due to the widespread ischemic damage decompressive hemicraniectomy would not be indicated.

A CONCLUDING NOTE

Acute occlusion of the carotid artery or MCA may cause acute bihemispheric infarcts. The mechanism is usually a known carotid artery occlusion followed by a carotid artery occlusion on the opposite side.

REFERENCES

1. Hu WT, Wijdicks EFM. Sudden coma due to acute bilateral M1 occlusion. Mayo Clin Proc 2007;82:1155.2. Nawashiro H, Wada K, Kita H. Decerebrate posture following bilateral middle cerebral artery occlusion.

Intern Med 2011;50:2063.3. Wijdicks EFM. Coma and abnormal consciousness. In: Bogousslavsky J, Caplan LR, eds. Stroke Syndromes,

2nd ed. Cambridge University Press, 2001.

386

A CONVERSATION

AN EXPLANATION

Acute occlusion of the basilar artery is uncommon and often has a perplexing clinical presentation. Some patients present initially with hemiparesis or hemiplegia, vertigo, and diplopia; other patients suddenly become comatose.1,8,16,18 The most common clinical mistake is not to recognize a locked-in syndrome in patients deemed comatose.

The causes of coma are shown in Table 27-1. Early infarction of the dorsal part of the pons (and mesencephalon) interrupts the ascending reticular formation. An embolus to the top of the basilar artery may further propagate and occlude the proximal posterior

Comatose and Basilar artery occlusion

/ / / 27 / / /

Comatose and Basilar artery occlusion / / 387

cerebral artery and, if present, the perforating arteries of Percheron. Bilateral parame-dian thalamic infarcts may occur.2,7,13 Propagation to the vertebral artery may result in a cerebellar infarct causing compression of the pons.

A hyperdense basilar artery sign on CT is an important feature but is rarely recog-nized (Fig. 27-1).3,6 An MR angiogram, CT angiogram, or cerebral angiogram is needed to confirm it. Early diagnosis of a basilar artery occlusion is relevant because the thera-peutic window is limited to the first 12 hours of presentation. When such an occlusion is found, it would lead to an effort to remove the obstructing clot.11,12 However, MRI may show significant infarction, obviating any therapeutic intervention (Fig. 27-2). In other patients, infarction may extend to mesencephalon and thalamus (Fig. 27-3).


Timing is crucial, but recanalization up to 48 hours has been associated with good out-come in 50% of patients.5,8,10,15 Successful recanalization after thrombolysis is common but not always associated with clinical improvement. Intravenous or intra-arterial thromboly-sis can improve outcome in the majority of patients. There have been well-documented instances of dramatically reversing clinical symptoms, including presentations similar to

TABLE 27-1 Causes of Coma in Basilar artery occlusion

• Pontine-mesencephalic infarction• Bithalamic infarction• Cerebellar infarct with brainstem compression

FIGURE 27-1 Hyperdense basilar artery sign.


FIGURE 27-2 MRI with hyperintensity in pons and mesencephalon (FLAIR and DWI) indicating

infarction.

FIGURE 27-3 Top of the basilar syndrome causing fluctuating consciousness due to mesencepha-

lon and bithalamic involvement.

Comatose and Basilar artery occlusion / / 389

a locked-in syndrome.4,11,12,14,17,19 Intra-arterial thrombolysis has become the standard of care despite the absence of a randomized trial, and patients should be transferred to cen-ters that provide the expertise.10 Mechanical thrombectomy is highly successful.9

Cerebellar infarction may be an additional problem, particularly when mass effect from swelling occurs. Decompressive suboccipital craniotomy with removal of necrotic cerebellar tissue is an option only if there is no extensive brainstem infarction. Poor prognosis is anticipated when uniform hyperintensity of the pons is present on MRI, if the patient remains in a coma, and if there is a continuous need for mechanical ventilation.20

A CONCLUDING NOTE

Brainstem signs should be carefully evaluated in an acutely comatose patient. In addi-tion, a hyperdense basilar artery is an underappreciated CT sign. Without intervention, a basilar artery thrombus permanently infarcts the pons and is associated with either pro-longed coma or a locked-in syndrome, both with devastating long-term consequences.14

Early endovascular therapy in basilar artery occlusive disease is a promising therapeutic option with a high probability of improving clinical signs after recanalization.

REFERENCES

1. Caplan LR, Wityk RJ, Glass TA, et al. New England Medical Center Posterior Circulation registry. Ann Neurol 2004;56:389–398.

2. Giannopoulos S, Kostadima V, Selvi A, Nicolopoulos P, Kyritsis AP. Bilateral paramedian thalamic infarcts. Arch Neurol 2006;63:1652.

3. Krings T, Noelchen D, Mull M, et al. The hyperdense posterior cerebral artery sign: a computed tomog-raphy marker of acute ischemia in the posterior cerebral artery territory. Stroke 2006;37:399–403.

4. Lindsberg PJ, Mattle HP. Therapy of basilar artery occlusion: a systematic analysis comparing intra-arterial and intravenous thrombolysis. Stroke 2006;37:922–928.

5. Lindsberg PJ, Sairanen T, Strbian D, Kaste M. Current treatment of basilar artery occlusion. Ann N Y Acad Sci 2012;1268:35–44.

6. Mandava P, Kent TA. Reversal of dense signs predicts recovery in acute ischemic stroke. Stroke 2005;36:2490–2492.

7. Matheus MG, Castillo M. Imaging of acute bilateral paramedian thalamic and mesencephalic infarcts. AJNR Am J Neuroradiol 2003;24:2005–2008.

8. Mattle HP, Arnold M, Lindsberg PJ, Schonewille WJ, Schroth G. Basilar artery occlusion. Lancet Neurol 2011;10:1002–1014.

9. Mourand I, Machi P, Milhaud D, et al. Mechanical thrombectomy with the Solitaire device in acute basi-lar artery occlusion. J Neurointerv Surg 2013 [Epub May 4].

10. Muller R, Pfefferkorn T, Vatankhah B, et al. Admission facility is associated with outcome of basilar artery occlusion. Stroke 2007;38:1380–1383.

11. Ostrem JL, Saver JL, Alger JR, et al. Acute basilar artery occlusion: diffusion–perfusion MRI character-ization of tissue salvage in patients receiving intra-arterial stroke therapies. Stroke 2004;35:e30–34.


12. Phan TG, Wijdicks EFM. Intra-arterial thrombolysis for vertebrobasilar circulation ischemia. Crit Care Clin 1999;15:719–742, vi.

13. Schmahmann JD. Vascular syndromes of the thalamus. Stroke 2003;34:2264–2278.14. Schonewille WJ, Algra A, Serena J, Molina CA, Kappelle LJ. Outcome in patients with basilar artery

occlusion treated conventionally. J Neurol Neurosurg Psychiatry 2005;76:1238–1241.15. Strbian D, Sairanen T, Silvennoinen H, et al. Thrombolysis of basilar artery occlusion: Impact of baseline

ischemia and time. Ann Neurol 2013;73:688–694.16. Toyoda K, Hirano T, Kumai Y, et al. Bilateral deafness as a prodromal symptom of basilar artery occlu-

sion. J Neurol Sci 2002;193:147–150.17. Veltkamp R, Jacobi C, Kress B, Hacke W. Prolonged low-dose intravenous thrombolysis in a stroke

patient with distal basilar thrombus. Stroke 2006;37:e9–11.18. Voetsch B, DeWitt LD, Pessin MS, Caplan LR. Basilar artery occlusive disease in the New England

Medical Center Posterior Circulation Registry. Arch Neurol 2004;61:496–504.19. Wijdicks EFM, Nichols DA, Thielen KR, et al. Intra-arterial thrombolysis in acute basilar artery throm-

boembolism: the initial Mayo Clinic experience. Mayo Clin Proc 1997;72:1005–1013.20. Wijdicks EFM, Scott JP. Outcome in patients with acute basilar artery occlusion requiring mechanical

ventilation. Stroke 1996;27:1301–1303.

391

A CONVERSATION

AN EXPLANATION

The majority of patients with bacterial meningitis present with headache, neck stiffness, and altered consciousness.16 This triad is more common in patients with pneumococcal meningitis than in patients with meningococcal meningitis.2 However, in one large series of patients, only 14% of the patients were initially comatose.6

Bacterial meningitis is a consequence of another infectious source, often otitis media. Acute bacterial meningitis is confirmed with a cerebrospinal fluid (CSF) examination showing an increase in CSF pressure, a substantial increase in neutrophils, increased

Comatose and Bacterial meningitis

/ / / 28 / / /


protein, and decreased glucose. Lymphocytic predominance is uncommon. Gram stains are usually positive. In a patient with clinical suspicion of acute bacterial meningitis, the diagnostic considerations should also include viral meningitis (more common in the summer months; lymphocytosis in subsequent CSF samples and positive PCR), tuber-culous meningitis (prior exposure to tuberculosis, prior infection with HIV, positive tuberculin tests, and predominant cranial nerve deficit), and carcinomatous meningitis (cranial nerve deficit, often prior breast cancer).

The causes of coma in bacterial meningitis are shown in Table 28-1. In many patients, acute bacterial meningitis extends diffusely into the cerebral cortex, and this explains the decrease in consciousness. It may lead to brain edema and increased intracranial pressure. Disruption of the blood–brain barrier due to inflammatory cytokines and lipid peroxi-dation may explain cerebral edema, but this is an unusual mechanism and brain edema is more often observed in a fulminant meningoencephalitis. Coma from meningitis can be due to infarctions in the pons, or thalami, or other strategic locations and is due to encasement of perforating arteries by pus pockets or the development of vasculitis.16,18 Necrotizing vasculitis is currently considered a predominant mechanism.7 Obstructive hydrocephalus is a less common mechanism.

MR findings in bacterial meningitis have been revealing and surprising at times. It may document infarction associated with vasculitis (Fig. 28-1), gadolinium enhance-ment, true pus (Fig. 28-2), or an unexpected infratentorial empyema in patients with prior otitis media and mastoidectomy (Fig. 28-3). Epidural or subdural empyema may present identically as bacterial meningitis and is usually a consequence of surgery for oti-tis media mastoidectomy.5 MRI may show multiple pus pockets and an extensive throm-bophlebitis (Fig. 28-4).


The antimicrobial therapy is shown in Table 28-2.7 Dexamethasone (10 mg IV) before or with the first intravenous administration of antibiotics reduces mortality in

TABLE 28-1 Causes of Coma in Bacterial meningitis

• Cortical involvement (meningoencephalitis)• Cerebral edema• Cerebral infarcts• Acute obstructive hydrocephalus• Status epilepticus• Empyema in the posterior fossa with brainstem compression

Comatose and Bacterial meningitis / / 393

pneumococcal meningitis and is mostly beneficial in patients with impaired conscious-ness.4,9 Dexamethasone is then followed by 10 mg IV every six hours for four days regardless of the causative organism.17 Further management to consider is monitoring intracranial pressure and intermittent administration of osmotic diuretics (mannitol or hypertonic saline) to maintain an intracranial pressure of less than 20 mm Hg and a cere-bral perfusion pressure of more than 60 mm Hg. In patients with acute hydrocephalus, repeated lumbar puncture, lumbar drain, or ventriculostomy may be warranted. Video-electroencephalographic monitoring should be considered in patients with a sus-picion of seizures and fluctuating consciousness.

Mortality for pneumococcal meningitis is 20% to 40%, with a third of patients having sequelae.3 Outcome remains poor in patients with systemic manifestations (e.g., shock),

FIGURE 28-1 MRI DWI: multiple infarcts after meningitis.

(A) (B)

FIGURE 28-2 (A) MRI: enhanced meninges after gadolinium. (B) MRI FLAIR. Pus in ventricles.


advanced age, presence of otitis media or sinusitis, immunodeficiency or immunocom-promised state,16 or prior splenectomy.1

A CONCLUDING NOTE

Bacterial meningitis may lead to serious secondary central nervous system complications. Coma can be due to infarctions from vasculitis, or impaired consciousness may occur from brainstem compression due to subdural or epidural empyema. Early recognition of bacterial meningitis is important because delayed administration of antibiotics and dexamethasone reduces the chance of full recovery.

(A) (B)

FIGURE 28-3 CT with few abnormalities other than hydrocephalus (A), but there is infratentorial

otogenic empyema on MRI (B).

TABLE 28-2 Recommendations for empirical antimicrobial Therapy in adults with Community-acquired Bacterial meningitis

Predisposing

Factor

Common Bacterial Pathogen Antimicrobial Therapy

Age 16–50 y Neisseria meningitidis, Streptococcus

pneumoniae

Vancomycin (1 g IV q12h), cefotaxime (1–2 g IV

q4h), or ceftriaxone (2–4 g/d q12h)Age >50 y S. pneumoniae, N. meningitidis, Listeria

monocytogenes, aerobic gram-negative

bacilli

Vancomycin plus cefotaxime, or cefotaxime

plus ampicillin (14 g IV q4h)

Presence of a risk

factor*

S. pneumoniae, L. monocytogenes,

Haemophilus influenzae

Vancomycin plus cefotaxime or cefotaxime plus

ampicillin

* Risk factors include alcohol abuse and immune deficiency. Adapted from van de Beek et al.17

Comatose and Bacterial meningitis / / 395

REFERENCES

1. Adriani KS, Brouwer MC, van der Ende A, van de Beek D. Bacterial meningitis in adults after splenec-tomy and hyposplenic states. Mayo Clin Proc 2013;88:571–578.

2. Attia J, Hatala R, Cook DJ, Wong JG. The rational clinical examination. Does this adult patient have acute meningitis? JAMA 1999;282:175–181.

3. Auburtin M, Porcher R, Bruneel F, et al. Pneumococcal meningitis in the intensive care unit: prognostic factors of clinical outcome in a series of 80 cases. Am J Respir Crit Care Med 2002;165:713–717.

4. de Gans J, van de Beek D. Dexamethasone in adults with bacterial meningitis. N Engl J Med 2002;347:1549–1556.

(A) (B)

(C) (D)

FIGURE 28-4. MRI of the brain performed 48 hours into coma revealed diffuse meningeal

enhancement, with infectious loculations scattered over the convexities (A, coronal T2 FLAIR

image), pus filling most sulci (B, axial T2 FLAIR image), diffuse cerebral venous sinus thrombo-

ses (C, MR venogram shows absent right transverse and sigmoid sinuses), and infarctions (D,

axial DWI showing scattered infarcts). From reference 12.


5. Durand ML, Calderwood SB, Weber DJ, et al. Acute bacterial meningitis in adults. A review of 493 epi-sodes. N Engl J Med 1993;328:21–28.

6. Kangsanarak J, Navacharoen N, Fooanant S, Ruckphaopunt K. Intracranial complications of suppurative otitis media: 13 years’ experience. Am J Otol 1995;16:104–109.

7. Klein M, Koedel U, Pfister HW. Oxidative stress in pneumococcal meningitis: a future target for adjunc-tive therapy? Prog Neurobiol 2006;80:269–280.

8. Nathoo N, Nadvi SS, van Dellen JR. Infratentorial empyema: analysis of 22 cases. Neurosurgery 1997;41:1263–1268; discussion 1268–1269.

9. Nguyen TH, Tran TH, Thwaites G, et al. Dexamethasone in Vietnamese adolescents and adults with bacterial meningitis. N Engl J Med 2007;357:2431–2440.

10. Penido Nde O, Borin A, Iha LC, et al. Intracranial complications of otitis media: 15 years of experience in 33 patients. Otolaryngol Head Neck Surg 2005;132:37–42.

11. Quagliarello VJ, Scheld WM. Treatment of bacterial meningitis. N Engl J Med 1997;336:708–716.12. Rubin M, Wijdicks EFM. Fulminant streptoccocal meningoencephalitis. JAMA Neurol 2013;70:51513. Tunkel AR. Bacterial Meningitis. Philadelphia: Lippincott Williams & Wilkins, 2001.14. van de Beek D, Brouwer MC, Thwaites GE, Tunkel AR. Advances in treatment of bacterial meningitis.

Lancet 2012;380:1693–1702.15. van de Beek D, Campeau NG, Wijdicks EFM. The clinical challenge of recognizing infratentorial empy-

ema. Neurology 2007;69:477–481.16. van de Beek D, de Gans J, Spanjaard L, et al. Clinical features and prognostic factors in adults with bacte-

rial meningitis. N Engl J Med 2004;351:1849–1859.17. van de Beek D, de Gans J, Tunkel AR, Wijdicks EFM. Community–acquired bacterial meningitis in

adults. N Engl J Med 2006;354:44–53.18. van de Beek D, Patel R, Wijdicks EFM. Meningococcal meningitis with brainstem infarction. Arch

Neurol 2007;64:1350–1351.

397

A CONVERSATION

AN EXPLANATION

Most brain abscesses are pyogenic. Spread is possible due to untreated infection including paranasal sinusitis, otitis media, mastoiditis, or dental infections.1,4 The bacteriology is a mixed polymicrobial flora. The microorganisms that can be isolated from brain abscesses are gram-positive organisms in approximately two-thirds of the cases, but they can also include anaerobic gram-positive bacilli and in some series Mycobacterium tuberculo-sis. In approximately 25% of cases, gram-negative bacteria are found, including aerobic

Comatose and Brain abscess/ / / 29 / / /


gram-negative bacilli, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis.

The causes of coma in brain abscess are shown in Table 29-1. Whether coma occurs is determined by the site of the abscess.5 Isolated pyogenic brainstem abscesses have been described.11 Our case example is a typical example of diminished level of consciousness associated with a thalamic localization (Fig. 29-1). Rupture into the ventricles causes ventriculitis, and deterioration is preceded by worsening headache and meningeal signs.

MRI has an important role in the diagnosis of a bacterial abscess.7 In the early phase of abscess formation, MRI shows hypointense signals on T2, but the postcontrast images will reveal enhancement of the capsule, and other abscesses may become apparent. DWI is a useful adjunctive test to differentiate a bacterial abscess from other ring-enhancing lesions (Fig. 29-2). Postcontrast T1 images can document a hyperintense necrotic center and ring enhancement, but this is not fully discriminating. Both FLAIR and DWI can show an increased signal representing pus.2,3 The proteins and inflammatory cells and viscous pus restrict the random motion of water molecules in an abscess, resulting in a lower signal intensity on DWI and a higher ADC. MRI can document enhancement in the ventricles, indicative of the development of ventriculitis. Brain abscesses generally are

TABLE 29-1 Causes of Coma in Brain abscess

• Hemispheric lesions with brainstem displacement• Thalamus lesion with mass effect• Intraventricular rupture• Cerebellar lesions with obstructive hydrocephalus• Isolated brainstem abscess

FIGURE 29-1 CT and MRI in a patient with bilateral thalamic abscesses due to histoplasmosis.

Comatose and Brain abscess / / 399

caused by bacterial species, but unfortunately most cerebrospinal fluid (CSF) cultures will be sterile. Blood samples may have a less than 30% yield on finding growth in culture.


Intravenous antimicrobial therapy should be administered for six weeks and should be aimed at the possible source (Table 29-2). Aspiration may be a first option.8 Excision is reserved for larger brain abscesses (more than 3 cm) and when they are superficially located. The overall mortality of brain abscesses remains high, at 50%.6 Our patient example with histoplasmosis is unusual. Histoplasmosis of the central nervous sys-tem (CNS) is more commonly associated with meningitis or progressive disseminated histoplasmosis. Generally serological tests for anti-Histoplasma antibodies in the CSF are positive (80% of the cases), but a culture of a large-volume sample of more than 10 cc is necessary.9,10,12 The treatment for CNS histoplasmosis is amphotericin B 0.7 to 1 mg/kg per day or a lipid formulation of amphotericin B (3–5 mg/kg per day) for two to four weeks. This is supplemented with itraconazole (200 mg t.i.d. or fluconazole 600 to 800 mg q.d.) for 12 months.

FIGURE 29-2 MRI FLAIR of thalamus abscess with edema and restricted diffusion on DWI.

TABLE 29-2 empirical antimicrobial Therapy in Brain abscess

Sinusitis Nafcillin (2 g q4h) and metronidazole (500 mg q6h), ceftriaxone (2 g q12h)Otitis media or dental Ceftazidime (2 g q8h) and metronidazoleabscess (500 mg q6h) and penicillin G (24 mU/d)

Infective endocarditis Nafcillin (2 g q4h) and ceftriaxone (2 g q12h)


A CONCLUDING NOTE

A ring-enhancing lesion on MRI can be a solitary abscess, and although mostly pyogenic brain abscesses are found, fungal infection should be considered. A lesion in the thalamus or a ring-enhancing lesion with mass effect or breakthrough into the ventricular system may explain impaired consciousness.

REFERENCES

1. Carpenter J, Stapleton S, Holliman R. Retrospective analysis of 49 cases of brain abscess and review of the literature. Eur J Clin Microbiol Infect Dis 2007;26:1–11.

2. Desprechins B, Stadnik T, Koerts G, et al. Use of diffusion-weighted MR imaging in differential diagnosis between intracerebral necrotic tumors and cerebral abscesses. AJNR Am J Neuroradiol 1999;20:1252–1257.

3. Ferreira NP, Otta GM, do Amaral LL, da Rocha AJ. Imaging aspects of pyogenic infections of the central nervous system. Top Magn Reson Imaging 2005;16:145–154.

4. Hakan T, Ceran N, Erdem I, Berkman MZ, Goktas P. Bacterial brain abscesses: an evaluation of 96 cases. J Infect 2006;52:359–366.

5. Kniss MS, Sivakumar K. Solitary pyogenic abscess of the medulla oblongata: survival after aspiration and antibiotics. Neurology 2006;66:1836.

6. Prasad KN, Mishra AM, Gupta D, et al. Analysis of microbial etiology and mortality in patients with brain abscess. J Infect 2006;53:221–227.

7. Rath TJ, Hughes M, Arabi M, Shah GV. Imaging of cerebritis, encephalitis, and brain abscess. Neuroimaging Clin North Am 2012;22:585–607.

8. Ratnaike TE, Das S, Gregson BA, Mendelow AD. A review of brain abscess surgical treat-ment—78 years: aspiration versus excision. World Neurosurg 2011;76:431–436.

9. Schestatsky P, Chedid MF, Amaral OB, et al. Isolated central nervous system histoplasmosis in immuno-competent hosts: a series of 11 cases. Scand J Infect Dis 2006;38:43–48.

10. Smith HD, Gupta S. Ring-enhancing brain lesion in a man with acquired immunodeficiency syndrome. Am J Med 2006;119:246–247.

11. Tonon E, Scotton PG, Gallucci M, Vaglia A. Brain abscess: clinical aspects of 100 patients. Int J Infect Dis 2006;10:103–109.

12. Wheat LJ, Musial CE, Jenny-Avital E. Diagnosis and management of central nervous system histoplas-mosis. Clin Infect Dis 2005;40:844–852.

401

A CONVERSATION

AN EXPLANATION

Escalating febrile episodes or febrile spikes associated with new focal findings such as hemiparesis, aphasia, or focal seizures should point toward a CNS infection and a sub-dural empyema. It may come soon after a neurosurgical procedure or it may be delayed, as in our patient. CT scan may unexpectedly demonstrate a subdural empyema or epi-dural abscess, either of which can clinically mimic acute bacterial meningitis. Empyema

Comatose and empyema/ / / 30 / / /


is the result of a middle ear infection2,6 or septicemia.4 Empyema may develop within two weeks after mastoidectomy. Using the tentorium as a dividing line, pus pockets may be in the supra- or infratentorial compartment. Infratentorial empyema is much less common but more problematic. Patients may initially do well but then may deteriorate from acute hydrocephalus or a direct compression of the brainstem. The most important triggers for empyema are ear, nose, and throat infections, and therefore present as otitis, sinus-itis, and mastoiditis in the majority of the patients. Infratentorial subdural empyema is often not recognized, and it is the same with supratentorial empyema. Noncontrast CT scan is not very useful in showing abnormalities because only hypodensities are seen. Empyema may become apparent only after contrast administration, thus it remains a clinical challenge to recognize any of these disorders, particularly because a CT scan is not an adequate imaging modality; MRI is more useful to further delineate the fluid collections but also to show its space-occupying effect (Fig 30.1).3 DWI is a useful addi-tional imaging modality.

Supratentorial empyema very frequently presents with focal seizures (or epilepsia partialis continua), and treatment may remain difficult even after surgical removal. Often a hemiparesis remains due to cortical irritation but improves rapidly. Infratentorial empy-ema may present with vertigo (often misattributed to cochlear involvement), but nystag-mus, appendicular ataxia, and dysarthria are expected. Acute pontine compression could lead to pinpoint pupils with minimal oculocephalic responses.7

The causes of coma in empyema are shown in Table 30-1. Apart from frequent seizures, shift and compression of the brainstem and hydrocephalus are the major mechanism.5

FIGURE 30-1 Large epidural abscess after prior cranietomy for stroke in the middle cerebral

artery territory.

Comatose and empyema / / 403


Standard management for patients with empyema is emergency drainage after surgical exploration followed by antibiotic therapy for eight weeks. Treatment of empyema is, in most instances, a neurosurgical emergency that requires evacuation of the empyema with washout and drainage of all pockets.5 In the supratentorial region it may require a burr hole rather than a wide craniotomy. One group even suggested the use of a hollow screw for diagnostic purposes if the MRI is ambiguous, but most neurosurgeons will do a pro-cedure with a full bone flap to expose the infected region.1 In the supratentorial compart-ment, it is mostly a neurosurgical procedure; in the infratentorial region, this is usually done with ear, nose, and throat physicians in order to more clearly explore the abnormal area. Acute hydrocephalus remains a major problem due to obstruction of the fourth ven-tricle, and outcome is poor if not treated with a ventriculostomy. Drainage of pus pockets and irrigation with antibiotic solutions can be very difficult and may be unsatisfactory. Empirical antibiotic therapy of a surgically accessible lesion in nonimmunocompromised patients involves cefotaxime and vancomycin with metronidazole. (Cefepime or ceftazi-dime can be used if Pseudomonas aeruginosa is suspected.) Meropenem is usually avoided due to a more than 70% risk of seizures, particularly if there is already structural brain dam-age. Because Staphylococcus aureus is a common pathogen, empirical antibiotic therapy should include a third-generation cephalosporin and a penicillinase-resistant penicillin. Gram-positives are more common in subdural empyema after a prior neurosurgical proce-dure. Gram-negatives can be seen in any spontaneous form of subdural empyema.

Prognosis is largely determined by early recognition, rapid initiation of broad-spectrum antibiotic treatment, and debridement. Mortality may reach 20%, mostly due to associ-ated septic shock. Morbidity with persistent hemiparesis and poor cognition due to cortical involvement is common.

A CONCLUDING NOTE

Empyema may mimic meningitis, and due to its rapidly occurring mass effect is a neuro-surgical emergency.

TABLE 30-1 Causes of Coma in empyema

• Thalamus and brainstem shift• Ventriculitis and hydrocephalus• Sepsis and shock• Nonconvulsive seizures


REFERENCES

1. Aldinger FA,Shiban E,Gempt J et al.Hollow screws: a diagnostic tool for intracranial empyema. Acta Neurochir 2013; 155: 373–377.

2. Dill SR, Cobbs CG, McDonald CK. Subdural empyema: analysis of 32 cases and review. Clin Infect Dis 1995;20:372–386.

3. Jaggi RS, Husain M, Chawla S, Gupta A, Gupta RK. Diagnosis of bacterial cerebellitis: diffusion imaging and proton magnetic resonance spectroscopy. Pediatr Neurol 2005;32:72–74.

4. Kojima A, Yamaguchi N, Okui S. Supra- and infratentorial subdural empyema secondary to septicemia in a patient with liver abscess—case report. Neurol Med Chir (Tokyo) 2004;44:90–93.

5. Nathoo N, Nadvi SS, Gouws E et al. Craniotomy improves outcomes for cranial subdural empyemas. Computed tomography–era experience in 699 patients. Neurosurgery 2001; 49: 872–877

6. Polyzoidis KS, Vranos G, Exarchakos G, et al. Subdural empyema and cerebellar abscess due to chronic otitis media. Int J Clin Pract 2004;58:214–217.

7. van de Beek D, Campeau NG, Wijdicks EFM. The clinical challenge of recognizing infratentorial empy-ema. Neurology 2007;69:477–481.

405

A CONVERSATION

AN EXPLANATION

Herpes simplex encephalitis usually results from an infection of herpes simplex virus type 1 (HSV-1). Herpes simplex encephalitis is preceded by a febrile illness, speech abnormalities, seizures (generalized tonic-clonic or complex partial seizures), and even chorea.1,10,13 In such patients, herpes simplex encephalitis is considered, although other treatable infectious disorders have been described with similar presentations. In 8% of patients in one series, a treatable disorder, again mostly other infections, mimicked her-pes simplex encephalitis.6

Comatose and Herpes simplex encephalitis

/ / / 31 / / /


The causes of coma in herpes simplex encephalitis are shown in Table 31-1. Two main features are virus-induced bihemispheric destruction and a swollen hemorrhagic tempo-ral lobe with brainstem compression. Hemorrhagic conversion of the involved temporal lobe may cause sudden deterioration. Nonconvulsive status epilepticus is uncommon, but infrequently recognized.

The diagnostic evaluation of comatose patients with a presumed clinical diagnosis of encephalitis has been facilitated by the use of MRI and cerebrospinal fluid (CSF) polymerase chain reaction (PCR).16,17 CSF PCR is now reliable for most herpes viruses, including herpes simplex virus, varicella-zoster virus, Epstein-Barr virus, and cytomega-lovirus. The CSF profile of encephalitis is a lymphocytic pleocytosis, increased protein level, normal glucose, and a number of oligoclonal bands. Polymorphonuclear neutro-phils do occur in viral encephalitis, but in less than 1% of the cases. The leukocyte count is typically in the 200/mm3 range but can be much lower in patients treated with immu-nosuppressive drugs and can be initially normal in elderly patients. Recognition of her-pes simplex encephalitis in these patients is very difficult, and often only MRI can point toward the disorder.

PCR is an important test with high sensitivity and specificity. The majority of cases identified with PCR are due to HSV-1. Some studies have estimated the sensitivity of HSV-PCR to be 69%, with a specificity of 99% to 100% (Fig. 31-1).2,3,8,15 Antiviral therapy has very little effect on detection of HSV DNA in CSF, and that includes the first week of treatment.

CT scan may be unrevealing or may show an early hint of a temporal lobe hypoden-sity (Fig. 31-2). It is important to differentiate the appearance of herpes simplex encephalitis from an ischemic stroke. MR appearance of encephalitis could further point to the etiology. MR findings with increased T2 signal in the temporal lobe, orbi-tofrontal, and subinsular regions are expected in comatose patients (Fig. 31-3).5,9,11,14 Bithalamic involvement has been demonstrated on MRI, but there is often involve-ment of other areas.7 Single photon emission computed tomography (SPECT) is a use-ful test, but the presence of reduced temporal lobe uptake is nonspecific (Fig. 31-4).

TABLE 31-1 Causes of Coma in Herpes simplex encephalitis

• Multifocal hemispheric lesions• Bithalamic lesions• Temporal lobe (hemorrhagic) swelling and brainstem shift• Nonconvulsive status epilepticus

Comatose and Herpes simplex encephalitis / / 407

1.81.6

1.41.2

1.0

0.80.6

0.40.2

0.0

–0.20 5 10 15 20 25 30 35 40 45

Temperature (˚C)

Neg

M62685

HSV

Fluo

resc

ence

(F2

)

FIGURE 31-1 PCR technique showing quantitative snap melting curves: M62685 is a sample

compared to HSV and control.

FIGURE 31-2 CT scan in herpes simplex encephalitis showing temporal lobe swelling.



Herpes simplex encephalitis is treated with a standard course of intravenous acyclo-vir. There is an emerging resistance to acyclovir in immunocompromised patients.12 Corticosteroids may be effective in patients with temporal lobe swelling, but there is a concern over increasing viral spread. Patients are typically treated with 10 mg/kg acy-clovir for 21 days and the dose is adjusted to creatinine clearance. It is often followed by 21 days of oral valacyclovir. Video-EEG recording may be warranted to detect subclini-cal seizures in a persistently comatose patient. Worsening from hemorrhagic conversion of a necrotic mass may require decompressive surgery with removal of the necrotic tis-sue and can be lifesaving.4 With early antiviral treatment, the prognosis can be good in patients younger than 30 years. The degree of MRI abnormalities could be predictive, but

FIGURE 31-3 Herpes simplex encephalitis: MRI shows hyperintensities in the temporal lobe and

subinsular cortex.

Comatose and Herpes simplex encephalitis / / 409

persistent MRI abnormalities translate into neither disease activity nor future morbidity. It can be expected that about 60% of the patients will have residual deficits, with improve-ment continued in the first six months after onset. A seizure disorder may evolve and would require long-term antiepileptic drugs.

A CONCLUDING NOTE

Herpes simplex encephalitis is a common form of encephalitis, and due to its destructive character, may lead to rapid decline in consciousness. CT scan may show a temporal lobe hypodensity, and hemorrhage into the necrotic mass may further worsen outcome due to brainstem compression. Antiviral therapy early in the course of illness reduces morbidity.

REFERENCES

1. Baringer JR. Herpes simplex infections of the nervous system. Neurol Clin 2008;26:657–674.2. DeBiasi RL, Kleinschmidt-DeMasters BK, Weinberg A, Tyler KL. Use of PCR for the diagnosis of her-

pesvirus infections of the central nervous system. J Clin Virol 2002;25 Suppl 1:S5–11.3. Domingues RB, Lakeman FD, Pannuti CS, Fink MC, Tsanaclis AM. Advantage of polymerase chain

reaction in the diagnosis of herpes simplex encephalitis: presentation of 5 atypical cases. Scand J Infect Dis 1997;29:229–231.

4. Gaieski DF, Nathan BR, Weingart SD, Smith WS. Emergency neurologic life support: meningitis and encephalitis. Neurocrit Care 2012;17 Suppl 1:S66–72.

AL A MPL

0 100 200 300

100

80

60

40

20

0

100% = 228 = Max Cerebellum

RightLeft

Angle (degrees)

% M

AX

PIX

EL V

ALU

E

FIGURE 31-4 SPECT showing nonspecific reduced uptake in both temporal lobes.


5. Gaviani P, Leone M, Mula M, et al. Progression of MRI abnormalities in herpes simplex encephalitis despite clinical improvement: natural history or disease progression? Neurol Sci 2004;25:104–107.

6. Gnann JW, Jr., Whitley RJ. Clinical practice. Herpes zoster. N Engl J Med 2002;347:340–346.7. Gumus H, Kumandas S, Per H, et al. Unusual presentation of herpes simplex virus encephalitis: bilateral

thalamic involvement and normal imaging of early stage of the disease. Am J Emerg Med 2007;25:87–89.8. Kleinschmidt-DeMasters BK, DeBiasi RL, Tyler KL. Polymerase chain reaction as a diagnostic adjunct

in herpesvirus infections of the nervous system. Brain Pathol 2001;11:452–464.9. Kuker W, Nagele T, Schmidt F, Heckl S, Herrlinger U. Diffusion-weighted MRI in herpes simplex

encephalitis: a report of three cases. Neuroradiology 2004;46:122–125.10. Marschitz I, Rodl S, Gruber-Sedlmayr U, et al. Severe chorea with positive anti-basal ganglia antibodies

after herpes encephalitis. J Neurol Neurosurg Psychiatry 2007;78:105–107.11. McCabe K, Tyler K, Tanabe J. Diffusion-weighted MRI abnormalities as a clue to the diagnosis of herpes

simplex encephalitis. Neurology 2003;61:1015–1016.12. Rozenberg F, Deback C, Agut H. Herpes simplex encephalitis : from virus to therapy. Infect Disord Drug

Targets 2011;11:235–250.13. Sabah M, Mulcahy J, Zeman A. Herpes simplex encephalitis. BMJ 2012;344:e3166.14. Sener RN. Herpes simplex encephalitis: diffusion MR imaging findings. Comput Med Imaging Graph

2001;25:391–397.15. Tang YW, Mitchell PS, Espy MJ, Smith TF, Persing DH. Molecular diagnosis of herpes simplex virus

infections in the central nervous system. J Clin Microbiol 1999;37:2127–2136.16. Whitley RJ. Herpes simplex encephalitis: adolescents and adults. Antiviral Res 2006;71:141–148.17. Whitley RJ, Gnann JW. Viral encephalitis: familiar infections and emerging pathogens. Lancet

2002;359:507–513.

411

A CONVERSATION

AN EXPLANATION

This is a patient who was seen in our institution during the 2009 H1NI epidemic.1 This outbreak may have been a single occurrence, but knowledge of this infection and its consequential clinical course is important because it is highly probable to expect more epidemics with avian influenza virus. This novel influenza A (H1N1) virus was first iden-tified in Mexico, the United States, and Canada and spread quickly around the world.5,7 It caused the first major influenza pandemic in over 30 years, and most of the reported literature is on children and young adults.5,6 H1N1 has a rapid course with what seems

Comatose and H1n1 influenza/ / / 32 / / /


like “a bad flu” followed by unexpected dyspnea and patients becoming rapidly critically ill from “flash” pulmonary edema or what seems clearly fitting the criteria for acute respi-ratory stress syndrome (ARDS).

Neurologic examination may reflect damage from longstanding refractory hypoxemia and shock, with some patients barely surviving this pulmonary onslaught and arriving moribund. During this epidemic, ICUs in many countries were flooded with critically ill patients, straining the ventilator availability. Many patients needed high doses of sedation and neuromuscular junction blockers, and their neurologic condition was not known for days. Seizures with H1N1 were uncommon. The causes of coma are shown in table 32-1.

In our patient, CT showed little change in the multifocal supratentorial white matter lesions. MRI revealed symmetric areas of restricted diffusion in the globus pallidi and caudate nuclei, consistent with anoxic brain injury (Fig. 32-1). We found additional evidence of acute hemorrhagic leukoencephalitis (AHL). Clinical features of AHL typically follow a respiratory infection and include headache, seizures, focal neurologic signs, and impaired consciousness, which may rapidly progress to coma. Brain MRI in Hurst’s disease reveals multifocal T2 white matter hyperintensities with marked edema and areas of hemorrhage. Thus, in H1N1, severe brain injury can occur by two different mechanisms—a postinfectious autoimmune demyelinating insult (AHL) and hypoxic injury resulting from severe ARDS—and there are com-pelling arguments for two disease processes in this patient example (and others pub-lished later).2–4 The marked restricted diffusion involving the striata and globi pallidi strongly indicates a major hypoxemic insult. The progressive white matter involve-ment, together with CSF findings of elevated IgG index, synthesis rate, and protein, are all consistent with AHL.


Our patient was treated with seven sessions of plasma exchange and 10 days of high-dose intravenous methylprednisolone without considerable clinical improvement.1 Expectedly, this is an unproven approach and it is unclear if this will make an impact, but patients are often young and one can make an argument to use immunosuppression. If Hurst’s disease is coexisting here—and knowing there have been favorable recoveries described in patients treated with immunosuppressive therapy—there is a good argu-ment to proceed aggressively. We can expect hypoxic brain injury in comatose survivors after treatment of major lung injury. However, the magnitude of this additional potential problem is unknown.

Comatose and H1n1 influenza / / 413

(A) (B)

(C) (D)

(E) (F)

FIGURE 32-1 Radiographic images of severe H1N1 infection. (A) Chest CT in H1N1 influenza

and ARDS shows extensive opacities. Brain MRI reveals subcortical hyperintensities (B, C),

with hemorrhages on gradient-echo sequence (D). (E, F) DWI and ADC images show restricted

diffusion in the basal ganglia consistent with hypoxic brain injury. From reference 2, used

with permission.


There is debate regarding permissive hypoxemia and optimal oxygen saturation in patients with ARDS secondary to H1N1 influenza. This is based on findings that inter-ventions in ARDS that improve hypoxemia (such as nitric oxide, high-frequency oscil-latory ventilation, or prone ventilation) have not translated into survival benefit, and most patients with ARDS die of multisystem organ failure rather than hypoxemia. There is concern for neurologic injury resulting from a prolonged period of hypoxemia. More aggressive oxygen administration may improve oxygen delivery in patients with massive intrapulmonary shunts. Permissive hypoxemia in H1N1 influenza treating ARDS may not be “permitted” by the brain.

A CONCLUDING NOTE

Avian flu virus infection can cause rapid neurologic damage from hypoxemia and from an immunologic response. Outcome may be determined by a dual injury to the brain.

REFERENCES

1. Fuchigami T, Imai Y, Hasegawa M, et al. Acute encephalopathy with pandemic (H1N1) 2009 virus infec-tion. Pediatr Emerg Care 2012;28:998–1002.

2. Fugate JE, Lam EM, Rabinstein AA, Wijdicks EFM. Acute hemorrhagic leukoencephalitis and hypoxic brain injury associated with H1N1 influenza. Arch Neurol 2010;67:756–758.

3. Kasai T, Togashi T, Morishima T. Encephalopathy associated with influenza epidemics. Lancet 2000;355:1558–1559.

4. Kedia S, Stroud B, Parsons J, et al. Pediatric neurological complications of 2009 pandemic influenza A (H1N1). Arch Neurol 2011;68:455–462.

5. Okumura A, Tsuji T, Kubota T, et al. Acute encephalopathy with 2009 pandemic flu: comparison with seasonal flu. Brain Dev 2012;34:13–19.

6. Orsted I, Molvadgaard M, Nielsen HL, Nielsen H. The first, second and third wave of pandemic influenza A (H1N1)pdm09 in North Denmark Region 2009–2011: a population-based study of hospitalizations. Influenza Other Respi Viruses 2013;7:776–782.

7. Richt JA, Webby RJ, Kahn RE. The pandemic H1N1 influenza experience. Curr Top Microbiol Immunol 2013;365:269–279.

TABLE 32-1 Causes of Coma in H1n1 influenza encephalitis

• Necrotic encephalopathy• Anoxic encephalopathy• Acute disseminated encephalomyelitis• Hurst Disease

415

A CONVERSATION

AN EXPLANATION

Rabies is caused by rabies virus genotype 1 and may result from dog or bat bites. The two types of rabies are furious (classic) rabies and paralytic rabies. Rabies is usually seen in the summer and early fall.4 Rabies is often considered in unexplained, rapidly progressive encephalitis. But the infection is rarely found in the United States—there

Comatose and Rabies encephalitis

/ / / 33 / / /


are two cases of rabies encephalitis a year in the United States,2,3,5 and many U.S. states have not reported rabies for decades.1 Because it is a reportable disease and organ dona-tion is precluded, it is included here in the vignette collection. This case was reported in 2007 and further investigation failed to detect viral antigen in CSF, saliva, and skin biopsy. Rabies virus neutralizing antibodies were detected in CSF and serum samples, confirming the diagnosis.

Coma in rabies encephalitis is mostly due to the progressive brainstem involvement. The clinical picture is usually detached from a bat exposure in the weeks prior, and the onset of symptoms may not be noticed if the patient did not seek attention for acute treat-ment (a superficial scratch may be just as likely to cause infection as a frank bite). Painful paresthesias are often reported and are a result of dorsal root involvement.1,2,4,5 The only clinical feature that points toward a diagnosis is hydrophobia, and requires questioning of family members for laryngospasm with drinking water or anxiety of the patient related to swallowing liquids.1

On examination patients may have myoclonus and hemichorea, and there are often brainstem findings. Flaccidity is common in both types of rabies infection. Many patients have severe paroxysmal hyperactivity syndrome, and cerebral vasospasm has been described. There are no characteristic MRI findings, and the MRI is often normal with no gadolinium enhancement. Repeat MRI may show evolving lesions in days to weeks. The MRI, may reveal abnormalities in the brainstem, hippocampus, basal gan-glia, and hypothalamus,3 but not with diffuse brain swelling. When examined at autopsy, there is usually severe neuronal destruction. This may also involve the brachial plexus and spinal cord.

The presence of Negri inclusion bodies is characteristic, but PCR of tissue may find virus antigen.3 Spinal cord abnormalities resembling transverse myelitis may precede the illness, and such a presentation is not commonly known. The diagnosis can only be confirmed with serum and CSF rabies-specific neutralizing antibodies and a PCR test of saliva, CSF, tears, urine, and skin biopsy, preferably from the nape of the neck containing hair follicles. The sensitivity of each test varies and depends on the fluid or tissue tested. Saliva, CSF, and urine most often show positive results. Hair follicle tests may be positive in only half of the cases with furious rabies. Rabies virus antigen can be detected on direct fluorescence antibody testing.

Coma is a result of multifocal lesions, often with a brainstem preference. The causes of coma in rabies encephalitis are shown in Table 33-1.

Comatose and Rabies encephalitis / / 417


Postexposure prophylaxis is the only treatment possibility (Table 33-2). High-dose corticosteroids, antithymocytic globulin, or other immunomodulating treatments are not effective. Treatment is usually supportive, although the so-called “Milwaukee” protocol resulted in survival of an unvaccinated teenager.6 This protocol basically involves

TABLE 33-1 Causes of Coma in Rabies encephalitis

• Primary brainstem lesion• Acute disseminated encephalomyelitis• Frontotemporal lesions• Nonconvulsive status epilepticus

TABLE 33.2 Rabies Postexposure Prophylaxis Guide, United states, 1991

Animal type Evaluation and disposition of animal

Postexposure prophylaxis recommendations

Dogs and cats Healthy and available for 10 days

observation

Rabid or suspected rabid

Unknown (escaped)

Should not begin phophylaxis unless

animal signs of rabies*

Immediate vaccination

Consult public health officialsSkunks, raccoons, bats, foxes,

and most other carnivores;

woodchucks

Regard as rabid unless geographic

area is known to be free of rabies

or until animal proven negative by

laboratory test†

Immediate vaccination

Livestock, rodents rodents, and

logomorphs (rabbits and hares)

Consider individually Consult public health officials. Bites

of squirrels, hamsters, guinea pigs,

gerbils, chipmunks, rats, mice,

other rodents, rabbits, and hares

almost never require antirabies

treatment

*During the 10-day holding period, begin treatment with Human Rabies Immune Globulin and

Human diploid cell vaccine or Rabies Vaccine, Adsorbed at first sign or rabies in a dog or cat

that has bitten someone. The symptomatic animal should be killed immediately and tested.

†The animal should be killed and tested as soon as possible. Holding for observation is not

recommendation. Discontinue vaccine if immunofluorescence test results of the animal are

negative.

Data from Centers for Disease control USA.


suppressing the autonomic storm and includes sedation aiming at a burst-suppression EEG and other measures (Table 33-2). A combination of midazolam, barbiturates, aman-tadine, and ketamine is used to minimize the excitotoxicity. Obviously, its effect has not been sufficiently tested and the protocol has changed over the years, adding more seda-tives. The protocol is reserved for patients who are already comatose, but patients who remain alert do not need to be transitioned into a drug-induced coma.

Rabies encephalitis is associated with nearly 100% mortality. There have been only seven near complete recoveries.4 The survival time is very short (1 to 2 weeks) but depends on the availability of intensive care support. Donation of organs continues to be a concern, as cases of transmission are occasionally reported.

A CONCLUDING NOTE

There are more rabid animals than patients with rabies encephalitis. The diagnosis is exceedingly uncommon, and there is unfortunately no effective treatment. Drug-induced coma may not help, and outcome is more often related to the host’s ability to eradicate the virus in the CNS—which very few can.

REFERENCES

1. Greer DM, Robbins GK, Lijewski V, Gonzalez RG, McGuone D. Case records of the Massachusetts General Hospital. Case 1-2013. A 63-year-old man with paresthesias and difficulty swallowing. N Engl J Med 2013;368:172–180.

2. Hankins DG, Rosekrans JA. Overview, prevention, and treatment of rabies. Mayo Clin Proc 2004;79:671–676.

3. Hemachudha T, Laothamatas J, Rupprecht CE. Human rabies: a disease of complex neuropathogenetic mechanisms and diagnostic challenges. Lancet Neurol 2002;1:101–109.

4. Hemachudha T, Ugolini G, Wacharapluesadee S, et al. Human rabies: neuropathogenesis, diagnosis, and management. Lancet Neurol 2013;12:498–513.

5. Warrell MJ. Emerging aspects of rabies infection: with a special emphasis on children. Curr Opin Infect Dis 2008;21:251–257.

6. Willoughby RE, Jr., Tieves KS, Hoffman GM, et al. Survival after treatment of rabies with induction of coma. N Engl J Med 2005;352:2508–2514.

TABLE 33-3 The “milwaukee” Protocol in Rabies

• Sedation and neuromuscular blockage• High doses of midazolam• Clonidine or opioids for dysautonomic manifestations• Ketamine to reduce excitotoxicity• Nimodipine to reduce vasospasm

419

A CONVERSATION

AN EXPLANATION

Mumps is a childhood viral disease causing parotitis with usually marked swelling and is virtually impossible to miss. Parotitis may not be present in 5% to 30% of patients with encephalitis, or the swelling may be subsiding and not be the predominant sign. Adult men may have mumps epididymo-orchitis.5 A person is infectious up to 2 days before the symptom onset and until 10 days after. Most cases start with myalgias, malaise, fever, and

Comatose and mumps encephalitis

/ / / 34 / / /


headache followed by parotitis or salivary gland swelling (sublingual or submaxillary). It may also start as a pancreatitis or mastitis.

In approximately 2 of 10,000 infections in children, some forme fruste of meningoencephalitis may occur.4,6 CNS infection is thus rare, but it occasionally presents in endemics. Recently, in the United States, there has been a marked increase in mumps encephalitis, with up to 15 cases of mumps in one year.1,3 The mumps vaccine may be much less effective than measles vaccine, and perhaps presentation is less recognized, allowing an outbreak to grow in numbers. Mumps encephalitis is associated with CSF pleocytosis and is typically seen several days after the onset of parotitis, but it can also precede parotitis by a week, making it very difficult to diagnose.

The causes of coma in mumps encephalitis are shown in table 34-1. Mumps meningo-encephalitis, in general, is mild and presents as high fever with headaches, vomiting, and neck stiffness; when it progresses to an encephalitis, it may be profound, causing focal neurologic symptoms. Hydrocephalus requiring ventriculostomy has been described.2 The diagnosis is made on the basis of IgM antibody concentrations, but there is a rapid sensitive and specific PCR available.7,8

MRI is usually nonspecific, as in our case, but bilateral symmetric claustrum lesions and reversible splenium lesions have been reported associated with mumps virus (Fig. 34-1).4,6


There is virtually no mortality or neurologic morbidity in patients with mumps encepha-litis, and impaired consciousness and poor outcome are typically seen in adults rather than children. More problematic is that deafness is seen in approximately 5% of patients with mumps in adults. There is no effective antiviral treatment, nor is there sufficient evi-dence that intramuscular administration of mumps immunoglobulin would be helpful at this stage. Early in the course of illness, immunoglobulin could be effective, and the same applies to intravenous IVIG as a treatment. Health care workers should get two vaccina-tions measles, mumps and rubella (MMR) one month apart.

There have been recent outbreaks in the United Kingdom and the United States with thousands of cases, mostly in the Midwest and Iowa.8 Even persons who have received two doses of mumps vaccine are not necessarily protected against mumps. Because patients are infectious for five days after the onset of parotitis, they should be placed in droplet isolation. The Centers for Disease Control and Prevention recommends controlling an outbreak by typically first defining the at-risk population and transmis-sion setting, and then vaccinating persons without presumptive evidence of immunity.

Comatose and mumps encephalitis / / 421

(A) (B)

(C)

FIGURE 34-1 (A) Axial FLAIR image showing patchy-confluent signal change in subcortical and

periventricular white matter and adjacent cortex in right superolateral frontal lobe. (B) Coronal

T1 image with gadolinium injection showing dural enhancement. (C) Axial FLAIR image showing

signal changes in right pons and right cerebellar peduncle. From reference 3.

TABLE 34-1. Causes of Coma in mumps encephalitis

• Diffuse white matter and cortical involvement• Nonconvulsive or complex partial status epilepticus• Acute hydrocephalus• Hyperthermia• Hyponatremia


Other control measures include cough etiquette, respiratory and hand hygiene, and iso-lation of infectious patients for five days.

A CONCLUDING NOTE

In susceptible nonvaccinated (MMR) patients, acute encephalitis may be due to mumps, and often in an outbreak.

REFERENCES

1. Mumps outbreak on a university campus—California, 2011. MMWR Morbidity and mortality weekly report 2012;61:986–989.

2. Aydemir C, Eldes N, Kolsal E, et al. Acute tetraventricular hydrocephalus caused by mumps meningoen-cephalitis in a child. Pediatr Neurosurg 2009;45:419–421.

3. Cooper AD, Wijdicks EFM, Sampathkumar P. Mumps encephalitis: return with a vengeance. Rev Neurol Dis 2007;4:100–102.

4. Hara M, Mizuochi T, Kawano G, et al. A case of clinically mild encephalitis with a reversible splenial lesion (MERS) after mumps vaccination. Brain Dev 2011;33:842–844.

5. Hviid A, Rubin S, Muhlemann K. Mumps. Lancet 2008;371:932–944.6. Ishii K, Tsuji H, Tamaoka A. Mumps virus encephalitis with symmetric claustrum lesions. AJNR Am J

Neuroradiol 2011;32:E139.7. Kanra G, Isik P, Kara A, et al. Complementary findings in clinical and epidemiologic features of mumps

and mumps meningoencephalitis in children without mumps vaccination. Pediatr Int 2004;46:663–668.8. Poggio GP, Rodriguez C, Cisterna D, Freire MC, Cello J. Nested PCR for rapid detection of mumps virus

in cerebrospinal fluid from patients with neurological diseases. J Clin Microbiol 2000;38:274–278.

423

A CONVERSATION

AN EXPLANATION

Acute necrotizing encephalopathy is more often seen in Far Eastern countries and is one of the most severe encephalopathies in children or young adults.4,7–11,13 It is seen after an antecedent illness (influenza A) in young individuals and is dramatic and alarming.6 High fever and flu-like symptoms are followed by rapid deterioration in consciousness. There is likely an overlap between acute necrotic encephalopathy of childhood and the adult acute hemorrhagic and necrotic leukoencephalitis.6 It has some resemblance with

Comatose and acute necrotizing encephalitis

/ / / 35 / / /


H1N1 encephalitis (Chapter 32). There might be a genetic and familial predisposition linked to RAN-binding protein 2 mutation.9 In Hurst disease, there is a combination of disseminated necrotic lesions and perivascular hemorrhages in both hemispheres, but the brainstem, diencephalon, and cerebellum may also be involved. The cause remains elusive and the presence of viruses such as herpes simplex virus (HSV), varicella-zoster virus (VZV), or human herpesvirus HHV-6,3 measles, and mumps have not been visual-ized with most in situ hybridization tests. Epstein-Barr virus infection, however, has been found in brain tissue in sporadic cases.5

The causes of coma in acute necrotizing encephalitis are shown in Table 35-1. In most reported cases, neurologic examination shows loss of many brainstem reflexes in a matter of hours, all due to diffuse brain edema. This rapid onset is reminiscent of Reye syndrome, but this syndrome is associated with increased ammonia and is today very uncommon.2 Recurrent seizures have been reported in some cases.1,2,7 CT scan can show rapidly developing diffuse cerebral edema (Fig. 35-1). MRI may show fairly typical bilat-eral basal ganglia lesions, white matter hyperintensity, or diffuse brain edema.1,2,7,12 The pathology often shows perivascular hemorrhage and necrosis of neurons and glial cells. There is congestion of arteries, veins, and capillaries and acute swelling of oligodendro-cytes. Inflammatory cells are absent.


The rapid onset of severe brain edema makes it difficult to intervene in time. Many patients are brain dead on admission or die several days later from massive brain edema. Owing to the very rapid progression of the disorder, treatment of increased intracranial pressure with conventional methods, or urgently administered high-dose intravenous methylprednisolone, may not be effective. The diagnosis is often made at autopsy.

A CONCLUDING NOTE

Rapid-onset brain edema after an antecedent infection in a child can indicate acute nec-rotizing encephalitis. The outcome is poor. No effective treatment is known.

TABLE 35-1 Causes of Coma in acute necrotizing encephalitis

• Massive cerebral edema• Thalamic demyelination and hemorrhage• Status epilepticus• Brainstem hemorrhages (Hurst variant)

Comatose and acute necrotizing encephalitis / / 425

REFERENCES

1. Alemdar M, Selekler HM, Iseri P, Demirci A, Komsuoglu SS. The importance of EEG and variability of MRI findings in acute hemorrhagic leukoencephalitis. Eur J Neurol 2006;13:e1–3.

2. Atlas SW, Grossman RI, Goldberg HI, et al. MR diagnosis of acute disseminated encephalomyelitis. J Comput Assist Tomogr 1986;10:798–801.

3. Dangond F, Lacomis D, Schwartz RB, Wen PY, Samuels MA. Acute disseminated encephalomyelitis progressing to hemorrhagic encephalitis. Neurology 1991;41:1697–1698.

4. Gika AD, Rich P, Gupta S, Neilson DE, Clarke A. Recurrent acute necrotizing encephalopathy following influenza A in a genetically predisposed family. Dev Med Child Neurol 2010;52:99–102.

5. Hofer M, Weber A, Haffner K, et al. Acute hemorrhagic leukoencephalitis (Hurst’s disease) linked to Epstein-Barr virus infection. Acta Neuropathol 2005;109:226–230.

6. Hurst EW. Acute hemorrhagic leukoencephalitis: A previously undefined entity. Med J Australia 1941;1:1–6.

FIGURE 35-1 Diffuse cerebral edema with decreased attenuation of cerebral and cerebellar hemi-

spheres, basal ganglia, and brainstem and loss of gray–white matter discrimination. There is also

effacement of cortical sulci and subarachnoid spaces.


7. Kato H, Hasegawa H, Iijima M, et al. Brain magnetic resonance imaging of an adult case of acute necro-tizing encephalopathy. J Neurol 2007;254:1135–1137.

8. Kirton A, Busche K, Ross C, Wirrell E. Acute necrotizing encephalopathy in Caucasian children: two cases and review of the literature. J Child Neurol 2005;20:527–532.

9. Marco EJ, Anderson JE, Neilson DE, Strober JB. Acute necrotizing encephalopathy in 3 brothers. Pediatrics 2010;125:e693–698.

10. Mastroyianni SD, Gionnis D, Voudris K, Skardoutsou A, Mizuguchi M. Acute necrotizing encepha-lopathy of childhood in non-Asian patients: report of three cases and literature review. J Child Neurol 2006;21:872–879.

11. Neilson DE. The interplay of infection and genetics in acute necrotizing encephalopathy. Curr Opin Pediatr 2010;22:751–757.

12. San Millan B, Teijeira S, Penin C, Garcia JL, Navarro C. Acute necrotizing encephalopathy of child-hood: report of a Spanish case. Pediatr Neurol 2007;37:438–441.

13. Yoshikawa H, Watanabe T, Abe T, Oda Y. Clinical diversity in acute necrotizing encephalopathy. J Child Neurol 1999;14:249–255.

427

A CONVERSATION

AN EXPLANATION

Zoonosis can be caused by several organisms and requires close contact with animals (Table 36-1). Horse trainers and veterinarians are theoretically at risk, but so are butchers and land scapers (mowing lawns, brush cutting).6 Each of these organisms causes neu-rologic symptoms, but most of them present with a nonspecific multisystem disease that includes fever, headaches, skin ulcerations, and regional lymph node enlargement

Comatose and Zoonotic Disease/ / / 36 / / /


(ulceroglandular disease). Generalized aches and shortness of breath, due to a developing pneumonia, are quite commonly reported. Nothing is characteristic, but atypical pneu-monia or hepatitis, endocarditis, and in particular in combination with aseptic meningi-tis and encephalitis, could point toward a zoonosis. Virtually every zoonosis can cause a meningitis or meningoencephalitis.

The causes of coma are listed in Table 36-2. Our patient presented with fever, head-ache, blurry vision, and impaired consciousness. On examination, uveitis and pulmonary infiltrates were found. MRI showed meningeal enhancement, hydrocephalus, and mul-tiple lesions.8 (Fig. 36-1) The cultures grew Francisella tularensis.

Most instances of tularemia meningitis are from rabbit or squirrel exposure, and landscapers can be exposed to infected dead animals. The source of infection can also be a rabbit, squirrel, cat, tick, or cat scratch. The incubation period of tularemia is usually several days, but the event may have been forgotten because inoculation symptoms may start up to two weeks after inoculation. Usually there is about five

TABLE 36-1 Zoonosis Causing neurologic Disease

• Brucellosis• Anthrax• Tularemia• Pasteurellosis• Pseudomonas mallei (Glanders)• Yersinia pestis (plague)• Melioidosis• Cat-scratch disease• Rat-bite fever• Q fever• Streptococcus suis

Data from references 2, 5, 7, 8.

TABLE 36-2 Causes of Coma in Zoonosis

• Meningoencephalitis• Multiple abscesses (intracranial nodules)• Multifocal white matter disease• Septic encephalopathy and shock

Comatose and Zoonotic Disease / / 429

to seven days of systemic illness followed by headache and meningeal symptoms. CSF shows marked pleocytosis, usually a mononuclear predominance, but there is a marked decrease in CSF glucose. Cellular response in CSF can be substantial, in the 1,000 range.

Many other zoonoses can produce neurologic symptoms. Many patients have bacteremic episodes that present with fever, arthralgias, headache, and aseptic menin-gitis. Brucellosis is known to cause chronic meningitis, encephalitis, and also multifocal white matter disease.3 Brucellosis has been associated with the development of epidural abscesses and subdural empyema. Several of the zoonoses are initially misdiagnosed as tuberculosis due to the multinodular presentation on MRI.

(A) (B)

(C)

FIGURE 36-1 FLAIR MRI (axial view [A–C]) showing meningeal enhancement, enlarged ventricles,

and hyperintense lesions in right temporal lobe and right posterior occipital lobe. From refer-

ence 8, with permission.


There are several new emerging zoonoses throughout the world, and many can cause severe neurologic manifestations. One recent example is Nipah encephalitis, a paramyxovirus-induced disorder endemic to India, Bangladesh, and several parts of South Asia. This virus exists endemically in fruit bats, and humans are infected after ingesting contaminated raw fruit or date palm juice or secretions of intermediate hosts, such as pigs and cows. Chikungunya, a mosquito-borne viral disorder, is common in Africa, India, and Southeast Asia. Other arthropod viruses that emerge in hot, humid, rainy areas and usually are endemic include dengue virus, a parechovirus. Human parechovirus in par-ticular has been detected in monkey feces and can cause permanent neurodevelopmental disability in infants.1


If recognized, a vast majority of zoonoses can be adequately and aggressively treated.7 There are septicemic forms that would need more aggressive treatment with trimethoprim-sulfamethoxazole plus intravenous ceftazidime for several weeks.4,5,7 Meningoencephalitis remains a serious manifestation with a high probability of poor outcome. Our patient was treated with streptomycin and doxycycline, but outcome remained poor. Neurobrucellosis may be associated with multiorgan involvement, and these patients also have a poor outcome.

A CONCLUDING NOTE

Intracranial nodules and enlarged lymph nodes after close contact with animals may point to a zoonosis. A meningoencephalitis is rare but serious.

REFERENCES

1. Bale JF, Jr. Emerging viral infections. Semin Pediatr Neurol 2012;19:152–157.2. Farlow J, Wagner DM, Dukerich M, et al. Francisella tularensis in the United States. Emerg Infect Dis

2005;11:1835–1841.3. Franco MP, Mulder M, Gilman RH, Smits HL. Human brucellosis. Lancet Infect Dis 2007;7:775–786.4. Hofinger DM, Cardona L, Mertz GJ, Davis LE. Tularemic meningitis in the United States. Arch Neurol

2009;66:523–527.5. Limaye AP, Hooper CJ. Treatment of tularemia with fluoroquinolones: two cases and review. Clin Infect

Dis 1999;29:922–924.

Comatose and Zoonotic Disease / / 431

6. Rao SS, Mariathas A, Teare L. Meningitis in a butcher. Emerg Med J 2008;25:607–608.7. Russell P, Eley SM, Fulop MJ, Bell DL, Titball RW. The efficacy of ciprofloxacin and doxycycline against

experimental tularemia. J Antimicrob Chemother 1998;41:461–465.8. van de Beek D, Steckelberg JM, Marshall WF, Kijpittayarit S, Wijdicks EFM. Tularemia with brain

abscesses. Neurology 2007;68:531.

432

A CONVERSATION

AN EXPLANATION

Fungal infections in immunocompromised patients are common. A CNS infection under these circumstances often is due to cerebral aspergillosis and therefore is a major concern in any transplant recipient. In many patients, a pulmonary infection precedes the development of CNS infection, but in a recent large series, the source was in the paranasal sinuses in a third of the patients.3 Vertebral disk involvement was also seen in several patients. Primary CNS involvement may occur in one-third of the patients

Comatose and opportunistic infections (i)

/ / / 37 / / /

Comatose and opportunistic infections (i) / / 433

without an obvious primary site, and that means the diagnosis may be difficult.3 In non-immunosuppressed patients with fungal infections, the prevalence of diabetes mellitus is quite high.2,5

Cerebral Aspergillus causes meningoencephalitis and brain abscesses. Hemorrhagic necrosis resulting in often-fatal intracerebral hematoma is frequently a feature of Aspergillus infection. Aspergillus invades the blood vessels and spreads along the lamina, causing vasculitis and thrombosis, and therefore hemorrhages or infarctions, and often combinations.4 Septic emboli can also be a cause of a stroke.1

Rapid onset of coma with generalized tonic-clonic seizures is not an uncommon pre-sentation. At Mayo Clinic we have only encountered occasionally CNS aspergillosis in transplant patients, but all cases were fatal. Systemic aspergillosis became more evident later with pulmonary involvement. Recurrent seizures and, finally, multiorgan failure preceded death.

Many patients initially present with fever, pointing toward an infection. Focal neu-rologic abnormalities are not common, but some patients develop seizures. CSF is usually abnormal, but positive galactomannan titers in fluid can clinch the diagnosis.7 Neurosurgical involvement is rarely necessary—only if a well-defined abscess is found. The causes of coma in neuroaspergillosis is shown in Table 37.1.

Treatment of systemic aspergillosis is generally intravenous voriconazole. Not uncommonly, patients are found to have suboptimal antifungal coverage. Sinusitis is an important infection that can lead to further dissemination of aspergillosis and needs to be recognized and explored (Fig. 37-1).


Neurosurgery and Otorhinolaryngology consult is needed, followed by surgical evacua-tion of the fungal tumor.6 Corticosteroids have generally increased the risk of spread of aspergillosis and need to be held. Again, preemptive antifungal treatment is important before the diagnosis is established. Amphotericin B can be prescribed, but voriconazole is needed when the diagnosis is established. In some patients a ventriculostomy might be necessary to deobstruct a hydrocephalus. The outcome of CNS aspergillosis, unfortu-nately, remains poor despite aggressive intervention.

TABLE 37-1 Causes of Coma in neuroaspergillosis

• Cerebral hematoma with shift• Multiple hemispheric infarcts• Brainstem infarcts


A CONCLUDING NOTE

CNS aspergillosis is an insidious fatal complication in an immunosuppressed patient. Once hemorrhages have occurred the outcome is poor. Both ischemic and hemorrhagic strokes are expected as a result of vessel invasion.

REFERENCES

1. Abenza-Abildua MJ, Fuentes-Gimeno B, Morales-Bastos C, et al. Stroke due to septic embolism resulting from Aspergillus aortitis in an immunocompetent patient. J Neurol Sci 2009;284:209–210.

2. Hiraga A, Uzawa A, Shibuya M, et al. Neuroaspergillosis in an immunocompetent patient successfully treated with voriconazole and a corticosteroid. Intern Med 2009;48:1225–1229.

3. Kourkoumpetis TK, Desalermos A, Muhammed M, Mylonakis E. Central nervous system aspergillosis: a series of 14 cases from a general hospital and review of 123 cases from the literature. Medicine (Baltimore) 2012;91:328–336.

FIGURE 37-1 Marked opacification of sphenoid sinus and subarachnoid and intraventricular

hemorrhage due to angioinvasive Aspergillus fumigatus.

Comatose and opportunistic infections (i) / / 435

4. Lacerda JF, Martins C, Carmo JA, et al. Invasive aspergillosis of the central nervous system after allogeneic stem cell transplantation. J Infect 2005;51:e191–194.

5. Narayan SK, Kumar K, Swaminathan RP, Roopeshkumar VR, Bhavna B. Isolated cerebral aspergilloma in a young immunocompetent patient. Pract Neurol 2009;9:166–168.

6. Siddiqui AA, Shah AA, Bashir SH. Craniocerebral aspergillosis of sinonasal origin in immunocompetent patients: clinical spectrum and outcome in 25 cases. Neurosurgery 2004;55:602–611.

7. Soeffker G, Wichmann D, Loderstaedt U, et al. Aspergillus galactomannan antigen for diagnosis and treat-ment monitoring in cerebral aspergillosis. Prog Transplant 2013;23:71–74.

436

A CONVERSATION

AN EXPLANATION

New neurologic signs and new MRI findings in an immunosuppressed patient challenge the clinical repertoire of any physician. Rapidly developing impaired consciousness is com-mon in opportunistic CNS infections, is also associated with more significant systemic manifestations, and is a relatively frequent complication after hematopoietic transplanta-tion.1,2,5,10,12 Some general observations are useful. Nocardia (an aerobic actinomycete) (Fig. 38-1) first enters the body through the respiratory tract, Toxoplasma gondii due to

Comatose and opportunistic infections (ii)

/ / / 38 / / /

Comatose and opportunistic infections (ii) / / 437

ingestion of undercooked meat, and Aspergillus fumigatus after pulmonary disease. In Chapter 37, we pointed out CNS involvement from A. fumigatus as a result of an indolent rhinosinusitis.15 Nocardia, T. gondii, A. fumigatus, coccidioidomycosis, and Cryptococcus neoformans can be invasive and widespread, causing multifocal lesions.4,8,14,15,18 Parasitic infections are uncommon, but visits to the tropics may predispose immunosuppressed patients (Table 38-1).16,17

The time on immunosuppressive drugs is an important variable because certain infections are more prevalent early in the course. In the first weeks after transplanta-tion, viral infections of the brain are more common and a result of reactivation due to immunosuppression (herpes simplex virus [HSV], varicella-zoster [VZV], and human herpes-virus 6 [HHV-6]).7,19 Reactivation of herpes viruses can cause encephalitis

FIGURE 38-1 Multiple lesions from Nocardia spp. abscesses.


due to HSV-1, VZV, and Epstein-Barr virus and may present unexpectedly early after initiation of immunosuppression. In hematopoietic stem cell transplantation, HHV-6 infection has been noted within the first month of transplantation, and its clinical pre-sentation with multiple areas of demyelination is identical to that of acute dissemi-nated encephalomyelitis (ADEM).3,9,11 Single mass lesions may indicate lymphoma or mycobacteria.

The causes of coma in opportunistic CNS infections are shown in Table 38-2. There are multiple organisms to consider, but there is a certain proclivity for regions of the brain and tendency to cause more lesions than a single abscess. Examples are Listeria (brain-stem), Cryptococcus (thalamus), and A. fumigatus (multiple hemorrhagic lesions).6,13 CNS

TABLE 38-1 other opportunistic Cns infections in Transplant Recipients

Organism CT or MRI CSF Diagnosis Therapy

Listeria

monocytogenes

Meningeal

enhancement only;

commonly brainstem

involvement

May be normal CSF culture Ampicillin, 10–12 g/d IV;

gentamicin,

1.0–1.5 mg/kg IV q8h

Nocardia

asteroides

Abscesses (may be

solitary)

Pleocytosis Brain biopsy, CSF or

blood culture

Trimethoprim–

sulfamethoxazole,

2.5–10.0 mg/kg b.i.d.Aspergillus

fumigatus

Ring lesion, scattered

hemorrhages

Pleocytosis Brain biopsy, blood

culture, CSF antigen

(galactomannan)

Amphotericin B, 1.0–1.5

mg/kg per day, and

voriconazole 6 mg/kg

q12hCryptococcus

neoformans

Thalamus, basal

ganglia; widespread

miliary; no edema

Pleocytosis; may

be normal

Brain biopsy Amphotericin B,

1.0–1.5 mg/kg per day;

fluconazole 400 mg/d IVToxoplasma

gondii

Multiple lesions,

subcortical meninges

spared

Pleocytosis; may

be normal

Brain biopsy Trimethoprim–

sulfamethoxazole,

2.5–10.0 mg/kg b.i.d.

Adapted from Wijdicks.18

TABLE 38-2 Causes of Coma in opportunistic Cns infections

• Infarction of pons (Aspergillus fumigatus)• Ganglionic or lobar hematoma (Aspergillus fumigatus)• Brainstem abscess (Listeria monocytogenes)• Thalamic abscess (Nocardia, Cryptococcus neoformans, Toxoplasma gondii)• Bihemispheric lesions (cytomegalovirus)

Comatose and opportunistic infections (ii) / / 439

infections may decrease consciousness due to multiple strategically placed lesions. Acute hydrocephalus may be a late complication, particularly when lesions are obstructing the fourth ventricle.


Systemic treatment is required. The diagnosis requires a brain biopsy. Many patients are gravely ill, and aggressive antimicrobial management is a last resort. Disease-specific treatment is summarized in Table 38-1. Outcome is poor despite antifungal or antiviral drugs, and surgical removal of large lesions does not measur-ably affect outcome.

A CONCLUDING NOTE

Sudden worsening in level of consciousness can be due to infections to the brain in immu-nosuppressed patients and most often in transplant recipients. Many organisms can cause a CNS infection, and there is a tendency for multiple lesions. These organisms commonly cause an overwhelming infection.

REFERENCES

1. Al Tawfiq JA, Mayman T, Memish ZA. Nocardia abscessus brain abscess in an immunocompetent host. J Infect Public Health 2013;6:158–161.

2. Ambrosioni J, Lew D, Garbino J. Nocardiosis: updated clinical review and experience at a tertiary center. Infection 2010;38:89–97.

3. Caserta MT, Mock DJ, Dewhurst S. Human herpesvirus 6. Clin Infect Dis 2001;33:829–833.4. Czartoski T. Central nervous system infections in transplantation. Curr Treat Options Neurol

2006;8:193–201.5. Denier C, Bourhis JH, Lacroix C, et al. Spectrum and prognosis of neurologic complications after hema-

topoietic transplantation. Neurology 2006;67:1990–1997.6. Foy PC, van Burik JA, Weisdorf DJ. Galactomannan antigen enzyme-linked immunosorbent assay for

diagnosis of invasive aspergillosis after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2007;13:440–443.

7. Fujimaki K, Mori T, Kida A, et al. Human herpesvirus 6 meningoencephalitis in allogeneic hematopoi-etic stem cell transplant recipients. Int J Hematol 2006;84:432–437.

8. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002;347:408–415.

9. Kamei A, Ichinohe S, Onuma R, Hiraga S, Fujiwara T. Acute disseminated demyelination due to primary human herpesvirus-6 infection. Eur J Pediatr 1997;156:709–712.

10. Kennedy KJ, Chung KH, Bowden FJ, et al. A cluster of nocardial brain abscesses. Surg Neurol 2007;68:43–49.

11. Pagano JS. Viruses and lymphomas. N Engl J Med 2002;347:78–79.


12. Singh N, Husain S. Infections of the central nervous system in transplant recipients. Transpl Infect Dis 2000;2:101–111.

13. Singh N, Pruett TL, Houston S, et al. Invasive aspergillosis in the recipients of liver retransplantation. Liver Transpl 2006;12:1205–1209.

14. Snydman DR. Epidemiology of infections after solid–organ transplantation. Clin Infect Dis 2001;33 Suppl 1:S5–8.

15. van de Beek D, Patel R, Campeau NG, et al. Insidious sinusitis leading to catastrophic cerebral aspergil-losis in transplant recipients. Neurology 2008;70:2411–2413.

16. Walker M, Kublin JG, Zunt JR. Parasitic central nervous system infections in immunocompro-mised hosts: malaria, microsporidiosis, leishmaniasis, and African trypanosomiasis. Clin Infect Dis 2006;42:115–125.

17. Walker M, Zunt JR. Parasitic central nervous system infections in immunocompromised hosts. Clin Infect Dis 2005;40:1005–1015.

18. Wijdicks EFM. Neurological complication after organ transplantation. In: Asbury AK, ed. Diseases of the Nervous System: Clinical Neuroscience and Therapeutic Principles, 3rd ed. Cambridge, UK; New York: Cambridge University Press, 2002:2082–2092.

19. Zerr DM. Human herpesvirus 6 and central nervous system disease in hematopoietic cell transplanta-tion. J Clin Virol 2006;37 Suppl 1:S52–56.

441

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AN EXPLANATION

Most astrocytomas originate from the temporal or frontal lobe; therefore, initial symp-toms are psychiatric syndromes (often depression) and speech or language difficulties. Seizures have been documented in approximately 50% of patients as an initial presenting symptom, and tumors growing into the cortex may result in recurrent seizures and status epilepticus.9,12 Not infrequently, brain tumors are misdiagnosed as ischemic strokes on CT, but the amount of swelling on CT does not generally fit with minimal clinical find-ings. Clinical examination may worsen quickly, mostly due to worsening edema.

Comatose and high-Grade astrocytoma

/ / / 39 / / /


The causes of coma in high-grade astrocytoma are shown in Table 39-1. In a growing brain tumor, it remains unresolved how much midline shift must occur during what period of time to impair consciousness. It is not always clear why patients acutely decompensate. Suddenly developing edema or hemorrhage in the tumor could expand the dormant mass and then produce further symptoms. However, presentation with intracranial hematoma in a glioblastoma multiforme has been documented in only 2% of patients in a large series.12 After resection of the tumor, postoperative cerebral edema due to hyperemia in the operating field may be a major cause of postoperative deterioration.

CT scan and MRI usually demonstrate a large tumor with significant vasogenic edema, and shift is expected (Fig. 39-1). MRI may suggest a high-grade astrocytoma when a thick rim of tissue is at the necrotic center, and ring enhancement and vascularity are present. The presence of cerebral edema also favors glioblastoma of higher grades. MRI may also detect leptomeningeal dissemination.


Surgical resection to debulk the tumor is common practice. Radiation and corticoste-roids are additional therapy options, and, more recently, temozolomide, particularly in patients with silencing of the MGMT gene (O6-methylquanine-DNA methyltransfer-ase).5 Temozolomide has been recently studied, and the two-year survival rate in one study was 26.5% with radiotherapy plus temozolomide and 10.4% with radiotherapy alone.6,13 Radiotherapy consists of fractionated focal irradiation at a dose of 2 Gy per fraction, once daily, five days a week, for six weeks. The median survival with radiother-apy was 12 months and that with radiotherapy plus temozolomide was 14.6 months. Glioblastoma multiforme is a highly resistant tumor and does not respond well to radio-therapy, but it is often offered.2,3 Radiosurgery is a salvage therapy.1 Morbidity and mor-tality may also increase in patients with intractable seizures and status epilepticus and is common in patients with early recurrence after debulking. Rapid fatal outcome in glio-blastoma is more common in patients with multifocal tumors and brainstem invasion.11 It

TABLE 39-1 Causes of Coma in high-Grade astrocytoma

• Mass effect and brainstem displacement• Hemorrhage into the tumor• Extension into the thalamus• Status epilepticus• Radiation necrosis and edema• Leptomeningeal dissemination and hydrocephalus

Comatose and high-Grade astrocytoma / / 443

is a sobering fact that the median survival—that is, less than one year—has not changed over the past two decades.8 Classification of brain tumors is constantly revised, and gem-istocytic astrocytomas are more aggressive.4,7 The KI-67 proliferation index has been used to estimate growth in gliomas, but the index has not consistently been associated with survival.

A CONCLUDING NOTE

Patients with malignant glioma multiforme can present with rapid worsening of tumor symptoms due to vasogenic edema. A tumor presents typically as a hypodensity on CT scan with mass effect and shift of the brainstem. Extension into the thalamus and status epilepticus are other causes of coma, both associated with poor outcome. Elderly patients

FIGURE 39-1 (A, B) CT shows mild hemorrhage into right frontal mass. (C, D) MRI shows right

frontal hemorrhagic mass with surrounding vasogenic edema and compression of the frontal

horn. There is some shift of midline structures.


have a poor prognosis and suffer treatment-related side effects.10 Temozolomide may have some benefit in selected patients.

REFERENCES

1. Barbarisi M, Romanelli P. The emerging role of stereotactic radiosurgery in the treatment of glioblas-toma multiforme. Curr Radiopharm 2012;5:292–299.

2. Barker FG, 2nd, Chang SM, Larson DA, et al. Age and radiation response in glioblastoma multiforme. Neurosurgery 2001;49:1288–1297.

3. Fiveash JB, Spencer SA. Role of radiation therapy and radiosurgery in glioblastoma multiforme. Cancer J 2003;9:222–229.

4. Geranmayeh F, Scheithauer BW, Spitzer C, et al. Microglia in gemistocytic astrocytomas. Neurosurgery 2007;60:159–166.

5. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glio-blastoma. N Engl J Med 2005;352:997–1003.

6. Henson JW. Treatment of glioblastoma multiforme: a new standard. Arch Neurol 2006;63:337–341.7. Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO classification of tumours of the central nervous

system. Acta Neuropathol 2007;114:97–109.8. McLendon RE, Halperin EC. Is the long-term survival of patients with intracranial glioblastoma multi-

forme overstated? Cancer 2003;98:1745–1748.9. Ricard D, Idbaih A, Ducray F, et al. Primary brain tumors in adults. Lancet 2012;379:1984–1996.

10. Sahebjam S, McNamara M, Mason WP. Management of glioblastoma in the elderly. Clin Adv Hematol Oncol 2012;10:379–386.

11. Silbergeld DL, Rostomily RC, Alvord EC, Jr. The cause of death in patients with glioblastoma is mul-tifactorial: clinical factors and autopsy findings in 117 cases of supratentorial glioblastoma in adults. J Neurooncol 1991;10:179–185.

12. Stark AM, Nabavi A, Mehdorn HM, Blomer U. Glioblastoma multiforme: report of 267 cases treated at a single institution. Surg Neurol 2005;63:162–169.

13. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolo-mide for glioblastoma. N Engl J Med 2005;352:987–996.

445

A CONVERSATION

AN EXPLANATION

Although its prevalence is increasing in immunocompetent patients, central nervous sys-tem (CNS) lymphoma is typically a B-cell lymphoma and is associated with acquired immunodeficiency syndrome.5,11 CNS lymphoma can involve single or multiple lesions and most often is situated supratentorially. The presenting symptoms are a focal neuro-logic deficit, psychiatric manifestations (depression, withdrawn and aggressive behav-ior), and finally raised intracranial pressure that causes impaired consciousness.

Comatose and Cns Lymphoma/ / / 40 / / /


The causes of coma in primary CNS lymphoma are shown in Table 40-1. Progressive swelling in a solitary mass lesion in patients with a malignant B-cell lymphoma causes impaired consciousness, but in others diffuse and multifocal cerebral edema, obstructive hydrocephalus, intracerebral hemorrhage, recurrent seizures, or a hypopituitarism due to infiltration of the tumor is the main mechanism. Infiltration of the brainstem is much less common.6 Worsening can occur with hemorrhage after biopsy, and the risk in this type of tumor is increased.9

Neuroimaging features are either an isodense or a hyperdense lesion on CT scan, but on MRI the lesions are often solitary and located in hemispheres and rarely in the thala-mus or corpus callosum, ventricular region, or cerebellum. In some patients there is often marked edema, and when examined, the cerebral arteries can be narrowed (Figs. 40-1 and 40-2). Diffuse contrast enhancement is typical.7 In addition, linear enhancement along the Virchow-Robin space is very characteristic. Cerebrospinal fluid (CSF) cytol-ogy can be abnormal and may show clumped pleomorphic cells with enlarged nuclei and coarse chromatin, but lumbar puncture may carry the risk of further causing intracranial shifts. Biopsy or open craniotomy is the preferred diagnostic test.


There are several therapeutic options. Surgical resection is not likely to benefit outcome.2 Corticosteroids may result in significant shrinkage of the tumor, even within days. This may reduce the yield of abnormalities with the neuropathologic examination, but an assessment can often be made. Other therapeutic options are systemic methotrexate with delayed irradiation (whole brain radiation therapy, 36-40 Gy). Methotrexate therapy consists of five cycles every two weeks of intravenous methotrexate (2.5 g/m2), intrave-nous vincristine (1.4 mg/m2), oral procarbazine (100 mg/m2 per day for seven days).1,10 There is a concern with the use of methotrexate. On MRI, neurotoxicity associated with methotrexate is recognized by a markedly increased signal throughout the white matter. Cortical atrophy or ventricular enlargement may occur later.

Age older than 60 years, low performance status at diagnosis, elevated serum lactate dehydrogenase, high CSF protein concentration, and tumor location within the deep

TABLE 40-1 Causes of Coma in Primary Central nervous system Lymphoma

• Mass effect and brainstem displacement• Obstructive hydrocephalus• Hypopituitarism• Postbiopsy hemorrhage

Comatose and Cns Lymphoma / / 447

regions of the brain such as the periventricular region, basal ganglia, or brainstem are all associated with poor outcome. Patients with multiple risk factors have a two-year overall survival rate of 20% to 50%.3,4

A CONCLUDING NOTE

CNS lymphoma is a brain tumor that is increasing in prevalence. The rapid resolution of MRI findings using corticosteroids could point toward the diagnosis, but lymphoma must be confirmed with brain biopsy. The diagnosis is often considered in patients pre-senting with a solitary mass lesion with significant edema. Some patients develop a rapid course with multifocal cerebral edema.

FIGURE 40-1 CNS lymphoma producing coma. CT scan shows multifocal edema and on MRA

arterial narrowing consistent with angiocentric B-cell lymphoma.


REFERENCES

1. Batchelor T, Loeffler JS. Primary CNS lymphoma. J Clin Oncol 2006;24:1281–1288.2. Bellinzona M, Roser F, Ostertag H, Gaab RM, Saini M. Surgical removal of primary central nervous

system lymphomas (PCNSL) presenting as space occupying lesions: a series of 33 cases. Eur J Surg Oncol 2005;31:100–105.

3. Ferreri AJ, Blay JY, Reni M, et al. Prognostic scoring system for primary CNS lymphomas: the International Extranodal Lymphoma Study Group experience. J Clin Oncol 2003;21:266–272.

4. Feuerhake F, Baumer C, Cyron D, et al. Primary CNS lymphoma in immunocompetent patients from 1989 to 2001: a retrospective analysis of 164 cases uniformly diagnosed by stereotactic biopsy. Acta Neurochir (Wien) 2006;148:831–838.

5. Gerstner ER, Batchelor TT. Primary central nervous system lymphoma. Arch Neurol 2010;67:291–297.6. Hochberg FH, Baehring JM, Hochberg EP. Primary CNS lymphoma. Nat Clin Pract Neurol 2007;3:24–35.7. Kuker W, Nagele T, Thiel E, Weller M, Herrlinger U. Primary central nervous system lymphomas

(PCNSL): MRI response criteria revised. Neurology 2005;65:1129–1131.8. Korfel A, Schlegel U. Diagnosis and treatment of primary CNS lymphoma. Nat Rev Neurol

2013:9:317–327.9. Phan TG, O’Neill BP, Kurtin PJ. Posttransplant primary CNS lymphoma. Neuro Oncol 2000;2:229–238.

10. Shenkier TN, Voss N, Chhanabhai M, et al. The treatment of primary central nervous system lymphoma in 122 immunocompetent patients: a population-based study of successively treated cohorts from the British Colombia Cancer Agency. Cancer 2005;103:1008–1017.

11. Werner MH, Phuphanich S, Lyman GH. The increasing incidence of malignant gliomas and primary central nervous system lymphoma in the elderly. Cancer 1995;76:1634–1642.

FIGURE 40-2 MRI showing multifocal edema and midline shift.

449

A CONVERSATION

AN EXPLANATION

The most common origins of brain metastases are lung cancer, breast cancer, and mela-noma.9 Breast, colon, and renal cell carcinoma appear to be single lesions, while mela-noma and lung cancer more often have multiple metastases. What seems to be a single metastasis on CT may turn out to be multiple lesions on MRI.

The causes of coma in a patient with multiple metastases are shown in Table 41-1. Impaired consciousness is mostly due to the multifocal localization of metastases

Comatose and metastasis/ / / 41 / / /


(Fig. 41-1). Prior metastases may hemorrhage (melanoma) and define themselves in a short time span. Meningeal invasion of cancer is a common complication of metastatic disease and may result in cerebral venous infarcts or hemorrhagic infarcts that may cause additional brain tissue shift. If a single metastasis is extirpated, seizures and peritumoral edema are possible postoperative complications.


The factors that tilt toward surgical removal in patients with brain metastases include the presence of a single tumor, surgical accessibility, age (<65 years), high Karnofsky performance score (70 or greater), control of systemic disease, and tumor size (<3 cm). Absence of leptomeningeal involvement also affects this decision. If the primary tumor is undiagnosed, adjuvant brachytherapy may result in improved survival.9,11 Multiple brain lesions, however, have been resected by some surgeons, and although quality of life may improve briefly, the outcome does not improve. The options for multiple metastases are therefore limited. There is potential benefit of stereotactic radiosur-gery.1,3,4,7,8,10 The delivery of chemotherapy is hampered by the blood–brain barrier, but there is experience with intra-arterial chemotherapy (e.g., carboplatin) enhanced by osmotic therapy.5 There is renewed interest in temozolomide, an oral alkylating agent, and it may have some effect in brain metastases.2 In addition, most neurosurgeons would prefer antiepileptic drugs, but there is no proven benefit when they are used on a prophylactic basis.6

A CONCLUDING NOTE

Multiple metastases often produce abnormal consciousness due to their multifocality and less often due to a mass effect. Sudden appearance of symptoms can be due to either hemorrhage or sudden worsening of perilesional edema.

TABLE 41-1 Causes of Coma in metastasis

• Multifocal hemispheric lesions• Hemorrhage into lesions and acute mass effect• Cerebral venous thrombosis (meningeal location)• Status epilepticus

Comatose and metastasis / / 451

FIGURE 41-1 Patient admitted with rapid onset of stupor. CT and corresponding MRI. Multiple

metastases from melanoma. Most notable is absence of shift but multifocal involvement.


REFERENCES

1. Abrey LE, Mehta MP. Treatment of brain metastases: a short review of current therapies and the emerg-ing role of temozolomide. Clin Adv Hematol Oncol 2003;1:231–236.

2. Agarwala SS, Kirkwood JM, Gore M, et al. Temozolomide for the treatment of brain metastases associ-ated with metastatic melanoma: a phase II study. J Clin Oncol 2004;22:2101–2107.

3. Bajaj GK, Kleinberg L, Terezakis S. Current concepts and controversies in the treatment of parenchymal brain metastases: improved outcomes with aggressive management. Cancer Invest 2005;23:363–376.

4. Barker FG, 2nd. Surgical and radiosurgical management of brain metastases. Surg Clin North Am 2005;85:329–345.

5. Fortin D, Gendron C, Boudrias M, Garant MP. Enhanced chemotherapy delivery by intraarterial infusion and blood–brain barrier disruption in the treatment of cerebral metastasis. Cancer 2007;109:751–760.

6. Gorantia V, Kirkwood JM, Tawbi HA. Melanoma brain metastasis: an unmet challenge in the era of active therapy. Curr Oncol Rep 2013;15:483–491.

7. Kaal EC, Niel CG, Vecht CJ. Therapeutic management of brain metastasis. Lancet Neurol 2005;4:289–298.8. Kirsch DG, Loeffler JS. Brain metastases in patients with breast cancer: new horizons. Clin Breast Cancer

2005;6:115–124.9. Patel CG, Pricola K, Sarmiento JM, et al. Whole brain radiation therapy (WBRT) alone versus WBRT

and radiosurgery for the treatment of brain metastasis.Cochrane Database Syst Rev 2012 CD006121.10. Patchell RA. The management of brain metastases. Cancer Treat Rev 2003;29:533–540.11. Rogers LR, Rock JP, Sills AK, et al. Results of a phase II trial of the GliaSite radiation therapy system for

the treatment of newly diagnosed, resected single brain metastases. J Neurosurg 2006;105:375–384.

453

A CONVERSATION

AN EXPLANATION

Gliomatosis cerebri is a diffuse infiltrating cerebral tumor that involves more than two lobes of the brain.1,4,7 Neoplastic oligodendroglial cells are uncommon in gliomatosis cerebri, and mostly astrocytic tumor cells are found. Gliomatosis cerebri could manifest with mundane clinical signs such as headaches, localized signs, or seizures, or a nondistinctive encephalop-athy. However, cerebral edema with progressive drowsiness may be an initial presentation.

The causes of coma in gliomatosis cerebri are shown in Table 42-1. In most instances, bifrontal lesions are responsible for impaired consciousness. Diffuse swelling of both

Comatose and Gliomatosis Cerebri

/ / / 42 / / /


hemispheres may compress the thalamus. The tendency of gliomatosis cerebri to infiltrate the corpus callosum may result in involvement of both cingulate gyri and cause akinetic mutism. Later, radiation may damage multiple critical regions for maintaining awareness, but usually radiation necrosis presents several months after treatment.

The findings on MRI are nonspecific and, due to its resemblance to acute dissemi-nated encephalomyelitis (ADEM) or encephalitis, patients have been misdiagnosed. The MR findings can also be mimicked by disorders such as isolated central nervous system (CNS) vasculitis, multiple sclerosis, lymphoma, neurosarcoidosis, or acute leukoenceph-alopathies, among others. MR abnormalities are characterized by high signal intensity on T2-weighted images, with the corpus callosum, frontal and temporal lobe, basal ganglia, brainstem, and meninges typically involved. Usually, there is no early mass effect. Even more challenging, the cerebral angiogram in gliomatosis cerebri may mimic isolated CNS vasculitis due to multiple constrictive areas in the cerebral vasculature (Fig. 42-1).5,6,9 MR spectroscopy may document elevated CHO/CR and CHO/NAA levels as a result of replacement of neurons with tumor.2


The prognosis is poor, but there is some benefit from radiotherapy or chemotherapy. The median survival is about 12 months.3,10 There is some reported success with temozolo-mide showing a radiologic response in about 25% of cases and more than a doubling of the median survival to 30 months. Poor outcome was more common in patients with loss of chromosome 13q and 10q and gains of chromosome 7q.3,11

A CONCLUDING NOTE

Rapidly progressive impaired consciousness with predominant frontal white matter involvement may indicate gliomatosis cerebri. This disorder is uncommon, making rec-ognition difficult. Despite radiotherapy or chemotherapy, mortality is very high in the first year after diagnosis.

TABLE 42-1 Causes of Coma in Gliomatosis Cerebri

• Diffuse infiltrative multilobular locations• Bilateral anterior cingulate lesions• Mass effect on thalamus due to diffuse brain edema• Radiation encephalopathy

Comatose and Gliomatosis Cerebri / / 455

REFERENCES

1. Caroli E, Orlando ER, Ferrante L. Gliomatosis cerebri in children. Case report and clinical consider-ations. Childs Nerv Syst 2005;21:1000–1003.

2. Desclee P, Rommel D, Hernalsteen D, et al. Gliomatosis cerebri, imaging findings of 12 cases. J Neuroradiol 2010;37:148–158.

3. Fukushima Y, Nakagawa H, Tamura M. Combined surgery, radiation, and chemotherapy for oligoden-droglial gliomatosis cerebri. Br J Neurosurg 2004;18:306–310.

4. Lantos PL, Bruner JM. Gliomatosis cerebri. In: Kleihues P, Cavenee WK, eds. World Health Organization Classification of Tumours: Pathology and Genetics: Tumours of the Nervous System. USA: Oxford University Press, 2000:92–93.

5. Maramattom BV, Giannini C, Manno EM, Wijdicks EF, Campeau NG. Gliomatosis cerebri angiographi-cally mimicking central nervous system angiitis: case report. Neurosurgery 2006;58:E1209.

6. Masters LT, Miller DC, Nelson PK. Cerebral vasculopathy secondary to leptomeningeal gliomato-sis: angiography. Neuroradiology 2000;42:139–141.

7. Nandhagopal R, Al-Asmi A, Arunodaya GR, et al. Gliomatosis cerebri. QJM 2011;104:619–620.8. Rudà R, Bertero L, Sanson M. Gliomatosis cerebri: a review. Curr Treat Options Neurol 2014:16:273.9. Singh M, Corboy JR, Stears JC, Kleinschmidt-DeMasters BK. Diffuse leptomeningeal gliomatosis asso-

ciated with multifocal CNS infarcts. Surg Neurol 1998;50:356–362.10. Taillibert S, Chodkiewicz C, Laigle-Donadey F, et al. Gliomatosis cerebri: a review of 296 cases from the

ANOCEF database and the literature. J Neurooncol 2006;76:201–205.11. Ware ML, Hirose Y, Scheithauer BW, et al. Genetic aberrations in gliomatosis cerebri. Neurosurgery

2007;60:150–158.

FIGURE 42-1 MRI showing white matter lesions consistent with gliomatosis cerebri. Note con-

strictions on cerebral angiogram (arrows). With permission of Neurosurgery.5

456

A CONVERSATION

AN EXPLANATION

Central nervous system (CNS) disorders other than the more common brain metastases have been associated with cancer. The most recognizable is limbic encephalitis, which may present with refractory status epilepticus or a dementing illness, with patients progress-ing more slowly to a minimally conscious state. Clinical features in most paraneoplas-tic limbic encephalitides are loss of short-term memory, seizures (often generating from the temporal lobe), affective disorders, and also further neurobehavioral dysfunction,

Comatose and Paraneoplastic encephalitis

/ / / 43 / / /

Comatose and Paraneoplastic encephalitis / / 457

including apraxia, aphasia, acalculia, and visual recognition abnormalities. Some patients simply become abulic. Cancer may have been diagnosed and treated earlier, but its pres-ence may also be unknown and become apparent even years after the paraneoplastic syn-drome has matured. The main argument for an immune-mediated process in this entity is the presence of antibodies. The tumor may express a neuronal protein that may lead not only to a mounted response to the tumor but also to neurons that carry an antigen similar to the tumor. However, animal models have not produced a comparable clinical picture. Limbic encephalitis is commonly associated with small cell lung cancer, testicular cancer, breast cancer, Hodgkin’s disease, and thymoma.3,5,12

Neuropathological findings in limbic encephalitis are inflammation and degenerative changes with neuronal loss, lipofuscin accumulation, reactive gliosis, and perivascular lymphocyte cuffing. Specific antibodies are associated with paraneoplastic syndromes, and new entities continue to emerge (Table 43-1).4,10,21

The causes of coma in paraneoplastic limbic encephalitis are shown in Table 43-2. Progression to coma is unusual but has been noted in certain subsets (e.g., anti-Ma). The location of abnormalities causing impaired consciousness is limbic, diencephalic, or brainstem.16 Nonconvulsive status epilepticus may be a presenting sign.7 Endocrine para-neoplastic manifestations may contribute and include severe hyponatremia (syndrome of inappropriate secretion of antidiuretic hormone [SIADH] or Addison’s disease) and hypercalcemia and could markedly confound the clinical assessment of conscious-ness.6,11,15,19 The anti-Ma2-associated encephalitis is often associated with daytime sleep-iness and narcolepsy in about one third of patients. Testicular tumors are common in anti-Ma2 encephalitis, although lung cancer and other tumors have been described. Further diencephalic dysfunction is indicated by weight gain, hyperthermia, and endo-crine abnormalities such as abnormal cortisol, diabetes insipidus, hypothyroidism, and inappropriate antidiuretic hormone (ADH) syndrome.

The MRI findings are characteristic with hyperintensities in the temporomedial structures, and early swelling can be seen (Fig. 43-1). The T1 gadolinium images rarely show enhancement. These findings are unlike those seen with lymphoma because with

TABLE 43-1 Causes of Coma in Paraneoplastic Limbic encephalitis

• Diencephalic involvement• Brainstem encephalitis• Nonconvulsive or complex partial status epilepticus• Endocrine paraneoplastic syndromes• Hyponatremia• Hypercalcemia

TABLE 43-2 antineuronal-antibody-associated Paraneoplastic Disorders

Antibody Neuronal Reactivity Protein Antigens Cloned Genes Tumor Clinical Presentations

Anti-Hu (ANNA-1) Nucleus more than

cytoplasm (all neurons)

35–40 kD HuD, HuC, Hel-N1 Small cell lung cancer,

neuroblastoma, and prostate

cancer

Paraneoplastic encephalomyelitis,

paraneoplastic sensory neuronopathy,

paraneoplastic cerebellar degeneration,

and autonomic dysfunctionAnti-amphiphysin Presynaptic nerve terminals 128 kD Amphiphysin Breast cancer and small cell

lung cancer

Stiff-person syndrome and paraneoplastic

encephalomyelitisAnti-CRMP5 Oligodendrocytes, neurons,

cytoplasm

66 kD CRMP5 (POP66) Small cell lung cancer and

thymoma

Encephalomyelitis, cerebellar degeneration,

chorea, and sensory neuropathyAnti-PCA-2 Purkinje cytoplasm and

other neurons

280 kD Small cell lung cancer Encephalomyelitis, cerebellar degeneration,

and Lambert-Eaton myasthenic syndromeAnti-Ma1 Neurons (subnucleus) 40 kD Ma1 Lung cancer and other cancers Brainstem encephalitis and cerebellar

degenerationAnti-Ma2 Neurons (subnucleus) 41.5 kD Ma2 Testicular cancer Limbic brainstem encephalitis

Adapted from Darnell and Posner.5

Comatose and Paraneoplastic encephalitis / / 459

lymphoma, significant contrast enhancement is seen. It cannot be confused with a pri-mary glioma because within its location—the limbic system—glioma often infiltrates to the insular cortex or thalami. Positron emission tomography (PET) scanning may show increased tracer activity in the medial temporal lobe. Cerebrospinal fluid (CSF) examina-tion can show a lymphocytic response, increased protein (less than 100 mg/dL), and oli-goclonal bands as indicators of inflammation. In the appropriate clinical setting, absence of CSF pleocytosis supports the presence of voltage-gated potassium channel antibody limbic encephalitis.


No effective treatment is known; however, some of these patients had a good response after discovery and removal of the primary tumor.1,2 Whole body PET with 18-fluorine fluoro-2-deoxy-glucose (FDG) may detect a small cell lung cancer in patients. Sensitivity of 70% was reported in one small study, but other studies found much less frequent dis-coveries.13,17,18 Criteria for evaluation have recently been proposed, and the search for the elusive cancer should remain comprehensive.9 After surgical removal, the immune response can be thwarted by using not only intravenous immunoglobulins and plasma exchange but also corticosteroids, cyclophosphamide, and rituximab.8,20 Paraneoplastic titers fluctuate and do not predict outcome.14 Poor response to therapy is a distinct pos-sibility, and also when seizures or status epilepticus are present. Clinical experience has shown a poor response to multiple trials of antiepileptic agents.

FIGURE 43-1 MRI showing bitemporal hyperintensities typical of limbic encephalitis. Note

metastasis of lung cancer in the cerebellum.


A CONCLUDING NOTE

Unexplained encephalopathy with mesotemporal lesions that are often bilateral should alert the physician to the possibility of underlying small cell lung cancer, testicular cancer, or ovar-ian cancer. Coma in limbic encephalopathy can be due to complex partial status epilepticus.

REFERENCES

1. Bataller L, Kleopa KA, Wu GF, et al. Autoimmune limbic encephalitis in 39 patients: immunopheno-types and outcomes. J Neurol Neurosurg Psychiatry 2007;78:381–385.

2. Candler PM, Hart PE, Barnett M, Weil R, Rees JH. A follow-up study of patients with paraneoplastic neurological disease in the United Kingdom. J Neurol Neurosurg Psychiatry 2004;75:1411–1415.

3. Dalmau J, Graus F, Villarejo A, et al. Clinical analysis of anti-Ma2-associated encephalitis. Brain 2004;127:1831–1844.

4. Dalmau J, Tuzun E, Wu HY, et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associ-ated with ovarian teratoma. Ann Neurol 2007;61:25–36.

5. Darnell RB, Posner JB. Paraneoplastic Syndromes. Oxford University Press, 2011.6. DeLellis RA, Xia L. Paraneoplastic endocrine syndromes: a review. Endocr Pathol 2003;14:303–317.7. Espay AJ, Kumar V, Sarpel G. Anti-Hu-associated paraneoplastic limbic encephalitis presenting as rap-

idly progressive non-convulsive status epilepticus. J Neurol Sci 2006;246:149–152.8. Fumal A, Jobe J, Pepin JL, et al. Intravenous immunoglobulins in paraneoplastic brainstem encephalitis

with anti-Ri antibodies. J Neurol 2006;253:1360–1361.9. Graus F, Delattre JY, Antoine JC, et al. Recommended diagnostic criteria for paraneoplastic neurological

syndromes. J Neurol Neurosurg Psychiatry 2004;75:1135–1140.10. Graus F, Vincent A, Pozo-Rosich P, et al. Anti-glial nuclear antibody: marker of lung cancer–related para-

neoplastic neurological syndromes. J Neuroimmunol 2005;165:166–171.11. Hiraki A, Ueoka H, Takata I, et al. Hypercalcemia–leukocytosis syndrome associated with lung cancer.

Lung Cancer 2004;43:301–307.12. Lieberman FS, Schold SC. Distant effects of cancer on the nervous system. Oncology (Williston Park)

2002;16:1539–1548.13. Linke R, Schroeder M, Helmberger T, Voltz R. Antibody-positive paraneoplastic neurologic syn-

dromes: value of CT and PET for tumor diagnosis. Neurology 2004;63:282–286.14. Llado A, Mannucci P, Carpentier AF, et al. Value of Hu antibody determinations in the follow-up of

paraneoplastic neurologic syndromes. Neurology 2004;63:1947–1949.15. Morita H, Hirota T, Mune T, et al. Paraneoplastic neurologic syndrome and autoimmune Addison dis-

ease in a patient with thymoma. Am J Med Sci 2005;329:48–51.16. Rajabally YA, Naz S, Farrell D, Abbott RJ. Paraneoplastic brainstem encephalitis with tetraparesis in a

patient with anti-Ri antibodies. J Neurol 2004;251:1528–1529.17. Rees JH. Paraneoplastic cerebellar degeneration: new insights into imaging and immunology. J Neurol

Neurosurg Psychiatry 2006;77:427.18. Rees JH. Paraneoplastic syndromes: when to suspect, how to confirm, and how to manage. J Neurol

Neurosurg Psychiatry 2004;75 Suppl 2:ii43–50.19. Tai P, Yu E, Jones K, et al. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) in

patients with limited stage small cell lung cancer. Lung Cancer 2006;53:211–215.20. Vedeler CA, Antoine JC, Giometto B, et al. Management of paraneoplastic neurological syn-

dromes: report of an EFNS Task Force. Eur J Neurol 2006;13:682–690.21. Zuliani L, Saiz A, Tavolato B, et al. Paraneoplastic limbic encephalitis associated with potassium channel

antibodies: value of anti-glial nuclear antibodies in identifying the tumour. J Neurol Neurosurg Psychiatry 2007;78:204–205.

461

A CONVERSATION

AN EXPLANATION

Anti-NMDAR-encephalitis is a newly recognized entity in young patients, mostly females, who might previously have been labeled as having unexplained viral encephalitis.2,8 This autoimmune encephalitis is caused by a large number of new antibodies directed to one subunit of the NMDA receptor and can be demonstrated mostly in CSF (and not always in serum with 15% false negative results). This dramatic encephalitis affects young women who, without any warning, develop a depression or what appears to be a first major psy-chotic episode. The clinical history may reveal several weeks of psychiatric treatment until

Comatose and autoimmune encephalitis

/ / / 44 / / /


the patient worsens, lapses into a coma, or starts to seize relentlessly. In some females, an ovarian teratoma can be found and is thought responsible. Finding these teratomas—which may have neuronal cells and could incite the neuroimmunologic response—may require comprehensive screening (MR of the pelvis). Removal of the tumor has been linked to clinical improvement and a better prognosis. CT scan of the abdomen and pelvis may falsely reveal normal-appearing ovaries.3,6

The causes of coma are shown in Table 44-1. Many of these patients progress to refractory status epilepticus, and often that is the main reason for long-term admission to a neurological intensive care unit.

Status epilepticus can be controlled only after the encephalitis is adequately treated with aggressive immunotherapy. The evaluation and treatment of autoimmune encepha-litis is different from that of other encephalitides. Immediate and full workup may include evaluation with MRI of the brain, EEG and EEG monitoring, CT of the abdomen and pelvis, a PET scan, and biopsy in uncertain lesions1,2 (Table 44-2).

TABLE 44-1 Causes of Coma in nmDaR encephalitis

• Multifocal and diffuse involvement of the hypothalamus• Bithalamic involvement• Cortical neuronal dropout from refractory seizures• Severe hyponatremia

TABLE 44-2 General Treatment approach in nmDa encephalitis

1. For any patient, search for (gynecologic examination, MR pelvis) and remove tumor (e.g., teratoma).2. For any patient, aggressively treat status epilepticus; patient may need long-term treatment of many

months.3. For patients with or without tumor removal, five-day course of concurrent IVIg and methylprednisolone.4. For patients with clear improvement, continue with supportive care.5. For patients with no response or limited response after one cycle of immunosuppression, initiate

cyclophosphamide (monthly) and rituximab (weekly for four weeks starting with the first dose of

cyclophosphamide).6. For patients with limited or no response to the approaches above, consider other forms of

immunosuppression.7. For patients without tumors, continue immunosuppression with mycophenolate mofetil or azathioprine for

at least one year after initial treatments are discontinued.


Comatose and autoimmune encephalitis / / 463

This autoimmune encephalitis is part of a spectrum of recently discovered encephalit-ides, and all seem to respond to immunotherapy, arguing for antibody-modulated disease.

The second most common autoimmune encephalitis in this category of rarities is voltage-gated potassium channel (VGCK) encephalitis. These patients may become comatose but may improve quickly with plasma exchange. Movement disorders are more common in patients with VGCK, and this may involve dystonia of the face and arm (facial-brachial dystonia). Neuropsychiatric features always precede movement dis-orders, and autonomic dysfunction and abnormal consciousness follow about two weeks after onset.3,4


The major issues are recognition and treatment of seizures requiring continuous video-EEG monitoring, intubation and mechanical ventilation in patients unable to protect the airway (due to marked dysautonomia-related bronchial secretions, abnor-mal consciousness, or requirement of anesthetic drugs). Many patients are admitted to intensive care units to treat refractory agitation. Even when the cause of the encephali-tis is not treatable, comprehensive supportive care increases the chance of a favorable outcome. Management of refractory status epilepticus predominates management, and multiple attempts at weaning are unsuccessful, leading to flare-up of electrographic abnormalities. Maintaining patients in prolonged anesthesia is not unusual and allows continuous immunotherapy to take effect.

Treatment often consists initially of five to 10 infusions of IVIG, five to 10 sessions of plasma exchange, and 1 g methylprednisolone for five to 10 days. In some patients, seizures can only be controlled with a combination of rituximab and cyclophospha-mide. Rituximab is usually used in a dose of 375 mg/m2 every week for four weeks, combined with cyclophosphamide 750 mg/m2 given with the first dose of rituximab, which is then followed by monthly cycles of cyclophosphamide.5 The clinical experience is less favorable in patients who have persistent and refractory status epilepticus despite ovariectomy and combinations of rituximab and cyclophosphamide. Some reports have emphasized that it is important to continue aggressive and sustained immunotherapy for several months before deciding to deescalate care. High CSF titers are associated with poor outcome but have not been used as a clinically useful marker.3 Most physicians feel that because these are young sick patients, care should not be withdrawn unless there are other clinical indicators of poor outcome such as super-refractory status epilepticus.


A CONCLUDING NOTE

Aggressive care of autoimmune NMDAR encephalitis may lead to good outcome if sta-tus epilepticus can be controlled. Finding a cause (ovarium teratoma) and subsequent removal may change the outlook.

REFERENCES

1. Dalmau J. Status epilepticus due to paraneoplastic and nonparaneoplastic encephalitides. Epilepsia 2009;50 Suppl 12:58–60.

2. Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol 2011;10:63–74.

3. Gresa-Arribas N, Titulaer MJ, Torrents A, et al. Antibody titers at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol 2014;13:167–177.

4. Graus F, Boronat A, Xifro X, et al. The expanding clinical profile of anti-AMPA receptor encephalitis. Neurology 2010;74:857–859.

5. Pozo-Rosich P, Clover L, Saiz A, Vincent A, Graus F. Voltage-gated potassium channel antibodies in lim-bic encephalitis. Ann Neurol 2003;54:530–533.

6. Rosenfeld MR, Dalmau J. Anti-NMDA-receptor encephalitis and other synaptic autoimmune disorders. Curr Treat Options Neurol 2011;13:324–332.

7. Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term out-come in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 2013;12:157–165.

8. Wingfield T, McHugh C, Vas A, et al. Autoimmune encephalitis: a case series and comprehensive review of the literature. QJM 2011;104:921–931.

465

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AN EXPLANATION

Acute disseminated encephalomyelitis (ADEM) is uncommon and difficult to diagnose.3,6,7 The reported clinical features include fever, episodes of irritability, and ataxia followed by impaired arousal.13,14,18 Some patients may develop predominantly a paraparesis due to involvement of the spinal cord. Because ADEM appears in young adults, there is an over-lap with multiple sclerosis, which has an age peak in the late 20s and early 30s.

The causes of coma in ADEM are shown in Table 45-1. Massive brain swelling with brainstem displacement could occur in fulminant cases. More often, coma is explained by

Comatose and acute Disseminated encephalomyelitis

/ / / 45 / / /


widespread demyelination of the white matter interrupting the thalamic cortical circuits. In some patients, certain areas are more specifically involved, including the brainstem and thalamus. Usually, ADEM is preceded by a prodromal illness such as an upper respiratory tract infection (50% of cases), gastrointestinal infection, or a vaccination (Table 45-2). The risk of vaccinations causing ADEM is low (e.g., measles 1/1,000; varicella 1/10,000) but increased with the administration of multiple vaccines.

On MRI, ADEM is recognized by numerous large areas of increased signal on T2-weighted images (Fig. 45-1). These lesions can be ring-shaped and may contain hemor-rhages. The short cortical association (U)-fibers are spared. Enhancement may be absent or minimal, and this finding is worth emphasizing (its absence indicates a minimal alteration

TABLE 45-1 Causes of Coma in acute Disseminated encephalomyelitis

• Diffuse hemispheric demyelination• Frontal lobe demyelination• Thalamic demyelination• Brainstem demyelination

TABLE 45-2 Triggers for acute Disseminated encephalomyelitis

Viral infections MeaslesMumpsInfluenzaHepatitisHerpes simplexVaricellaRubellaEpstein-BarrCytomegalovirusHIV

Other infections Mycoplasma pneumoniaeChlamydiaLegionellaCampylobacterStreptococcusRickettsia rickettsii

Vaccines RabiesDiphtheria, tetanus, pertussisSmallpoxMeaslesHepatitis BInfluenza

Comatose and acute Disseminated encephalomyelitis / / 467

of the blood–brain barrier at onset). MRI often also shows lesions in the cerebellum, cere-brum, white matter, brainstem, and spinal cord. The lesions are patchy and asymmetric and could involve both white and gray matter, and there may be thalamic lesions.11,12,17 After gadolinium is administered, there is nodular gyral-ring or diffuse contrast enhancement.13 Restricted diffusion is common in the acute phase.1 The differentiation with fulminant multiple sclerosis remains difficult.4 However, a distinctive MRI feature of ADEM is the absence of a lesion in the corpus callosum, although these lesions may be present in chil-dren.6,16 Thus, MRI abnormalities in any acute leukoencephalopathy are nonspecific, and these areas of signal abnormalities can be seen in patients with gliomatosis (Chapter 42), neurosarcoidosis, osmotic demyelination (Chapter 47), central nervous system vasculitis (Chapter 87), a hereditary metabolic disorder such as MELAS (Chapter 93), eclampsia, and other entities such as progressive multifocal leukoencephalopathy. The rapid clinical onset argues in most cases in favor of ADEM.

Cerebrospinal fluid (CSF) examination shows mononuclear pleocytosis and protein elevation. However, intrathecal IgG production with elevated IgG index is much less common in ADEM and is present in less than 10% of the cases.5 (For comparison, in acute exacerbations of multiple sclerosis, oligoclonal bands are typically found in up to 70% of the cases.)


Treatment of ADEM is immediate suppression of the immune response. High-dose IV methylprednisolone should be administered, 1 g IV daily for one week, followed by

FIGURE 45-1 MRI (FLAIR) with characteristic diffuse white matter involvement in ADEM.


high-dose prednisone 60 mg orally for six weeks. If within days of starting corticosteroids no clinical response is apparent, the patient should be additionally treated with intravenous immunoglobulin (0.4 g/kg) for five consecutive days. In more severe cases, alternate-day plasma exchanges are preferred before using immunoglobulin. Improvement is anticipated after the second or third plasma exchange, and rarely plasma exchange is continued for more than five or seven exchanges.9,14,17,19 If the patient fails to respond to plasma exchange, intravenous immunoglobulin,10 or corticosteroids, the remaining options are mitoxan-trone and cyclophosphamide. This treatment regimen is identical to the proposed treat-ment regimen for fulminant multiple sclerosis. However, the outcome in ADEM is much more favorable, with about two thirds of the patients making a full or nearly full recovery.8 However, improvement is more protracted in adults than in children.2

A CONCLUDING NOTE

Impaired consciousness together with a rapid development of bihemispheric subcortical white matter abnormalities on MRI scan after a viral illness should suggest the diagno-sis of ADEM. This MR finding is nonspecific and can be mimicked by any other leu-koencephalopathy. Early immunomodulating therapy, mostly corticosteroids or plasma exchange, can be successful.

REFERENCES

1. Balasubramanya KS, Kovoor JM, Jayakumar PN, et al. Diffusion-weighted imaging and proton MR spectros-copy in the characterization of acute disseminated encephalomyelitis. Neuroradiology 2007;49:177–183.

2. de Seze J, Debouverie M, Zephir H, et al. Acute fulminant demyelinating disease: a descriptive study of 60 patients. Arch Neurol 2007;64:1426–1432.

3. Garg RK. Acute disseminated encephalomyelitis. Postgrad Med J 2003;79:11–17.4. Hartung HP, Grossman RI. ADEM: distinct disease or part of the MS spectrum? Neurology

2001;56:1257–1260.5. Hollinger P, Sturzenegger M, Mathis J, Schroth G, Hess CW. Acute disseminated encephalomyelitis in

adults: a reappraisal of clinical, CSF, EEG, and MRI findings. J Neurol 2002;249:320–329.6. Hynson JL, Kornberg AJ, Coleman LT, et al. Clinical and neuroradiologic features of acute disseminated

encephalomyelitis in children. Neurology 2001;56:1308–1312.7. Leake JA, Albani S, Kao AS, et al. Acute disseminated encephalomyelitis in childhood: epidemiologic,

clinical and laboratory features. Pediatr Infect Dis J 2004;23:756–764.8. Lin CH, Jeng JS, Hsieh ST, Yip PK, Wu RM. Acute disseminated encephalomyelitis: a follow-up study in

Taiwan. J Neurol Neurosurg Psychiatry 2007;78:162–167.9. Lin CH, Jeng JS, Yip PK. Plasmapheresis in acute disseminated encephalomyelitis. J Clin Apher

2004;19:154–159.10. Marchioni E, Marinou-Aktipi K, Uggetti C, et al. Effectiveness of intravenous immunoglobulin treat-

ment in adult patients with steroid-resistant monophasic or recurrent acute disseminated encephalomy-elitis. J Neurol 2002;249:100–104.

Comatose and acute Disseminated encephalomyelitis / / 469

11. Menge T, Hemmer B, Nessler S, et al. Acute disseminated encephalomyelitis: an update. Arch Neurol 2005;62:1673–1680.

12. Murthy SN, Faden HS, Cohen ME, Bakshi R. Acute disseminated encephalomyelitis in children. Pediatrics 2002;110:e21.

13. Nasr JT, Andriola MR, Coyle PK. ADEM: literature review and case report of acute psychosis presenta-tion. Pediatr Neurol 2000;22:8–18.

14. Rahmlow MR, Kantarci O.Fulminant demyelinating diseases. Neurohospitalist 2013;3:81–91.15. RamachandranNair R, Parameswaran M, Girija AS. Acute disseminated encephalomyelitis treated with

plasmapheresis. Singapore Med J 2005;46:561–563.16. Rossi A. Imaging of acute disseminated encephalomyelitis. Neuroimaging Clin North Am 2008;18:

149–161.17. Sahlas DJ, Miller SP, Guerin M, Veilleux M, Francis G. Treatment of acute disseminated encephalomy-

elitis with intravenous immunoglobulin. Neurology 2000;54:1370–1372.18. Scolding N. Acute disseminated encephalomyelitis and other inflammatory demyelinating variants.

Handb Clin Neurol 2014:122:601–611.19. Tardieu M, Mikaeloff Y. What is acute disseminated encephalomyelitis (ADEM)? Eur J Paediatr Neurol

2004;8:239–242.

470

A CONVERSATION

AN EXPLANATION

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system and has a relapsing–remitting clinical course, with acute worsening often followed by a secondary progressive course. A progressive phase spares 50% of the patients, but the disorder may manifest itself again approximately 10 years after the onset.9 Variants of a more severe form of MS have been reported; the most familiar is the Marburg variant. This variant is a severe, often monophasic, form with large tumefactive lesions.4,7 Another variant is neuromyelitis optica (NMO), which is characterized by optic neuritis and

Comatose and Fulminant multiple sclerosis

/ / / 46 / / /

Comatose and Fulminant multiple sclerosis / / 471

acute myelitis with spinal cord lesions extending over several segments. In fulminant MS, within days to weeks, patients may develop acute demyelinating lesions and often severe permanent axonal damage.10

The causes of coma in fulminant MS are shown in Table 46-1. Impaired conscious-ness in fulminant MS can be explained not only by lesions in the cingulate gyrus and the thalamus, but also by lesions in the brainstem, particularly in the NMO variant. In our patient example, multiple lesions at different locations could explain her presenting symptoms, but the lesions in the anterior cingulate gyrus were most consistent with aki-netic mutism (Fig. 46-1).

The diagnostic criteria of MS have recently been revised and now include MRI find-ings. These criteria provide a more detailed description of brain and spinal cord pathol-ogy and emphasize that the MRI can be diagnostic without supportive cerebrospinal fluid (CSF) findings.5 Biopsy of the lesion may be needed to confirm the diagnosis, par-ticularly in more fulminant cases. An extended protocol for evaluation of brain and spinal cord MRI has been recently suggested and includes sagittal fast FLAIR (convenient for identifying corpus callosum lesions), axial fast spin-echo (infratentorial lesions), axial fast FLAIR (juxtacortical and paraventricular lesions), and axial postcontrast T1-weighted images using at least the standard IV dose of 0.1 mmol/kg gadolinium, injected over 30 seconds. Double inversion recovery fast spin-echo images increase the detection of the demyelinating lesions.8 Newer MRI techniques have documented lesions in the corpus callosum that are often ovoid-shaped or flame-shaped. Dawson fingers, noted on sagittal T2-weighted images or FLAIR images, are oval elongated lesions in the corona radiata and centrum semiovale. They are mostly oriented along the subependymal veins and per-pendicular to the walls of the ventricles and represent perivenular inflammation. Lesions may also involve the brainstem and cerebellum and enhance on T1-weighted gadolinium images. About one third of T2 lesions are hypointense on T1-weighted images, termed a black hole. When these “black holes” do not enhance, they may represent chronic or stable lesions. These lesions are often associated with greater tissue destruction and axonal loss and therefore may correlate with a worse prognosis.

The differential diagnosis of inflammatory disorders is very wide and includes acute disseminated encephalomyelitis (ADEM; Chapter 45), systemic lupus erythematosus

TABLE 46-1 Causes of Coma in Fulminant multiple sclerosis

• Demyelination in anterior cingulate gyrus (akinetic mutism)• Demyelination with mass effect (Marburg variant) and brainstem displacement• Demyelination in thalamus• Demyelination in tegmentum of the pons


(Chapter 86) and connective tissue disorders, Sjögren syndrome, sarcoidosis, Baló’s con-centric sclerosis, and many infectious disorders, particularly neuroborreliosis, progres-sive multifocal leukoencephalopathy, toxoplasmosis, human immunodeficiency virus, and cysticercosis. In most situations, the etiology is obvious. When a tumefactive form of MS is considered, lymphoma (Chapter 40), metastases (Chapter 41), and gliomatosis cerebri (Chapter 42) should be excluded.


Fulminant MS is treated with high-dose corticosteroids (five days of intravenous methyl-prednisolone 1 g daily). This is followed by plasma exchanges (e.g., five plasma exchanges on alternate days).2 The effects of these treatments are uncertain, and other therapeutic

FIGURE 46-1. Multiple images of patient with fulminant MS. MRI shows Dawson fingers (A

and B), “black holes,” interrupted ring lesions (C), and lesions in the cerebellum and pons (D).

The clinical manifestation, akinetic mutism, corresponds with lesions in the anterior cingulate cortex.

Comatose and Fulminant multiple sclerosis / / 473

options should be considered. One possibility is the use of mitoxantrone3 or, more recently, rituximab, a human mouse chimeric monoclonal antibody directed against CD-20, a cell surface antigen. Rituximab is currently in safety and tolerability studies and results have initially been promising.1,11 Daclizumab (interleukin-2 receptor antibody) reduced MRI lesions and improved clinical scores.6 Alternatively, cyclophosphamide can be considered or IVIG.1 Prognosis of fulminant MS is generally poor, with a high (80%–90%) mortality and often severe disability, but surprising recoveries have been noted.

A CONCLUDING NOTE

MS is typically intermittent, relapsing, and remitting, but it may present with a progres-sive fulminant course. Impairment of consciousness may occur from bilateral lesions in the cingulate gyrus or brainstem or due to a large demyelinating lesion with mass effect.

REFERENCES

1. Cree B. Emerging monoclonal antibody therapies for multiple sclerosis. Neurologist 2006;12:171–178.2. Jacquerye P, Ossemann M, Laloux P, Dive A, De Coene B. Acute fulminant multiple sclerosis and plasma

exchange. Eur Neurol 1999;41:174–175.3. Jeffery DR, Lefkowitz DS, Crittenden JP. Treatment of Marburg variant multiple sclerosis with mitoxan-

trone. J Neuroimaging 2004;14:58–62.4. Mendez MF, Pogacar S. Malignant monophasic multiple sclerosis or “Marburg’s disease.” Neurology

1988;38:1153–1155.5. Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the

“McDonald Criteria.” Ann Neurol 2005;58:840–846.6. Rose JW, Burns JB, Bjorklund J, et al. Daclizumab phase II trial in relapsing and remitting multiple scle-

rosis: MRI and clinical results. Neurology 2007;69:785–789.7. Susac JO, Daroff RB. Magnetic resonance images on Marburg variant. J Neuroimaging 2005;15:206;

author reply 206.8. Wattjes MP, Lutterbey GG, Gieseke J, et al. Double inversion recovery brain imaging at 3T: diagnostic

value in the detection of multiple sclerosis lesions. AJNR Am J Neuroradiol 2007;28:54–59.9. Weinshenker BG. Therapeutic plasma exchange for acute inflammatory demyelinating syndromes of the

central nervous system. J Clin Apher 1999;14:144–148.10. Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG The spectrum of neuromy-

elitis optica. Lancet Neurol 2007;6:805–815.11. Wingerchuk DM, Weinshenker BG. White matter disease: optimizing rituximab therapy for neuromyeli-

tis optica. Nat Rev Neurol 2011;7:664–66512. Wingerchuk DM. Neuromyelitis optica: potential roles for intravenous immunoglobulin. J Clin Immunol.

2013 ;33: Suppl 1:S33–37

474

A CONVERSATION

AN EXPLANATION

A classic clinical scenario for osmotic demyelination is a patient who has impaired con-sciousness from acute hyponatremia but who fails to awaken after reaching normal sodium plasma values.1,2 Most instances involve demyelination of the pons. Extrapontine myelinolysis can be found in 80% of cases after treatment of hyponatremia, but it is much less common as an isolated finding (40%).12 Osmotic demyelination mostly occurs in malnourished patients with hyponatremia associated with prior alcohol abuse or after prolonged use of diuretics. Severe acute hyponatremia has been reported due to

Comatose and osmotic Demyelination

/ / / 47 / / /

Comatose and osmotic Demyelination / / 475

polydipsia, due to major osmotic shifts associated with surgery and fluid administration, or as a result of an eating disorder.3,9,10,15

The causes of coma in osmotic demyelination are shown in Table 47-1. The patho-physiologic mechanism of osmotic demyelination remains unresolved. In a hypo-osmotic state, brain swelling may occur as a result of osmotic gradient created by osmolytes (e.g., glu-tamate, taurine, and myo-inositol). The pontine fibers may not be able to tolerate further pres-sure from fluid shifts and could be particularly susceptible (Chapter 6). However, this does not explain the bithalamic, caudate, putamen, and pallidum lesions (Fig. 47-1). Impairment of consciousness in osmotic demyelination is far more common than the later defining signs of spastic quadriparesis, ataxia, and pseudobulbar palsy.7 Decline in consciousness is expected if the lesion extends to the tegmentum, but then it also produces oculomotor abnormalities. A locked-in syndrome occurs if the lesion involves a large part of the base of the pons.

Using MR diffusion-weighted sequences, the diagnosis can be confirmed if restricted diffusion is present (usually within 48 hours of symptoms).4 Abnormalities on MR FLAIR may occur later, because demyelination would take at least two weeks to become noticed.8,14


The published recommendations on the treatment of severe hyponatremia have been summarized and emphasized the major uncertainties with the rate of correction and tar-get value of serum sodium10 (Table 47-2). An overshoot to hypernatremia could be a factor. Rapid correction of hyponatremia is often unexpected despite careful calculations of water surplus. (Treatment of severe hyponatremia is discussed in Chapter 81.) Plasma exchange and corticosteroids have been attempted in the treatment of osmotic demy-elination but have not definitively been shown to improve patient outcome.5,6,13,16 The outcome is poor once patients become comatose.11

A CONCLUDING NOTE

The syndrome of osmotic demyelination has been linked to correction of hyponatremia. Rapid correction of hyponatremia has been implicated, but safe correction rates are not

TABLE 47-1 Causes of Coma in osmotic Demyelination

• Diffuse bihemispheric demyelination• Bithalamic demyelination• Tegmental pontine demyelination• Acute hypernatremia (overshoot after correction)


FIGURE 47-1 MRI demonstrates T2 signal abnormality in the pons sparing the cortical-spinal

tracts and at the junction of the lentiform and external capsules. High T2 signal is noted in both

globus pallidi and thalami.

TABLE 47-2 Published Recommendations for Correction of hyponatremia

• >20 mmol/L over three days is too rapid.• If serum sodium <105 mmol/L, correct at 2 mmol/L/h for first 20 mmol/L, then allow to drift to normal. If

serum sodium ≥105 mmol/L, correct at 2 mmol/L/h to 125–130 mmol/L.• Not more than 12 mmol/L/day for first day, and subsequent days slower• <2.5 mmol/L/h and no more than 20 mmol/day• <15 mmol/L in 24 h• <10 mmol/L/ day in first 24 h and less on subsequent days• Should not exceed 1–2 mmol/L/h• Should not exceed 8 mmol/L on any day of correction

Data adapted from Martin.10

Comatose and osmotic Demyelination / / 477

exactly known. MRI is able to demonstrate the typical demyelination sites, mostly in the pons.

REFERENCES

1. Abbott R, Silber E, Felber J, Ekpo E. Osmotic demyelination syndrome. BMJ 2005;331:829–830.2. Adams RD, Victor M, Mancall EL. Central pontine myelinolysis: a hitherto undescribed disease occur-

ring in alcoholic and malnourished patients. AMA Arch Neurol Psychiatry 1959;81:154–172.3. Cheng JC, Zikos D, Skopicki HA, Peterson DR, Fisher KA. Long-term neurologic outcome in psycho-

genic water drinkers with severe symptomatic hyponatremia: the effect of rapid correction. Am J Med 1990;88:561–566.

4. Cramer SC, Stegbauer KC, Schneider A, Mukai J, Maravilla KR. Decreased diffusion in central pontine myelinolysis. AJNR Am J Neuroradiol 2001;22:1476–1479.

5. Grimaldi D, Cavalleri F, Vallone S, Milanti G, Cortelli P. Plasmapheresis improves the outcome of central pontine myelinolysis. J Neurol 2005;252:734–735.

6. Huq S, Wong M, Chan H, Crimmins D. Osmotic demyelination syndromes: central and extrapontine myelinolysis. J Clin Neurosci 2007;14:684–688.

7. Kim J, Song T, Park S, Choi IS. Cerebellar peduncular myelinolysis in a patient receiving hemodialysis. J Neurol Sci 2007;253:66–68.

8. Kumar SR, Mone AP, Gray LC, Troost BT. Central pontine myelinolysis: delayed changes on neuroim-aging. J Neuroimaging 2000;10:169–172.

9. Malhotra K, Ortega L. Central pontine myelinolysis with meticulous correction of hyponatraemia in chronic alcoholics. BMJ Case Rep 2013, Jun 21.

10. Martin RJ. Central pontine and extrapontine myelinolysis: the osmotic demyelination syndromes. J Neurol Neurosurg Psychiatry 2004;75 Suppl 3:iii22–28.

11. Menger H, Jorg J. Outcome of central pontine and extrapontine myelinolysis (n = 44). J Neurol 1999;246:700–705.

12. Miller GM, Baker HL, Jr., Okazaki H, Whisnant JP. Central pontine myelinolysis and its imitators: MR findings. Radiology 1988;168:795–802.

13. Murase T, Sugimura Y, Takefuji S, Oiso Y, Murata Y. Mechanisms and therapy of osmotic demyelination. Am J Med 2006;119:S69–73.

14. Ruzek KA, Campeau NG, Miller GM. Early diagnosis of central pontine myelinolysis with diffusion-weighted imaging. AJNR Am J Neuroradiol 2004;25:210–213.

15. Singer C, Lorenzo D, Papapetropoulos S, Mesa A, Bowen B. Pontine/extrapontine myelinolysis occur-ring in the setting of an eating disorder. Neurology 2005;64:2156–2157.

16. Sugimura Y, Murase T, Takefuji S, et al. Protective effect of dexamethasone on osmotic-induced demy-elination in rats. Exp Neurol 2005;192:178–183.

478

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AN EXPLANATION

Broadly speaking, all acute hydrocephalus is a consequence of obstruction of cerebro-spinal fluid (CSF) passage, but enlargement of the ventricular system is typically divided into two types: a communicating hydrocephalus (at the level of arachnoid granulations) or obstructive hydrocephalus (at the level of ventricular outlets and ventricular spaces). The clinical presentation of acute hydrocephalus may be acute and not heralded by severe intermittent headaches. When a tumor is gradually obstructing, the increased CSF

Comatose and acute hydrocephalus

/ / / 48 / / /

Comatose and acute hydrocephalus / / 479

pressure may produce papilledema. Before impairment of consciousness occurs, pressure on the quadrigeminal plate can produce paralysis of upgaze, lid retraction, and a light–near dissociation of the pupillary light reflex (Argyll Robertson pupils; pupils constrict to accommodation, not to light).4 In many patients with an acute hydrocephalus, a down-ward gaze emerges (Fig. 48-1).

The causes of coma in acute hydrocephalus are shown in Table 48-1. Acute hydro-cephalus may cause decreased arousal from lesions at multiple locations. Impaired con-sciousness may be explained by compression of the white matter and cortex or due to enlargement (funneling) of the aqueduct that puts pressure on the ascending reticular for-mation. The third ventricle may expand and kink the upper brainstem or impair function of the thalami. Equally important, acute hydrocephalus may be a secondary manifesta-tion of a neurologic disorder that itself can impair consciousness (Table 48-2). Examples are acute hydrocephalus in aneurysmal subarachnoid hemorrhage, tumors infiltrating the thalami, and cerebellar swelling obstructing the ventricles and also simultaneously displac-ing the pons. Acute obstructions, particularly those due to colloid cysts obstructing at the foramen of Monro, may cause rapid deterioration of consciousness or sudden death.2,6,8,9

FIGURE 48-1 Downward gaze and small pupils in acute hydrocephalus associated with aneurys-

mal subarachnoid hemorrhage.

TABLE 48-1 Causes of Coma in acute hydrocephalus

• Dilated bifrontal ventricles compressing white matter and cortex• Dilated aqueduct or fourth ventricle compressing reticular formation• Dilated third ventricle compressing thalami


The cause of aqueductal stenosis in adults remains obscure, and it is considered a decompensation of a marginally compensated CSF flow system. Some of these patients may have had a prior traumatic brain injury or childhood infection.1,5

Neuroimaging should include CT (Fig. 48-2) and MRI. MRI is particularly helpful in demonstrating the site of obstruction (Figs. 48-3 and 48-4) and also the presence of transependymal extravasation of CSF into the adjacent white matter. MR flow studies may provide additional information. 3,5


Ventriculostomy is preferred over a lumbar drain or lumbar puncture when the distinc-tion between an obstructive and communicating hydrocephalus is not clear. Lumbar drainage is increasingly used in acute communicating hydrocephalus, particularly in aneurysmal subarachnoid hemorrhage and more recently in cerebral hemorrhage. Other neurosurgical options can be considered (e.g., third ventriculostomy and aqueducto-plasty).7 The next step is to treat the cause of obstruction. Intraventricular tumors (e.g., plexus papilloma, ependymoma, oligodendroglioma, astrocytoma, and epidermoid cyst) can be resected or stereotactically aspirated (colloid cyst). Pineal region tumors (pineo-blastoma or pineocytoma) require resection and radiotherapy. Prognosis is determined by the nature of the compressing lesion causing impairment of CSF flow and absorption.

A CONCLUDING NOTE

Acute hydrocephalus—communicating or obstructive—can rapidly cause impaired consciousness. There is an urgency to treat acute obstructive hydrocephalus, and it has

TABLE 48-2 Causes of acute hydrocephalus

COMMUNICATING• Aneurysmal subarachnoid hemorrhage• Bacterial meningitis• Intraventricular hemorrhageOBSTRUCTIVE• Acute shunt malfunction• Aqueductal stenosis• Intraventricular tumors (colloid cyst, plexus papilloma)• Pineal tumors• Cerebellar mass• Cerebellar stroke

Comatose and acute hydrocephalus / / 481

FIGURE 48-3 Serial MRI studies showing development of funneling of hydrocephalus consistent

with aqueduct stenosis. Cerebrospinal fluid flow study showed no flow through aqueduct.

FIGURE 48-2 CT: acute hydrocephalus with sparing of the fourth ventricle suggesting aqueduct

stenosis.


many causes. After a ventriculostomy is placed, the obstructive lesion may require surgi-cal extirpation.

REFERENCES

1. Birkhahn RH, Sweeny AH, Lopez O. Chronic meningitis presenting with acute obstructive hydrocepha-lus. J Emerg Med 2002;22:175–178.

2. Buxton N, Punt J. Failure to follow patients with hydrocephalus shunts can lead to death. Br J Neurosurg 1998;12:399–401.

3. Greitz D. Radiological assessment of hydrocephalus: new theories and implications for therapy. Neurosurg Rev 2004;27:145–165.

4. Maramattom BV, Wijdicks EF. Dorsal mesencephalic syndrome and acute hydrocephalus after subarach-noid hemorrhage. Neurocrit Care 2005;3:57–58.

5. Robertson IJ, Leggate JR, Miller JD, Steers AJ. Aqueduct stenosis—presentation and prognosis. Br J Neurosurg 1990;4:101–106.

6. Rosenstengel C, Baldauf J, Muller JU, Schroeder HW. Sudden intraaqueductal dislocation of a third ventri-cle ependymoma causing acute decompensation of hydrocephalus. J Neurosurg Pediatr 2011;8:154–157.

7. Schroeder HW, Oertel J, Gaab MR. Endoscopic treatment of cerebrospinal fluid pathway obstructions. Neurosurgery 2007;60:ONS44–51.

8. ter Meulen BC, Kros JM, Jacobs BC. Sudden death after air travel in a patient with colloid cyst. Neurology 2006;67:1005.

9. Yano S, Kuroda J, Makino K, et al. Third ventricular ependymal cyst presenting with acute hydrocephalus. Pediatr Neurosurg 2006;42:245–248.

FIGURE 48-4 Colloid cyst on roof of the third ventricle causing acute hydrocephalus.

483

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AN EXPLANATION

CSF hypotension does not cause coma frequently, but consciousness changing with position is immediately worrisome. However, when severe CSF hypotension occurs it is often not recognized because it remains an exceptional clinical situation. It is common that in the most severe cases of CSF hypotension, coma is initially attributed to bilat-eral subdural hematomas (despite minimal mass effect). It is then typically followed by

Comatose and CsF hypotension/ / / 49 / / /


evacuation of the subdural hematoma that not only fails to relieve the symptoms but even more problematically worsens the clinical condition2 (Fig. 49-1).

The diagnosis can be quickly confirmed by MRI scan. A sagittal image can detect significant “sagging” of the brain that leads to buckling of the diencephalon, flattening the ventral “belly” of the pons, and downward displacement of cerebellar tonsils3 (Fig. 49-2). If contrast is used, pachymeningeal enhancement is seen and the cerebral venous sinuses are engorged. This observation of increased venous volume might be simply the Monro-Kellie doctrine—in reverse. The rule of a constant intracranial volume is that decrease of volume in one of the components—CSF in this situation—should be accom-panied by an increase in intracranial blood volume, and that leads to venous hyperemia.

FIGURE 49-1 CT scan with bilateral subdural hematoma from CSF hypotension.

FIGURE 49-2 MRI showing sagging of the brain. Note absent dome of the corpus callosum,

absent pontine belly, and low-level cerebellar tonsils.

Comatose and CsF hypotension / / 485

In extreme situations, severe sagging results in brainstem or hemispheric infarcts—it is a result of arterial stretch and thus reduced flow.4 With brainstem displacement, patients could develop a respiratory arrest that requires intubation and that may lead to secondary anoxic-ischemic injury.1

The subdural hematomas are often attributed to the clinical presentation because some patients may develop pupillary asymmetry and ophthalmoparesis that could suggest brainstem shift. The so-called tight-looking brain on CT scan with subdural hematomas is often therefore misinterpreted. The causes of coma in CSF hypotension are shown in Table 49-1.


Clinically, some patients become stuporous any time they are in a sitting-up position (or even at 30 degrees head elevation). The treatment is to place the patient immediately flat or in a Trendelenburg positions to investigate the underlying CSF leak and treat it appropriately.5 The diagnosis is usually made with CT myelogram or MRI of the spine, which hopefully will show an extrathecal CSF collection. CSF leak can also occur after a craniotomy for any reason, particularly if there is evidence of a dural opening.6 The CSF leak can be effectively treated with an epidural blood patch or more extensive surgical repair. Additional use of acetolamide to reduce CSF production may also be helpful in some patients.

A CONCLUDING NOTE

Spontaneous intracranial hypotension can cause coma and mimic clinical signs of bilat-eral subdural hematomas. Important clues are position-related headaches before the patient’s condition deteriorates.

TABLE 49-1 Causes of Coma in CsF hypotension

• Diencephalic buckling• Tonsillar compression• Multiple cerebral infarcts• Duret hemorrhage• Anoxic-ischemic encephalopathy


REFERENCES

1. Dhillon AK, Rabinstein AA, Wijdicks EFM. Coma from worsening spontaneous intracranial hypoten-sion after subdural hematoma evacuation. Neurocrit Care 2010;12:390–394.

2. Evan RW, Mokri B. Spontaneous intracranial hypotension resulting in coma. Headache 2002;42:159–160.3. Kelley GR, Johnson PL. Sinking brain syndrome: craniotomy can precipitate brainstem herniation in

CSF hypovolemia. Neurology 2004;62:157.4. Schievink WI. Stroke and death due to spontaneous intracranial hypotension. Neurocrit Care

2013;18:248–251.5. Schievink WI, Moser FG, Pikul BK. Reversal of coma with an injection of glue. Lancet 2007;369:1402.6. Schievink WI, Palestrant D, Maya MM, Rappard G. Spontaneous spinal cerebrospinal fluid leak as a cause of

coma after craniotomy for clipping of an unruptured intracranial aneurysm. J Neurosurg 2009;110:521–524.

487

A CONVERSATION

AN EXPLANATION

Status epilepticus implies ongoing clinical seizures or the presence of continuous or nearly continuous epileptic activity on electroencephalogram (EEG). The spectrum of causes of status epilepticus is different in children versus adults.2 In children, bacterial meningitis is common; in adults, status epilepticus is often a result of change in medica-tion in a patient with a prior intractable seizure disorder, acute encephalitis, stroke, or recurrent brain tumor.

Comatose and Convulsive status epilepticus

/ / / 50 / / /


Status epilepticus is divided into several types and includes convulsive status epi-lepticus, generalized nonconvulsive forms with absence, and atypical absence status epilepticus or focal nonconvulsive forms with simple partial or complex partial status epilepticus. Epilepsia partialis continua is characterized by persistent jerking of face and limbs and is commonly associated with an underlying structural cause. These patients may be awake or in a twilight state. In adults, generalized myoclonic status epilepticus takes a separate place.3

The causes of coma in convulsive status epilepticus are shown in Table 50-1. During seizure activity, the enhancement of synaptic excitation reduces gamma-aminobutyric acid (GABA) inhibition but also activates the n-methyl-d-aspartate (NMDA) recep-tor. The system runs amok due to excessive NMDA receptor activation, causing a major calcium influx and neuronal dropout. The transition to NMDA activation is considered the point of no return and explains pharmacoresistance in patients with a prolonged status epilepticus. Bihemispheric cortical spreading depression is consid-ered the main mechanism for abnormal consciousness, but the original seizure focus in the brain may play a role, and some studies found virtually no impairment of con-sciousness in right temporal and frontal lobe seizures.11 Neuronal “exhaustion” has been put forward as a mechanism for a postictal state, but this explanation has not been corroborated.

Video-EEG monitoring is mandatory. Repetitive sharp- and slow-wave complexes or rhythmic, theta, or delta activity is usually present (Fig. 50-1). Documentation of improvement after intravenous injection of an antiepileptic drug may be diagnostic. Periodic discharges that occur at regular intervals have been described. They can be uni-lateral or bilateral, and these periodic lateralized epileptiform discharges (PLEDs) are often recorded in patients who remain comatose. There is continuing controversy as to whether PLEDs represent an interictal or ictal phenomenon.

Nonconvulsive status epilepticus is far more difficult to detect. Most patients do not open eyes to pain or localize to pain, and they often display episodes of gaze devia-tion, blinking, or irregular eyelid twitching. A clinical response to benzodiazepines is expected.

TABLE 50-1 Causes of Coma in Convulsive status epilepticus

• Enhancement of synaptic excitation and GABA inhibition• Underlying acute bihemispheric injury (e.g., encephalitis)• Barbiturate or midazolam accumulation (after treatment)• Anoxic-ischemic injury (associated with poor airway control during seizures)

Comatose and Convulsive status epilepticus / / 489


Several treatment algorithms have been suggested, and one example is shown in Figure 50-2.10,12 There is a general agreement among experts that most patients should be treated with lorazepam followed by phenytoin or fosphenytoin and an additional bolus of fosphenytoin if seizures recur.9 If further treatment is needed, physicians then enter an area of therapeutics that is totally arbitrary. The most commonly used intravenous drugs to treat refractory status epilepticus are midazolam, propofol, and, more recently, valproate, levetiracetam and ketamine.13,14 Failure to respond to first- and second-line drugs, used properly, is a bad omen.

The ease of use of propofol has made it a preferred drug. However, with its increased use, a propofol infusion syndrome has been more often described. This syndrome has a very high mortality and occurs with a high dose of propofol (>5 mg/kg/h). Cardiac arrest may occur within 24 to 48 hours of starting an infusion but is more common with pro-longed use.16 This syndrome may appear suddenly and is in many cases not anticipated by the development of metabolic acidosis, increased lactate, hyperlipidemia, or incremental doses of vasopressors to control propofol-induced hypotension. This complication is a major concern despite propofol’s excellent safety record and excellent control of refrac-tory status epilepticus. Another option is intravenous pentobarbital, but this drug has

FIGURE 50-1 EEG epoch in a longitudinal bipolar montage shows generalized sharp- and

slow-wave discharges.


been associated with an unacceptably high number of infections.1,17 Midazolam is a better alternative, although its efficacy in countering status epilepticus is not clear, particularly when used after failure of a prior benzodiazepine such as lorazepam. Gradual titration of the drug to maximal effect followed by maintenance for 24 hours, aiming at an EEG without epileptic activity, is recommended.7 It should be emphasized that a seizure-free EEG is the main objective. A burst-suppression pattern does not guarantee that an inter-mittent seizure burst cannot occur. Weaning of midazolam, propofol, or pentobarbital is considered after a seizure-free period of 24 hours, but only after documentation of adequate maintenance levels of antiepileptic drugs. Gradual decrease of the infusate is preferred (e.g., 10% total dose every hour) and includes careful monitoring of continu-ous EEG. Poor outcome of status epilepticus is determined by the initial time needed to control seizures, recurrence of seizures after weaning of antiepileptic drugs, persistent coma, age >65 years, status epilepticus due to a stroke, and prior history of seizures.5,6,8,15 Systemic complications in patients with prolonged anesthesia for status epilepticus can be a cause of morbidity. Whether MRI may be able to document neuronal loss on diffusion-weighted images (DWI) and predict outcome remains unclear.4

Midazolam IV 10 mg

At the scene ED ICU

Midazolam IV 0.2-3 mg/kg/hr

Lorazepam IV4 mg

Lorazepam IV4 mg

(Fos) Phenytoin IV20 mg/kg

Valproic Acid IV30 mg/kg

Levetiracetam IV1000 mg

Propofol50-150 mg/kg/min

Pentobarbital IV 1-5 mg/kg/hr

Isoflurane0.8-1%

Ketamine IV2-10 mg/kg/hr

FIGURE 50-2 Treatment options in status epilepticus.

Comatose and Convulsive status epilepticus / / 491

A CONCLUDING NOTE

Status epilepticus is a neurologic emergency. If (fos)phenytoin and benzodiazepines are unsuccessful, the next choice of an antiepileptic drug is arbitrary; there are many options. Video-EEG monitoring is necessary to maintain a seizure-free EEG.

REFERENCES

1. Ala-Kokko TI, Saynajakangas P, Laurila P, et al. Incidence of infections in patients with status epilepticus requiring intensive care and effect on resource utilization. Anaesth Intensive Care 2006;34:639–644.

2. Chin RF, Neville BG, Peckham C, et al. Incidence, cause, and short-term outcome of convulsive status epilepticus in childhood: prospective population-based study. Lancet 2006;368:222–229.

3. Cockerell OC, Rothwell J, Thompson PD, Marsden CD, Shorvon SD. Clinical and physiological features of epilepsia partialis continua. Cases ascertained in the UK. Brain 1996;119(Pt 2):393–407.

4. Engelhorn T, Hufnagel A, Weise J, Baehr M, Doerfler A. Monitoring of acute generalized status epilep-ticus using multilocal diffusion MR imaging: early prediction of regional neuronal damage. AJNR Am J Neuroradiol 2007;28:321–327.

5. Hocker S, Wijdicks EFM, Rabinstein AA. Refractory status epilepticus: new insights in presentation, treatment, and outcome. Neurol Res 2013;35:163–168.

6. Hocker SE, Britton JW, Mandrekar JN, Wijdicks EF, Rabinstein AA. Predictors of outcome in refractory status epilepticus. JAMA Neurol 2013;70:72–77.

7. Kaplan PW. The EEG of status epilepticus. J Clin Neurophysiol 2006;23:221–229.8. Knake S, Rochon J, Fleischer S, et al. Status epilepticus after stroke is associated with increased long-term

case fatality. Epilepsia 2006;47:2020–2026.9. Lang ES, Andruchow JE. Evidence–based emergency medicine. What is the preferred first-line therapy

for status epilepticus? Ann Emerg Med 2006;48:98–100.10. Lawn ND, Wijdicks EFM. Progress in clinical neurosciences: Status epilepticus: a critical review of man-

agement options. Can J Neurol Sci 2002;29:206–215.11. Lux S, Kurthen M, Helmstaedter C, et al. The localizing value of ictal consciousness and its constituent

functions: a video-EEG study in patients with focal epilepsy. Brain 2002;125:2691–2698.12. Meierkord H, Boon P, Engelsen B, et al. EFNS guideline on the management of status epilepticus. Eur

J Neurol 2006;13:445–450.13. Misra UK, Kalita J, Patel R. Sodium valproate vs phenytoin in status epilepticus: a pilot study. Neurology

2006;67:340–342.14. Ramael S, Daoust A, Otoul C, et al. Levetiracetam intravenous infusion: a randomized, placebo-controlled

safety and pharmacokinetic study. Epilepsia 2006;47:1128–1135.15. Rossetti AO, Logroscino G, Bromfield EB. A clinical score for prognosis of status epilepticus in adults.

Neurology 2006;66:1736–1738.16. Vasile B, Rasulo F, Candiani A, Latronico N. The pathophysiology of propofol infusion syndrome: a

simple name for a complex syndrome. Intensive Care Med 2003;29:1417–1425.17. Wijdicks EFM. The multifaceted care of status epilepticus. Epilepsia 2013;54(Suppl 6):61–63.

492

A CONVERSATION

AN EXPLANATION

Nonconvulsive status epilepticus is a condition that often is associated with high mortal-ity rates.1,2 It is unclear whether it damages the brain, as with convulsive status epilepticus. Morbidity is perhaps due to overly aggressive management, which may include intuba-tion, line placement, and anesthetic drugs. The increased morbidity and mortality associ-ated with nonconvulsive status epilepticus may thus be iatrogenic rather than a result of seizures.

Comatose and Nonconvulsive Status Epilepticus

/ / / 51 / / /

Comatose and Nonconvulsive Status Epilepticus / / 493

Nonconvulsive status epilepticus is often associated with older age, but specific etiologies cannot be detected in the vast majority of patients.3 Prior ischemic strokes, neurotoxicity, or a new structural lesion could be implicated. It has been quite a common observation after surgery for a subdural hematoma.3 Any patient with new convulsive status epilepticus should be investigated for a possible encephalitis, particularly a herpes simplex encephalitis, which can cause partial complex seizures. Nonconvulsive status epi-lepticus has been associated with increased intracranial pressure, suggesting that EEG monitoring may be needed in traumatic brain injury.5

Nonconvulsive status epilepticus is a well-recognized cause of coma or stupor but may be overdiagnosed. Its consideration is certainly a reason for numerous EEG requests, with many that merely show generalized slowing. Patients in nonconvulsive status epilepticus often have a waxing and waning conscious state rather than total unresponsiveness. The diagnosis is clear if there is eyelid twitching, chewing movements and jerking myoclonic movements in the extremities (VC 51-1). The diagnosis is based on EEG criteria showing frequent or continuous generalized spike and wave or polyspike discharges, but new rhythmic periodic lateralized epileptiform discharges (PLEDS) or bilateral periodic epileptiform discharges (BIPEDS) may also be seen as indicative of ongoing seizures and certainly would justify an IV lorazepam challenge to see if the pattern disappears.6

In intensive care units, nonconvulsive status epilepticus occurred in 8% of comatose patients who did not have overt clinical signs of seizure activity.6 Mortality in this series reached 50%, and given the high incidence of anoxic-ischemic injury, the EEG manifesta-tions of rhythmic sharp waves, slow spike-wave complexes, or generalized periodic dis-charges may have simply reflected structural damage rather than a potentially treatable ictal phenomenon. (It remains very difficult even for the epileptologist to be certain in some cases.)

The most common triggers for nonconvulsive status epilepticus remain a drug effect (cefepime, cyclosporin, tacrolimus, and psychotropic medication) and much less com-monly a new metabolic abnormality such as a severe hyponatremia. The causes of coma are shown in Table 51-1.

TABLE 51-1 Causes of Coma in Nonconvulsive Status Epilepticus

• Toxin• Any structural cortical lesion• Encephalitis• Acute hyperglycemia• Coexisting anoxic-ischemic encephalopathy

494 / / ThE ComaToSE PaTiENT

(A)

(B)

FIGURE 51-1 Typical EEG of nonconvulsive status epilepticus: ongoing spike wave activity

(A) stops after IV lorazepam (B).

Comatose and Nonconvulsive Status Epilepticus / / 495


If the patient improves and the EEG improves, further treatment is warranted; if not, the nonconvulsive status epilepticus may not need to be aggressively treated and it may be an indicator of brain injury. Nonaggressive management is usually favored.4

The challenge has been to differentiate treatable comatose patients with nonconvul-sive status epilepticus from patients who have a an irreversible injury and generalized epileptiform discharges. Nonconvulsive status epilepticus after cardiopulmonary resus-citation often is associated with a poor outcome. Nonconvulsive status in herpes simplex encephalitis may have a good outcome if adequately treated.

A CONCLUDING NOTE

Any patient with fluctuating responsiveness and muscle twitching may need an EEG to demonstrate a nonconvulsive status epilepticus followed by intravenous lorazepam challenge.

REFERENCES

1. Agathonikou A, Panayiotopoulos CP, Giannakodimos S, Koutroumanidis M. Typical absence status in adults: diagnostic and syndromic considerations. Epilepsia 1998;39:1265–1276.

2. Bauer G, Trinka E. Nonconvulsive status epilepticus and coma. Epilepsia 2010;51:177–190.3. de Assis TM, Costa G, Bacellar A, Orsini M, Nascimento OJ. Status epilepticus in the elderly: epidemiol-

ogy, clinical aspects and treatment. Neurol Int 2012;4:e17.4. Ferguson M, Bianchi MT, Sutter R, et al. Calculating the risk benefit equation for aggressive treatment of

non-convulsive status epilepticus. Neurocrit Care 2013;18:216–227.5. Sutter R, Kaplan PW. Electroencephalographic criteria for nonconvulsive status epilepticus: synopsis and

comprehensive survey. Epilepsia 2012;53 Suppl 3:1–51.6. Towne AR, Waterhouse EJ, Boggs JG, et al. Prevalence of nonconvulsive status epilepticus in comatose

patients. Neurology 2000;54:340–345.

496

A CONVERSATION

AN EXPLANATION

Delayed awakening after a surgical procedure has been loosely defined as a failure of the patient to respond to specific questions one hour after the end of anesthesia. Delayed awakening from anesthesia is well known to anesthesiologists but highly uncommon.3 A large study of 17,000 patients using common anesthetic agents (e.g., enflurane, halo-thane, isoflurane, and fentanyl) found 6% of patients not recovering at one hour and 3% of patients not recovering at 90 minutes.2,3

Comatose in the Recovery Room/ / / 52 / / /

Comatose in the Recovery Room / / 497

In our patient, a patent foramen ovale was found and could have contributed to fat embolization to the brain. A large fat globule must have lodged in the artery of Percheron that interrupted the cerebral blood flow to both thalamic structures (Fig. 52-1).8 A more proximal lesion in the basilar artery or on top of the basilar artery would have produced an intrinsic brainstem syndrome (Chapter 3).

The causes of coma in the recovery room are shown in Table 52-1. Prolonged effect of anesthetic drugs is mostly due to an excessive dose or delayed clearance.2,6,8,13,14 Reduced clearance of anesthetic agents and delayed emergence of the patient may occur with hypothermia. Moreover, hypovolemia is known to alter drug distribution due to reduced cardiac output. More surprisingly, a new structural lesion such as an intracerebral hema-toma or a massive ischemic stroke may present after what seems to be an uncomplicated

FIGURE 52-1 Failure to awaken after surgery: MRI shows bithalamic lesions. CT scan a day later

confirmed the abnormalities.


surgery.10 Fat or air embolism is exceedingly rare. Finally, a brain tumor may unveil itself for the first time after surgery, but these are very uncommon and unexpected complica-tions of general surgery.4,12

Most recently, delayed emergence occurred after injection of a large bupivacaine bolus into the surgical incision site,9 and a similar mechanism in a retrobulbar block with bupi-vacaine or lidocaine during cataract surgery resulted in “brainstem anesthesia.”5,11 The mechanism in these cases was most likely tracking of the anesthetic agent to the respira-tory centers of the brainstem, causing apnea and loss of consciousness. Finally, failure to emerge from anesthesia has been described in patients with a dissociative disorder and often after cosmetic surgery1 (Chapter 112).


Treatment is predicated on finding the cause of failure to awaken after surgery. In patients with localized neurologic findings, CT scan followed by MRI or MRA is useful, but the therapeutic options may be limited. Recent surgery precludes thrombolytic agents; only clot retrieval can be considered, and then only in patients who had a short anesthesia time (less than 8 hours). Residual paralysis due to neuromuscular function blockers must be treated with atropine, glycopyrrolate, or naloxone. Physostigmine may fully reverse fail-ure to awaken due to scopolamine.7 Flumazenil is indicated to reverse benzodiazepines.

A CONCLUDING NOTE

Delayed emergence from anesthesia could be due to prolonged effects of anesthetic drugs under certain circumstances or less likely due to a structural lesion of the brain. Lesions in both thalami can result in fluctuating responsiveness, and this is difficult to distinguish from fluctuating responsiveness in a patient emerging from anesthesia. CT scan may

TABLE 52-1 Causes of Coma in The Recovery Room

• Excessive anesthesia or preoperative self-medication• Occult intracranial mass lesion with swelling• Stroke in the posterior circulation territories (thalami or pons)• Massive air or fat embolization• Marked hypothermia (<28°C)• Acute hyponatremia or hypoglycemia• Psychogenic unresponsiveness

Comatose in the Recovery Room / / 499

surprisingly show an acute intracerebral hematoma, ischemic stroke, or hemorrhage or swelling in a previously undiscovered glioma.

REFERENCES

1. Albrecht RF, 2nd, Wagner SRt, Leicht CH, Lanier WL. Factitious disorder as a cause of failure to awaken after general anesthesia. Anesthesiology 1995;83:201–204.

2. Bruder N, Ravussin P. Recovery from anesthesia and postoperative extubation of neurosurgical patients: a review. J Neurosurg Anesthesiol 1999;11:282–293.

3. Forrest JB, Cahalan MK, Rehder K, et al. Multicenter study of general anesthesia. II. Results. Anesthesiology 1990;72:262–268.

4. Gercek A, Konya D, Babayev R, Ozgen S. Delayed recovery from general anesthesia from intracranial tumor. Anesth Analg 2007;104:235–236.

5. Gunja N, Varshney K. Brainstem anaesthesia after retrobulbar block: a rare cause of coma presenting to the emergency department. Emerg Med Australas 2006;18:83–85.

6. Haugen FP. The failure to regain consciousness after general anesthesia. Anesthesiology 1961;22:657–666.7. Holzgrafe RE, Vondrell JJ, Mintz SM. Reversal of postoperative reactions to scopolamine with physostig-

mine. Anesth Analg 1973;52:921–925.8. Kostanian V, Cramer SC. Artery of Percheron thrombolysis. AJNR Am J Neuroradiol 2007;28:870–871.9. Munis JR, Marcukaitis AW, Sprung J. Delayed emergence from anesthesia associated with absent brain-

stem reflexes following suboccipital craniotomy. Neurocrit Care 2006;5:206–209.10. Nakazawa K, Yamamoto M, Murai K, et al. Delayed emergence from anesthesia resulting from cerebellar

hemorrhage during cervical spine surgery. Anesth Analg 2005;100:1470–1471.11. Nicoll JM, Acharya PA, Ahlen K, Baguneid S, Edge KR. Central nervous system complications after

6000 retrobulbar blocks. Anesth Analg 1987;66:1298–1302.12. Phan TG, Wijdicks EFM. Meningioma revealed after general anaesthesia. Anaesthesia

1999;54:1123–1125.13. Sinclair RCF, Faleiro RJ. Delayed recovery of consciousness after anaesthesia. Continuing Education in

Anaesthesia, Critical Care & Pain 2006;6:114–118.14. Toker P. Hyperosmolar hyperglycemic nonketotic coma, a cause of delayed recovery from anesthesia.

Anesthesiology 1974;41:284–285.

500

A CONVERSATION

AN EXPLANATION

Surgeons expect an easily distressed and confused patient after a major surgical procedure such as heart, heart-lung, or liver transplantation. More concerning are wildly agitated patients and patients with persistently impaired consciousness due to acute metabolic derangements, drug toxicity, or an acute structural brain injury. In clinical practice, neu-rotoxicity from immunosuppressive drugs should remain the first diagnostic consider-ation in a deteriorated transplant recipient.

Coma after organ Transplantation

/ / / 53 / / /

Coma after organ Transplantation / / 501

The clinical features of calcineurin inhibitor neurotoxicity are now very recognizable.14 Many patients start with a fine tremor followed by visual hallucinations that may become kaleidoscopic configurations. This may further evolve into abnormal language or speech output, and the clinical picture can be punctuated by a single generalized tonic-clonic seizure. Severe neurotoxicity rarely, if at all, occurs with other immunosuppressant drugs such as sirolimus and mycophenolate mofetil and could be explained by a different cell target of the drug (Fig. 53-1).8 A recent study on sirolimus neurotoxicity found none in liver and kidney transplant patients. Mycophenolate mofetil has been recently exam-ined for side effects in 191 patients after liver transplantation and was found to be safe.11 Both sirolimus and mycophenolate mofetil can therefore be used as a replacement drug in patients with neurotoxicity.11

There is a predisposition to neurotoxicity after bone marrow transplantation. With the frequent use of antineoplastic agents such as busulfan, methotrexate, and

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O

O

O

NN

HO

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HO

HO

CH3OCH3O OCH2

OCH2

OCH2

CH3O

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Calcineurin

Lymphocyte activation

Activation of S6K1Phosphorylation of PHAS-1

IL-2

NF-AT

FKBP 12 FKBP 12

T S

mTOR

Tacrolimus Sirolimus

FIGURE 53-1 Mechanisms of toxicity. The action is through calcineurin in tacrolimus, but siro-

limus operates through a different mechanism. Adapted from Maramattom and Wijdicks8 with

permission of Neurology.


cisplatin, the risk of neurotoxicity in bone marrow transplantation increases with lengthier conditioning regimens and allogeneic transplantation.1,3,9,13 In general, a high incidence of neurotoxicity was found when cyclosporine and total body irradia-tion was instituted for four days. Possibly, radiation therapy may cause endothelial injury, which may be further enhanced by cyclosporin or tacrolimus.10 This will even-tually result in breaching of the blood–brain barrier, setting into motion a cascade that may result in apoptosis. Other tentative mechanisms are cerebral vasospasm, which could potentially lead to anoxic-ischemic injury in susceptible watershed areas. However, the injury associated with neurotoxicity involves mostly vasogenic brain edema and not infarction.

The causes of coma after organ transplantation are shown in Table 53-1. Neurotoxicity associated with immunosuppressive (calcineurin inhibitors) drugs is common and remains an important cause of altered consciousness.2,7,10 Alternative causes for coma after transplantation are intracerebral hematoma, hemolytic-uremic syndrome in bone marrow transplantation, encephalopathy associated with acute rejection after orthotopic liver or kidney transplantation, and more generally the accumulation of anesthetic and sedative drugs. Structural causes are less likely, but there are circumstances that may lead to intraoperative or perioperative hypotension. Patients undergoing heart transplanta-tion may have been resuscitated after an intraoperative asystole or ventricular fibrillation, but the postoperative care of the heart transplant recipient may also be complicated by hypovolemia or hypotension. After lung transplantation, patients could develop marked oxygenation difficulties, and these may be a result of pulmonary hemorrhage, infection, or pulmonary edema from reperfusion injury to the pulmonary graft. This profound hypoxemia may cause shock and lead to a combination of anoxic-ischemic brain injury. Infectious causes of coma—except for a systemic overwhelming infection and sepsis—are uncommon within the first month of transplantation.

MRI has demonstrated a spectrum of abnormalities associated with calcineurin inhibitor neurotoxicity and is identical to PRES radiographically.12 (Fig. 53-2). High sig-nal intensity on FLAIR is present in subcortical white matter preferentially but is not lim-ited to occipital regions. Symmetry of the lesions is common, enhancement is absent, and gray matter can be involved.5 There is sufficient evidence that the abnormalities represent

TABLE 53-1 Causes of Coma after organ Transplantation

• Calcineurin inhibitor neurotoxicity (any transplantation)• Intracerebral hematoma (liver transplantation)• Ischemic strokes (heart transplantation)• Acute rejection encephalopathy (kidney or liver transplantation)

Coma after organ Transplantation / / 503

vasogenic (and not cytotoxic) edema, and this points toward a drug-induced endothelial injury. Profound abnormalities on MRI are potentially reversible.


Evaluation of impaired consciousness in a transplant patient is complex, but the fol-lowing scrutiny is advised. The records should be evaluated for the presence of sedative drugs, and the time remaining to clearance should be estimated. If appropriate, fluma-zenil or naloxone can be administered. Serum levels of cyclosporine or tacrolimus can be measured and persistent upward trends might be helpful. However, this is useful only if neurotoxicity is seen beyond the first week of intravenous loading because, dur-ing this period, an increase in serum levels is anticipated. Laboratory values should be

FIGURE 53-2 MRI characteristics (FLAIR) of tacrolimus neurotoxicity. Note the multifocal areas

of edema.


obtained that should include at a minimum electrolyte panel, liver and renal function, and arterial blood gas. When the MRI findings are consistent with neurotoxicity, replace-ment of cyclosporine or tacrolimus with sirolimus or mycophenolate mofetil should be the first line of action, even in patients with normal plasma levels.4,6 The outcome of immunosuppression-associated neurotoxicity is generally good.

A CONCLUDING NOTE

After organ transplantation, drug-induced neurotoxicity remains a common cause of impaired consciousness in the early hospital course. It has been decreasing in frequency due to better monitoring of immunosuppressive drugs and familiarity of attending sur-geons with the neurologic manifestations. However, severe neurotoxicity after transplan-tation has not disappeared and should be considered first as a potential cause for coma.

REFERENCES

1. Bartynski WS, Zeigler ZR, Shadduck RK, Lister J. Pretransplantation conditioning influence on the occurrence of cyclosporine or FK-506 neurotoxicity in allogeneic bone marrow transplantation. AJNR Am J Neuroradiol 2004;25:261–269.

2. Bechstein WO. Neurotoxicity of calcineurin inhibitors: impact and clinical management. Transpl Int 2000;13:313–326.

3. Denier C, Bourhis JH, Lacroix C, et al. Spectrum and prognosis of neurologic complications after hema-topoietic transplantation. Neurology 2006;67:1990–1997.

4. Di Benedetto F, Di Sandro S, De Ruvo N, et al. Sirolimus monotherapy in liver transplantation. Transplant Proc 2007;39:1930–1932.

5. Jansen O, Krieger D, Krieger S, Sartor K. Cortical hyperintensity on proton density-weighted images: An MR sign of cyclosporine-related encephalopathy. AJNR Am J Neuroradiol 1996;17:337–344.

6. Junna MR, Rabinstein AA. Tacrolimus-induced leukoencephalopathy presenting with status epilepticus and prolonged coma. J Neurol Neurosurg Psychiatry 2007;78:1410–1411.

7. Lloveras JJ, Larrue V, Suc E, Fourtanier G, Durand D. Leukoencephalopathy after cyclosporine in a liver transplant. Clinical Transplantation 1990;4:58–62.

8. Maramattom BV, Wijdicks EFM. Sirolimus may not cause neurotoxicity in kidney and liver transplant recipients. Neurology 2004;63:1958–1959.

9. Pfitzmann R, Klupp J, Langrehr JM, et al. Mycophenolate mofetil for immunosuppression after liver transplantation: a follow-up study of 191 patients. Transplantation 2003;76:130–136.

10. Reece DE, Frei-Lahr DA, Shepherd JD, et al. Neurologic complications in allogeneic bone marrow trans-plant patients receiving cyclosporin. Bone Marrow Transplant 1991;8:393–401.

11. Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of mycophenolate in solid organ transplant recipients. Clin Pharmacokinet 2007;46:13–58.

12. Wu Q, Marescaux C, Wolff V, et al. Tacrolimus-associated posterior reversible encephalopathy syndrome after solid organ transplantation. Eur Neurol 2010:64:169–177.

13. Zimmer WE, Hourihane JM, Wang HZ, Schriber JR. The effect of human leukocyte antigen disparity on cyclosporine neurotoxicity after allogeneic bone marrow transplantation. AJNR Am J Neuroradiol 1998;19:601-608; discussion 609–610.

14. Zoja C, Furci L, Ghilardi F, et al. Cyclosporin-induced endothelial cell injury. Lab Invest 1986;55:455–462.

505

A CONVERSATION

AN EXPLANATION

What initially has the appearance of a delay in awakening after surgery may unfold as per-sistent coma. Often the prolonged effect of anesthetic agents can be held responsible—the doses of opioids during these types of surgery are substantial—for the decreased level of consciousness. Coma is uncommon after a successful major surgical procedure but is also one of the most devastating complications.1,5 In our comprehensive study, spanning six years, we found only 35 patients with postoperative coma. These patients were part

Comatose after Coronary artery Bypass Surgery

/ / / 54 / / /


of more than 275,000 surgeries under general anesthesia, many which were cardiac sur-gery.5 Cardiac surgery predisposes a patient to postoperative complications when there has been hemodynamic instability (e.g., cardiac arrhythmia with subsequent insufficient cardiac output or inability to maintain blood pressure) or failure to oxygenate the patient adequately.

The causes of coma after cardiac surgery are shown in Table 54-1. Perioperative seda-tion (fentanyl, propofol, and midazolam) may play a major role in prolonged postopera-tive awakening. Moreover, cardiopulmonary resuscitation during surgery (<1%) may cause diffuse anoxic-ischemic injury in addition to the particulate matter embolized dur-ing the cardiopulmonary bypass procedure. With clamping of an atherosclerotic ascend-ing aorta, emboli to large branches are expected and most involve infarcts in watershed areas and white matter.9 Repetitive periodic decreases in blood pressure are poorly toler-ated and possibly more consequential than a persistent decrease in blood pressure. This could be explained by the ability of the cerebral vessels to autoregulate, but not when repetitively challenged with marked hypotension. This failure to compensate could be particularly relevant in a patient with prior hypertension and a cerebral autoregulation curve (blood pressure vs. cerebral blood flow) shifted to the right.5 Still, despite this blood pressure challenge, the majority of patients awaken fine after cardiac surgery.

An embolus to a single large cerebral artery may occur. Brain swelling may occur in patients with a proximal middle cerebral artery occlusion and may become recognized only after the sudden appearance of a fixed wide pupil or midsize fixed pupils in a heav-ily sedated patient. Embolus to the basilar artery is a major complication: it may present with a postoperative locked-in syndrome, but more often causes coma.5 Cerebellar infarct may not be recognized and results in impaired consciousness only after hydrocephalus.3 The risk of ischemic stroke is substantially higher when cardiac surgery is combined with carotid endarterectomy (5.4°% vs. 1.30%).4 Hyperglycemia is a common complication after cardiopulmonary bypass and monitoring of intraoperative glucose is advised.8 This may be due to a combination of surgical stress and administration of glucogenic cathechol-amines.8 Unfortunately, attempts to control hyperglycemia did not improve outcome, but increased the risk for severe hypoglycemia.2 Open-heart surgery may predispose patients

TABLE 54-1 Causes of Coma after Cardiac Surgery

• Multiple vascular territorial infarcts• Diffuse cortical laminar necrosis (intraoperative cardiac arrest and resuscitation)• Embolus to basilar artery• Air emboli (rare)• Hypoglycemia (insulin treatment)

Comatose after Coronary artery Bypass Surgery / / 507

to air emboli, but it is a very uncommon complication. Patients with a patent foramen ovale or pulmonary arteriovenous malformation may be at risk. CT scan in postoperative patients may show (hypodense) arteries filled with air.

In evaluating patients with postoperative coma, structural abnormalities should be actively sought. MRI should be considered despite initial reassurance from a normal CT scan. In comatose patients, cerebral infarction is often apparent in multiple vascular ter-ritories (Figs. 54-1 and 54-2).9,10

FIGURE 54-1 CT scan in a comatose patient following cardiac surgery (mitral valve replacement)

showing multiple territorial infarcts involving watershed areas, consistent with embolization.

FIGURE 54-2 MRI in a patient with prolonged unconsciousness after cardiac surgery showing

ischemic injury after cardiopulmonary bypass. Note that the watershed areas (right anterior cere-

bral artery-middle cerebral artery (ACA-MCA) and middle cerebral artery-posterior cerebral artery

(MCA-PCA) are preferentially involved. Most likely, the MRI underestimates the ischemic injury.



Options for treatment are limited. Thrombolytic agents are contraindicated. Because high doses of fentanyl are commonly used in cardiac surgery and they may confound neurologic examination, a naloxone challenge is needed before a final assessment of a possible neurologic injury. If an ischemic stroke is likely, an emergency cerebral angio-gram is an option, followed by mechanical clot retrieval, but it is likely that there is already irreversible substantial damage. Due to its considerable morbidity, aggressive endovas-cular intervention remains a feasible option in acute basilar artery occlusion. Persistent coma, days to weeks after cardiopulmonary surgery, is a poor sign.7 One study found that patients with multiple watershed infarcts on MRI or CT were 17 times more likely to die and 12 times more likely to be discharged to a nursing home.6

A CONCLUDING NOTE

Perioperative sedation (e.g. fentanyl, propofol, and midazolam) plays a major role in pro-longed postoperative awakening, but failure to awaken after cardiac surgery within one to two days could indicate bihemispheric cerebral infarcts.

REFERENCES

1. Bendszus M, Reents W, Franke D, et al. Brain damage after coronary artery bypass grafting. Arch Neurol 2002;59:1090–1095.

2. Butterworth J, Wagenknecht LE, Legault C, et al. Attempted control of hyperglycemia during cardiopul-monary bypass fails to improve neurologic or neurobehavioral outcomes in patients without diabetes mellitus undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg 2005;130:1319.

3. Chamberlain MH, Ratnatunga C. Fluctuating consciousness caused by hydrocephalus: a complication of aortic valve replacement. J Thorac Cardiovasc Surg 2002;123:566–567.

4. Dubinsky RM, Lai SM. Mortality from combined carotid endarterectomy and coronary artery bypass surgery in the US. Neurology 2007;68:195–197.

5. Gootjes EC, Wijdicks EFM, McClelland RL. Postoperative stupor and coma. Mayo Clin Proc 2005;80:350–354.

6. Gottesman RF, Sherman PM, Grega MA, et al. Watershed strokes after cardiac surgery: diagnosis, etiol-ogy, and outcome. Stroke 2006;37:2306–2311.

7. Rodriguez RA, Nair S, Bussière M, Nathan HJ. Long-lasting functional disabilities in patients who recover from coma after cardiac operations. Ann Thorac Surg. 2013;95:884–890.

8. Restrepo L, Wityk RJ, Grega MA, et al. Diffusion- and perfusion-weighted magnetic resonance imaging of the brain before and after coronary artery bypass grafting surgery. Stroke 2002;33:2909–2915.

9. Vaage J, Jensen U, Ericsson A. Neurologic injury in cardiac surgery: aortic atherosclerosis emerges as the single most important risk factor. Scand Cardiovasc J 2000;34:550–557.

10. Wityk RJ, Restrepo L. Cardiac surgery and magnetic resonance imaging of the brain. Arch Neurol 2002;59:1074–1076.

509

A CONVERSATION

AN EXPLANATION

Extracorporeal membrane oxygenation (ECMO) provides support for a patient with severe cardiopulmonary collapse. The procedure is usually applied in patients who have undergone complicated cardiac surgery that is followed by cardiogenic shock. ECMO is also applied after a cardiopulmonary arrest with prolonged resuscitation. It may be used as a bridge for heart and lung transplantation, and most recently has been used in patients with marked respiratory distress during the H1N1 influenza outbreak.2–6 In children,

Comatose on ECmo/ / / 55 / / /


ECMO is typically used to support cardiopulmonary function in patients who fail to respond to conventional resuscitation protocols.1

Coma is explained by multiple structural CNS lesions, and they are typically severe. Our recent study of 87 adults found that three out of four patients who have been on ECMO for more than 12 hours had a neurologic event, with less than one-third surviving to discharge.7 The neurologic diagnosis, in our experience, included brain death in three cases and, in others, subarachnoid hemorrhage, intraventricular hemorrhage, bihemi-spheric ischemic infarcts, and frontal lobe ischemic infarcts in addition to subarach-noid hemorrhage and marked diffuse cerebral edema (Figs. 55-1 and 55-2).7 Survival following ECMO can happen, but it is likely that the neurologic sequelae—at least in

FIGURE 55-1 Example of injury after ECMO, with neuropathologic findings of major ischemic and

hemorrhagic changes.

Comatose on ECmo / / 511

adults—are underestimated. It remains unknown whether the neurologic sequelae are a result of ECMO treatment or of a more severe manifestation of the primary illness that led to ECMO placement.

Other triggers for CNS injuries may include hypoxemia, hyperglycemia, metabolic acidosis, and other electrolyte abnormalities.8 In contrast, a study of ECMO use for acute respiratory distress syndrome recently found that the vast majority of patients survived to discharge.3 Neurologic injury after pediatric cardiopulmonary resuscitation is also quite common, and one study found 22% evidence of acute neurologic injury.1 The presence of metabolic acidosis before the ECMO deployment was a major risk factor for acute neurologic injury in children.1 A recent study found—mostly asymptomatic—cerebral microbleeds in children treated with ECMO, and these microbleeds were in the same carotid arterial territory that the venoarterial bypass was placed.6

FIGURE 55-2 CT scans of comatose patients on ECMO.


Neurologic injury in patients with ECMO may be due to emboli, gaseous emboli, or other particulate matter. The causes of coma in patients supported by ECMO are shown in Table 55-1.


ECMO has salvaged many patients, but neurologic injury is highly probable, mostly as a result of prolonged resuscitation.9,10 Nonetheless, we found cases of intracranial hemor-rhage and diffuse cerebral edema that may be related to the procedure itself. Assessment of patients in ECMO requires a CT scan or MRI to carefully address the injury, which may help in prognostication. Whether a cognitive injury remains in survivors is not exactly known.

In most severe cases, all brainstem reflexes disappear; we have seen some patients who appeared to have lost all their brainstem reflexes as a result of severe anoxic-ischemic injury. A brain death examination is possible following the standard criteria and assess-ments, but challenges remain, and this usually involves performing a reliable apnea test. Gradually increasing CO2 levels in the system has been proposed and has been successful in some reported cases. Alternative tests for absent cerebral blood flow may be only be an option if brain death determination is needed, but many of these patients can still donate organs through a DCD protocol. Parenthetically, ECMO has also been used in patients who are markedly unstable following brain death examination.

A CONCLUDING NOTE

A select group of comatose patients are “salvaged” on ECMO, but neurologic injury is substantial. There is a small proportion of surviving adults.

REFERENCES

1. Barrett CS, Bratton SL, Salvin JW, et al. Neurological injury after extracorporeal membrane oxygenation use to aid pediatric cardiopulmonary resuscitation. Pediatr Crit Care Med 2009;10:445–451.

2. Chen YS, Chao A, Yu HY, et al. Analysis and results of prolonged resuscitation in cardiac arrest patients rescued by extracorporeal membrane oxygenation. J Am Coll Cardiol 2003;41:197–203.

TABLE 55-1 Causes of Coma in Patients on ECmo

• Multiple watershed infarctions• Subarachnoid hemorrhage• Diffuse anoxic brain edema• Bilateral thalamic infarctions

Comatose on ECmo / / 513

3. Davies A, Jones D, Bailey M, et al. Extracorporeal membrane oxygenation for 2009 influenza A(H1N1) acute respiratory distress syndrome. JAMA 2009;302:1888–1895.

4. Liebeskind DS, Sanossian N, Sapo ML, Saver JL. Cerebral microbleeds after use of extracorporeal mem-brane oxygenation in children. J Neuroimaging 2013;23:75–78.

5. Maggio P, Hemmila M, Haft J, Bartlett R. Extracorporeal life support for massive pulmonary embolism. J Trauma 2007;62:570–576.

6. Marasco SF, Lukas G, McDonald M, McMillan J, Ihle B. Review of ECMO (extracorporeal membrane oxygenation) support in critically ill adult patients. Heart Lung Circ 2008;17 Suppl 4:S41–47.

7. Mateen FJ, Muralidharan R, Shinohara RT, et al. Neurological injury in adults treated with extracorpo-real membrane oxygenation. Arch Neurol 2011;68:1543–1549.

8. Schwarz B, Mair P, Margreiter J, et al. Experience with percutaneous venoarterial cardiopulmonary bypass for emergency circulatory support. Crit Care Med 2003;31:758–764.

9. Thiagarajan RR, Brogan TV, Scheurer MA, et al. Extracorporeal membrane oxygenation to support car-diopulmonary resuscitation in adults. Ann Thorac Surg 2009;87:778–785.

10. Thiagarajan RR, Laussen PC, Rycus PT, Bartlett RH, Bratton SL. Extracorporeal membrane oxygenation to aid cardiopulmonary resuscitation in infants and children. Circulation 2007;116:1693–1700.

514

A CONVERSATION

AN EXPLANATION

Brain biopsy and microscopic examination may be used to determine the pathology of a mass and, if malignant, to grade its severity. Brain biopsy also has been used as a last resort to obtain abnormal brain tissue that could explain a relentless neurologic condi-tion leading to impaired consciousness. The diagnostic yield of a brain biopsy under these circumstances is low, but in one study of 171 patients with indeterminate MR abnor-malities (excluding HIV or brain tumors), 20% had a central nervous system (CNS)

Comatose after Brain Biopsy and Craniotomy

/ / / 56 / / /

Comatose after Brain Biopsy and Craniotomy / / 515

lymphoma, 15% had Creutzfeldt-Jakob disease, 14% had viral encephalitis, and 9% had CNS vasculitis.3

Brain biopsy includes targeting techniques, mostly with stereotactic frames, but fra-meless image-guided stereotaxy has been used with a diagnostic yield of about 90%, per-manent morbidity of 6%, and mortality of 1%.1,2,5,7 A recent study of 270 image-guided stereotactic biopsy procedures found that both frameless and frame-based stereotactic biopsy procedures had an almost identical incidence of symptomatic hemorrhage at the biopsy site (3% to 4%).12 The number of stereotactic needle biopsy passes or biopsy of deep-seated lesions could increase biopsy-related morbidity, but this has not been proven in recent studies. It has been suggested that hemosiderin deposition on a prior MRI may increase the risk of postbiopsy hemorrhage.6,9

The causes of coma after brain biopsy or craniotomy are shown in Table 56-1. In many instances, hemorrhages are at the biopsy site and asymptomatic.12 Most tumor hemor-rhages may remain within the tumor mass (Fig. 56-1). In one study, hemorrhage at the biopsy site was found more often after an interval, and these patients had a better out-come than patients who had an acute postbiopsy hemorrhage.12 An alternative expla-nation for postbiopsy coma is worsening edema in a glioblastoma5 or complex partial status epilepticus. Biopsy in a highly vascularized tumor (e.g., pinealoma) may lead to acute breakthrough into the ventricles (Fig. 56-2) and postoperative coma from acute hydrocephalus.

Craniotomy for more elective procedures (metastasis, abscess, glioma bulk removal) results in brief postoperative drowsiness, and the vast majority of patients improve within 24 to 48 hours. Some patients may remain intubated, ventilated, or sedated for agitation. Surgery within the temporal lobe may result in edema with hemorrhagic areas that may cause mass effect and lead to brainstem shift. Major com-plications of craniotomy for nonvascular procedures are uncommon but include the development of a remote (in a different compartment) hemorrhage and are probably due to mechanical shift. Venous obstruction and hemorrhagic infarction have been proposed as a mechanism in cerebellar hematoma.11 However, these hemorrhages rarely cause mass effect.

TABLE 56-1 Causes of Coma after Brain Biopsy and Craniotomy

• Intraventricular hemorrhage (pinealoma)• Lobar hematoma in tumor with mass effect (lymphoma or glioma)• Hypernatremia (pituitary tumors)• Cerebral venous occlusion and hemorrhagic infarct (meningioma)


Craniotomy to remove a meningioma can be complicated, sacrificing an important cerebral venous branch and causing postoperative edema. Postoperative deteriora-tion can be reduced with reconstruction of the venous system invaded by the tumor.10 Neuroendoscopic surgery is a safe procedure; however, intraventricular hemorrhage and diabetes insipidus with hypernatremia have been reported in patients undergoing this procedure for pituitary surgery.4,8


Management of a biopsy-associated hemorrhage may include evacuation or placement of a ventriculostomy. When there is a hemorrhage in a tumor, dexamethasone 4 mg every

FIGURE 56-1 Prebiopsy MRI shows brain tumor. Postbiopsy CT shows large intracranial hemor-

rhage with mass effect. Cytology confirmed the presence of lymphoma.

Comatose after Brain Biopsy and Craniotomy / / 517

six hours can be considered to reduce edema and could be followed by further debulking of the tumor, depending on clinical deterioration. The severity of intratumoral hemor-rhage and intraventricular hemorrhage determines outcome, but mortality has been less than 1% and is highly uncommon in most biopsy series.

A CONCLUDING NOTE

Complications with brain biopsy are uncommon. Due to high vascularization, biopsy in CNS lymphoma or pinealoma is associated with an increased risk of intracranial hematoma. Craniotomy can be associated with postoperative edema and shift that may cause transiently impaired consciousness. A rapid course leading to progressive loss of

FIGURE 56-2 Intraventricular hemorrhage after biopsy (CT scan) for pineal gland tumor (MRI).


consciousness may be caused by injury to cerebral veins, particularly after meningioma surgery.

REFERENCES

1. Amin DV, Lozanne K, Parry PV, et al. Image-guided frameless stereotactic needle biopsy in awake patients without the use of rigid head fixation. J Neurosurg 2011;114:1414–1420.

2. Ferreira MP, Ferreira NP, Pereira Filho Ade A, Pereira Filho Gde A, Franciscatto AC. Stereotactic com-puted tomography-guided brain biopsy: diagnostic yield based on a series of 170 patients. Surg Neurol 2006;65 Suppl 1:S1:27–21:32.

3. Josephson SA, Papanastassiou AM, Berger MS, et al. The diagnostic utility of brain biopsy procedures in patients with rapidly deteriorating neurological conditions or dementia. J Neurosurg 2007;106:72–75.

4. Kelley RT, Smith JL, 2nd, Rodzewicz GM. Transnasal endoscopic surgery of the pituitary: modifications and results over 10 years. Laryngoscope 2006;116:1573–1576.

5. Kim JE, Kim DG, Paek SH, Jung HW. Stereotactic biopsy for intracranial lesions: reliability and its impact on the planning of treatment. Acta Neurochir (Wien) 2003;145:547–554; discussion 554–545.

6. Kongkham PN, Knifed E, Tamber MS, Bernstein M. Complications in 622 cases of frame-based stereo-tactic biopsy, a decreasing procedure. Can J Neurol Sci 2008;35:79–84.

7. Kreth FW, Muacevic A, Medele R, et al. The risk of haemorrhage after image guided stereotactic biopsy of intra-axial brain tumours—a prospective study. Acta Neurochir (Wien) 2001;143:539–545; discus-sion 545–536.

8. Peretta P, Ragazzi P, Galarza M, et al. Complications and pitfalls of neuroendoscopic surgery in children. J Neurosurg 2006;105:187–193.

9. Phan TG, O'Neill BP, Kurtin PJ. Posttransplant primary CNS lymphoma. Neuro Oncol 2000;2:229–238.10. Sindou MP, Alvernia JE. Results of attempted radical tumor removal and venous repair in 100 consecu-

tive meningiomas involving the major dural sinuses. J Neurosurg 2006;105:514–525.11. Tondon A, Mahapatra AK. Superatentorial intracerebral hemorrhage following infratentorial surgery.

J Clin Neurosci 2004;11:762–765.12. Woodworth GF, McGirt MJ, Samdani A, et al. Frameless image-guided stereotactic brain biopsy proce-

dure: diagnostic yield, surgical morbidity, and comparison with the frame-based technique. J Neurosurg 2006;104:233–237.

519

A CONVERSATION

AN EXPLANATION

Temporal lobe epilepsy associated with mesial temporal sclerosis not responding to anti-epileptic drugs has been an accepted indication for temporal lobectomy after volumet-ric measurements of MRI detect mesial temporal sclerosis. Interictal diffusion-weighted imaging may assist in localization.16 There has been an expansion of indications for epi-lepsy surgery, which has resulted in seizure-free outcomes for many patients. Moreover, resection to treat refractory status epilepticus has been successful in selected cases.1

Comatose after Epilepsy Surgery

/ / / 57 / / /


Surgery has evolved into selective subtemporal amygdalohippocampectomy.6 Epilepsy surgery, strip, and grid electrode placement are usually without major complications.

The causes of coma after epilepsy surgery are shown in Table 57-1. Most frequently, postoperative seizures may lead to a prolonged postictal state or complex partial status epilepticus. Postoperative seizures are more common after extratemporal cortical resec-tions and have been reported in one of four patients.9 Subdural, epidural, or lobar hema-toma is uncommon but all have been recognized in series of patients with epilepsy surgery, with some requiring reoperation after temporal lobe resection (Fig. 57-1). Although the changed anatomical dimensions surrounding the incisure and brainstem after temporal lobectomy reduce the chance of direct brainstem compression, the lateral shift can be substantial. Remote hemorrhages (contralateral hemisphere or, more often, cerebellum) may occur and may be due to sagging of the cerebellar hemisphere—due to cerebro-spinal fluid hypovolemia— damaging superior bridging veins.4 Following surgery, some temporal lobe swelling may occur and could produce dysnomia, which resolves within two weeks of surgery and is not associated with impairment of consciousness. Frank swelling in the operative bed and infarction due to damage to draining cerebral veins may occur. Postoperative seizures are similar in type to those before surgery, but generalized tonic-clonic seizures and, less common, status epilepticus have been observed. Most studies have recognized that early postoperative seizures bode poorly for later control of epilepsy.2,3,8–10,13,15 Complications associated with invasive electrode placement are very uncommon and, if present, are seldom serious or require reoperation.7,11,12,14 Most com-monly, small epidural or subdural fluid collections or hemorrhages are seen on postsurgi-cal CT scan.


Lobar hematoma with mass effect (compression of frontal horn and displacement of the septum pellucidum) requires evacuation. Management of postoperative seizures and nonconvulsive status epilepticus warrants video-EEG monitoring and titration with stan-dard antiepileptic drugs. Most patients would benefit from treatment with levetiracetam

TABLE 57-1 Causes of Coma after Epilepsy Surgery

• Lobar hematoma• Postoperative brain swelling• Subdural hematoma• Complex partial status epilepticus

Comatose after Epilepsy Surgery / / 521

FIGURE 57-1 Coronal MRI showing atrophy in the left temporal lobe, suggestive of mesial sclero-

sis. Postsurgical resection CT shows a frontal hematoma.


(up to 3,000 mg/d). Valproate is avoided owing to its potential for increased bleeding as a result of decreased factor XIII and thrombocytopenia.5

A CONCLUDING NOTE

If nonconvulsive status epilepticus is excluded, coma following epilepsy surgery can be the result of a major complication due to cerebral hematoma, subdural hematoma, or epidural hematoma originating from the surgical bed. Complications with grid electrode placement are uncommon.

REFERENCES

1. Alexopoulos A, Lachhwani DK, Gupta A, et al. Resective surgery to treat refractory status epilepticus in children with focal epileptogenesis. Neurology 2005;64:567–570.

2. Bate H, Eldridge P, Varma T, Wieshmann UC. The seizure outcome after amygdalohippocampectomy and temporal lobectomy. Eur J Neurol 2007;14:90–94.

3. Cohen-Gadol AA, Wilhelmi BG, Collignon F, et al. Long-term outcome of epilepsy surgery among 399 patients with nonlesional seizure foci including mesial temporal lobe sclerosis. J Neurosurg 2006;104:513–524.

4. Friedman JA, Piepgras DG, Duke DA, et al. Remote cerebellar hemorrhage after supratentorial surgery. Neurosurgery 2001;49:1327–1340.

5. Gerstner T, Teich M, Bell N, et al. Valproate-associated coagulopathies are frequent and variable in chil-dren. Epilepsia 2006;47:1136–1143.

6. Hori T, Yamane F, Ochiai T, et al. Selective subtemporal amygdalohippocampectomy for refractory tem-poral lobe epilepsy: operative and neuropsychological outcomes. J Neurosurg 2007;106:134–141.

7. Johnston JM, Jr., Mangano FT, Ojemann JG, et al. Complications of invasive subdural electrode moni-toring at St. Louis Children’s Hospital, 1994-2005. J Neurosurg 2006;105:343–347.

8. Jutila L, Immonen A, Mervaala E, et al. Long term outcome of temporal lobe epilepsy surgery: analyses of 140 consecutive patients. J Neurol Neurosurg Psychiatry 2002;73:486–494.

9. Mani J, Gupta A, Mascha E, et al. Postoperative seizures after extratemporal resections and hemispherec-tomy in pediatric epilepsy. Neurology 2006;66:1038–1043.

10. McIntosh AM, Kalnins RM, Mitchell LA, et al. Temporal lobectomy: long-term seizure outcome, late recurrence and risks for seizure recurrence. Brain 2004;127:2018–2030.

11. Onal C, Otsubo H, Araki T, et al. Complications of invasive subdural grid monitoring in children with epilepsy. J Neurosurg 2003;98:1017–1026.

12. Sansur CA, Frysinger RC, Pouratian N, et al. Incidence of symptomatic hemorrhage after stereotactic electrode placement. J Neurosurg 2007;107:998–1003.

13. Sindou M, Guenot M, Isnard J, et al. Temporo-mesial epilepsy surgery: outcome and complications in 100 consecutive adult patients. Acta Neurochir (Wien) 2006;148:39–45.

14. Sweet JA, Hdeib AM, Sloan A, Miller JP. Depths and grids in brain tumors: Implantation strategies, techniques, and complications. Epilepsia 2013;54 Suppl 9:66–71.

15. Voltzenlogel V, Despres O, Vignal JP, Kehrli P, Manning L. One-year postoperative autobiographi-cal memory following unilateral temporal lobectomy for control of intractable epilepsy. Epilepsia 2007;48:605–608.

16. Wehner T, Lapresto E, Tkach J, et al. The value of interictal diffusion-weighted imaging in lateralizing temporal lobe epilepsy. Neurology 2007;68:122–127.

523

A CONVERSATION

AN EXPLANATION

Complications of neurovascular procedures (cerebral angiography, stenting) are less com-monly of neurologic origin and more often involve local or systemic complications (e.g., acute renal failure from contrast exposure, groin hematoma, or retroperitoneal hematoma). Neurologic complications of cerebral angiography are more likely present in patients older than 55 years, patients with prior cardiovascular disease, and patients undergoing a cerebral angiogram for transient ischemic attacks. Complications often are related to the surgeon’s

Comatose after Cerebral angiography

/ / / 58 / / /


skill, with more complications occurring in trainees.2–5 A retrospective study at the Mayo Clinic found an incidence of neurologic complications of 2.6% in 19,826 patients under-going cerebral angiogram.3 However, in a prospective study, neurologic complications occurred in 1.5% of 2,899 procedures, and stroke occurred in very few patients (0.3%).9

In another recent study of 1,715 patients undergoing cerebral angiography, no stroke or permanent neurologic deficit was found, suggesting that skilled operators matter.8 The causes of coma after a diagnostic cerebral angiogram or MRI are shown in Table 58-1. Sudden onset of coma usually results from multiple ischemic strokes. There are several explanations for persistent coma after cerebral angiogram: inadvertent dislodging of an atheromatous clot, hypotension associated with large-volume blood loss in the retroperi-toneal space resulting in multiple watershed infarcts, or a large artery dissection. MRI and MRA are required to document the lesions. In this example, large territorial infarcts in bihemispheric regions caused coma, which was permanent (Fig. 58-1). Conversely, contrast toxicity rarely causes a considerable depression of consciousness but is more often preceded by delirium, acute cortical blindness, or seizures. A prolonged postictal state may explain coma in many cases.

Prior impaired renal function is usually the contributing factor in contrast toxicity causing profound encephalopathy. However, gadolinium encephalopathy with a marked decline in consciousness has been recently described and may be more common than originally thought.1,6 The mechanism is impaired renal function, which may substantially reduce clearance of gadolinium from two hours to 30 hours. MRI may show cerebrospi-nal fluid (CSF) hyperintensity due to diffusion of gadolinium into the CSF.1,6


Outcome is poor in comatose patients with multiple cerebral infarcts, some of which may be further complicated by cerebral edema. When seizures occur, intravenous loading with phosphenytoin is desirable. Contrast toxicity usually spontaneously resolves and long-term effects of contrast agent toxicity are unknown. Hemodialysis is warranted only in patients with presumed high contrast levels and is effective, resulting in more than 95% washout after three cycles of dialysis.7

TABLE 58-1 Causes of Coma after Cerebral angiography and mRi

• Multiple hemispheric strokes (cerebral angiogram)• Carotid or vertebral dissection (cerebral angiogram)• Seizures (cerebral angiogram)• Gadolinium neurotoxicity (MRI)

Comatose after Cerebral angiography / / 525

A CONCLUDING NOTE

Coma after cerebral angiography may be due to emboli from dissected artery or plaque dislodgement during catheter manipulation. Contrast toxicity mostly occurs in patients with prior renal failure, but it is rare as a cause of a profound encephalopathy. Dialysis may rapidly reduce gadolinium levels.

REFERENCES

1. Arlt S, Cepek L, Rustenbeck HH, Prange H, Reimers CD. Gadolinium encephalopathy due to accidental intrathecal administration of gadopentetate dimeglumine. J Neurol 2007;254:810–812.

2. Cloft HJ, Joseph GJ, Dion JE. Risk of cerebral angiography in patients with subarachnoid hemorrhage, cerebral aneurysm, and arteriovenous malformation: a meta-analysis. Stroke 1999;30:317–320.

FIGURE 58-1 MRI showing evolving bilateral cerebral infarcts after routine cerebral angiogram

(FLAIR and DWI).


3. Gradinscak DJ, Young N, Jones Y, O’Neil D, Sindhusake D. Risks of outpatient angiography and interven-tional procedures: a prospective study. AJR Am J Roentgenol 2004;183:377–381.

4. Johnston DC, Chapman KM, Goldstein LB. Low rate of complications of cerebral angiography in routine clinical practice. Neurology 2001;57:2012–2014.

5. Kaufmann TJ, Huston J, 3rd, Mandrekar JN, et al. Complications of diagnostic cerebral angiography: eval-uation of 19,826 consecutive patients. Radiology 2007;243:812–819.

6. Maramattom BV, Manno EM, Wijdicks EFM, Lindell EP. Gadolinium encephalopathy in a patient with renal failure. Neurology 2005;64:1276–1278.

7. Rodby RA. Preventing complications of radiographic contrast media: is there a role for dialysis? Semin Dial 2007;20:19–23.

8. Thiex R, Norbash AM, Frerichs KU. The safety of dedicated-team catheter-based diagnostic cerebral angi-ography in the era of advanced noninvasive imaging. AJNR Am J Neuroradiol 2010;31:230–234.

9. Willinsky RA, Taylor SM, TerBrugge K, et al. Neurologic complications of cerebral angiography: prospec-tive analysis of 2,899 procedures and review of the literature. Radiology 2003;227:522–528.

527

A CONVERSATION

AN EXPLANATION

Good-grade patients (World Federation of Neurosurgical Societies [WFNS] grade I and II) are expected to be lucid within 24 to 36 hours after an uncomplicated surgery for repair of a ruptured cerebral aneurysm. Patients with poor-grade subarachnoid hemor-rhage (WFNS grade III and V) may also improve after surgery, when the effects of the ini-tial impact have subsided or an associated hematoma has been evacuated. Postoperative deterioration after craniotomy for clipping of a cerebral aneurysm is serious.

Comatose after Clipping of a Ruptured Cerebral aneurysm

/ / / 59 / / /


The causes of coma after clipping of a ruptured cerebral aneurysm are shown in Table 59-1. Postoperative brain swelling (Fig. 59-1) might be attributed to manipulation of the temporal lobe and instrumentation in the sylvian fissure1 during repair of a middle cerebral artery aneurysm.14,15 More recently, it has been suggested that a venous occlusion might be the most important factor in postoperative swelling and might be specifically related to distal occlusion of a large superior superficial middle cerebral vein.4 The post-operative CT scan often shows images that have characteristics of mixed hypodensity and hyperdensity. Early hypodensity in the subcortical white matter can also be seen on CT scan (see Fig. 59-1).12 Injury to the superior middle cerebral vein should be specifically sought on a postoperative cerebral angiogram, and in a venous phase these veins may not fill.3,5,6,8 Cerebral vasospasm is a far less likely explanation for postoperative stupor so early in the course but may occur when clipping of the aneurysm is performed during the vasospasm period (four to 10 days after aneurysmal rupture).11 Acute hydrocepha-lus after early surgical repair of the aneurysm should be considered. Hydrocephalus can occur immediately after a subarachnoid hemorrhage, but the maximal time is within the first two to three days. In some patients intraoperative aneurysmal rupture has occurred and resulted in filling of ventricles and acute hydrocephalus.9 After clipping, a remote lobar hematoma may occur in the opposite hemisphere or even in the cerebellum, but both are unusual causes for postoperative coma. Usually, a substantial hematoma in the operative bed is highly uncommon.


Clipping of a middle cerebral artery aneurysm often remains the primary intervention in repair of these aneurysms.2 This is largely due to the presence of major branches arising from the aneurysmal sac, making coiling unsafe. Prognosis in many of these patients is good, and swelling resolves with marked improvement in consciousness. When cerebral edema occurs, postoperative corticosteroids can be considered, but they are likely not very effective in vasogenic edema. Rarely, re-exploration with decompressive craniotomy is necessary, but this procedure may be successful in patients with persistently increased intracranial pressure and mass effect that will not subside.7,10,13

TABLE 59-1 Causes of Coma after Clipping of a Ruptured Cerebral aneurysm

• Postoperative brain swelling (retraction injury)• Postoperative brain swelling and hemorrhage (venous injury)• Massive intraventricular hemorrhage (intraoperative rupture)• Acute hydrocephalus

Comatose after Clipping of a Ruptured Cerebral aneurysm / / 529

(A) (B)

FIGURE 59-1 (A) Serial CT scans in a patient with subarachnoid hemorrhage followed by (B) post-

clipping edema after clipping of an aneurysm of the middle cerebral artery (MCA).


A CONCLUDING NOTE

Postoperative edema after clipping of a ruptured aneurysm may be due to venous occlu-sive disease associated with retraction. Attention to preserving the superior medial cere-bral vein and additional venous structures is important. Postoperative brain swelling usually subsides spontaneously.

REFERENCES

1. Chyatte D, Porterfield R. Nuances of middle cerebral artery aneurysm microsurgery. Neurosurgery 2001;48:339–346.

2. Collice M, D’Aliberti G, Talamonti G. Current indications for aneurysm surgery. Neuroimaging Clin North Am 2006;16:497–512, ix.

3. Dean BL, Wallace RC, Zabramski JM, et al. Incidence of superficial sylvian vein compromise and post-operative effects on CT imaging after surgical clipping of middle cerebral artery aneurysms. AJNR Am J Neuroradiol 2005;26:2019–2026.

4. Kageyama Y, Fukuda K, Kobayashi S, et al. Cerebral vein disorders and postoperative brain damage asso-ciated with the pterional approach in aneurysm surgery. Neurol Med Chir (Tokyo) 1992;32:733–738.

5. Kaminogo M, Hayashi H, Ishimaru H, et al. Depicting cerebral veins by three-dimensional CT angiog-raphy before surgical clipping of aneurysms. AJNR Am J Neuroradiol 2002;23:85–91.

6. Kyoshima K, Oikawa S, Kobayashi S. Preservation of large bridging veins of the cranial base: technical note. Neurosurgery 2001;48:447–449.

7. Lad SP, Babu R, Rhee MS, et al. Long-term economic impact of coiling vs clipping for unruptured intra-cranial aneurysms. Neurosurgery 2013;72:1000–1011; discussion 1011–1003.

8. Lang FF, Olansen NE, DeMonte F, et al. Surgical resection of intrinsic insular tumors: complication avoidance. J Neurosurg 2001;95:638–650.

9. Leipzig TJ, Morgan J, Horner TG, et al. Analysis of intraoperative rupture in the surgical treatment of 1694 saccular aneurysms. Neurosurgery 2005;56:455–468; discussion 455–468.

10. McDonald JS, McDonald RJ, Fan J, et al. Comparative effectiveness of unruptured cerebral aneurysm therapies: propensity score analysis of clipping versus coiling. Stroke 2013;44:988–994.

11. McLaughlin N, Bojanowski MW. Early surgery-related complications after aneurysm clip placement: an analysis of causes and patient outcomes. J Neurosurg 2004;101:600–606.

12. Mullins ME, Grant PE, Wang B, Gonzalez RG, Schaefer PW. Parenchymal abnormalities associated with cerebral venous sinus thrombosis: assessment with diffusion-weighted MR imaging. AJNR Am J Neuroradiol 2004;25:1666–1675.

13. Schirmer CM, Hoit DA, Malek AM. Decompressive hemicraniectomy for the treatment of intractable intracranial hypertension after aneurysmal subarachnoid hemorrhage. Stroke 2007;38:987–992.

14. Stoodley MA, Macdonald RL, Weir BK. Surgical treatment of middle cerebral artery aneurysms. Neurosurg Clin N Am 1998;9:823–834.

15. Suzuki Y, Matsumoto K. Variations of the superficial middle cerebral vein: classification using three-dimensional CT angiography. AJNR Am J Neuroradiol 2000;21:932–938.

531

A CONVERSATION

AN EXPLANATION

There has been a substantial increase in endovascular procedures to repair a cerebral aneurysm after a subarachnoid hemorrhage, but also in unruptured aneurysms.7 Major complications are uncommon: the incidence was recently estimated at 6%.11 Aneurysmal rupture during coiling is very uncommon (Fig. 60-1). In a specialized center, 1% of 600 consecutively treated patients with intracranial aneurysms had a procedure-associated

Comatose after Endovascular Treatment of Ruptured Cerebral aneurysm

/ / / 60 / / /


FIGURE 60-1 Coil procedure: CT scan and cerebral angiogram catheter in an aneurysm showing

extravasation of contrast into the subarachnoid space.

Comatose after Endovascular Treatment of Ruptured Cerebral aneurysm / / 533

rupture. No correlation was found between operator volume and years of experience since the introduction of Guglielmi detachable coils technology.4,6,9

The causes of coma after endovascular treatment of ruptured cerebral aneurysm are shown in Table 60-1. The risk of rupture in a recent subarachnoid hemorrhage is four times higher than in unruptured aneurysms.3 It may also be related to the timing of coil-ing (less than 24 hours after rupture vs. later), and there remains an increased risk of rerupture when coils are introduced soon after the initial rupture.

Another major complication is prolapsing of coils following endovascular treatment, resulting in occlusion of a major artery (e.g., basilar artery). This complication occurs mostly in aneurysms with a wide neck and after multiple coil placements. Underpacking is also a risk factor for coil prolapse. A strand can be seen outside the aneurysm, often at the end of the procedure. Snare retrieval is at times successful, but only when the coil is pulsating is it feasible for the interventional neuroradiologist to retrieve it.

Thrombus formation with Guglielmi detachable coils typically occurs in less than 4% of procedures, but a recent study found that there were thromboembolic compli-cations in 10% of 220 procedures.5 In most of these complications, it is assumed that these are erythrocyte-rich or so-called red clots rather than fibrin-rich, white clots. In at least one case, heparin-induced thrombocytopenia could account for thrombo-embolic complications during coiling.5 Impaired consciousness may also occur as a consequence of infarction of the pons in a recently coiled basilar artery aneurysm (Fig. 60-2).


Once rupture has occurred, initial management likely calls for an acute ventriculostomy and an attempt to occlude the aneurysmal dome with coils. Neurosurgical interven-tion to clip the aneurysm, with a substantial degree of morbidity, is likely necessary to repair the aneurysm. Considering thromboembolic complications, neuroradiologists performing endovascular procedures have prophylactically used intravenous eptifibatide (Integrelin) at the conclusion of the procedure.10 This drug is a synthetic heptapeptide

TABLE 60-1 Causes of Coma after Endovascular Coiling of Cerebral aneurysm

• Rerupture with intraventricular extension and acute hydrocephalus• Coil perforation of the aneurysm with lobar hematoma and brainstem shift• Occluded basilar artery due to coil migration• Multiple cerebral infarcts


with specificity for glycoprotein IIB–IIIA receptors. Others have used antiplatelet agents to decrease the incidence of thromboembolic complications. Most institutions now use aspirin and clopidogrel after treatment of an unruptured aneurysm with endovascular coiling. Thromboembolic complications with aneurysm occlusion using coil placement could be treated with abciximab. Abciximab is a powerful platelet antiaggregant that has been used to reduce propagation of the clot or to dissolve it.1 This chimeric human mouse monoclonal antibody is a platelet glycoprotein IIB–IIIA receptor inhibitor. It prevents platelet binding to fibrinogen and platelet aggregation.

A CONCLUDING NOTE

There is an increased use of coil embolization in ruptured and unruptured aneurysms. The complication rate is low; complications involve rupture of the aneurysm—more likely due to a weak wall of a recent ruptured aneurysm rather than the procedure itself.2,8 Thromboembolic complications may occur, causing cerebral or brainstem infarcts. Rupture of the aneurysm requires an acute ventriculostomy and surgical clipping. Early treatment with abciximab can be successful in coil-associated thrombus formation.

REFERENCES

1. Aviv RI, O’Neill R, Patel MC, Colquhoun IR. Abciximab in patients with ruptured intracranial aneu-rysms. AJNR Am J Neuroradiol 2005;26:1744–1750.

2. Brinjikji W, McDonald JS, Kallmes DF, Cloft HJ. Rescue treatment of thromboembolic complications during endovascular treatment of cerebral aneurysms. Stroke 2013;44:1343–1347.

FIGURE 60-2 Persistent hypersomnolence after a coil placement of a ruptured basilar aneurysm.

Note hyperintensity in the pons in proximity to the coil.

Comatose after Endovascular Treatment of Ruptured Cerebral aneurysm / / 535

3. Cloft HJ, Kallmes DF. Cerebral aneurysm perforations complicating therapy with Guglielmi detachable coils: a meta-analysis. AJNR Am J Neuroradiol 2002;23:1706–1709.

4. Doerfler A, Wanke I, Egelhof T, et al. Aneurysmal rupture during embolization with Guglielmi detach-able coils: causes, management, and outcome. AJNR Am J Neuroradiol 2001;22:1825–1832.

5. Gupta V, Tanvir R, Garg A, Gaikwad SB, Mishra NK. Heparin-induced thrombocytopenia in a case of endovascular aneurysm coiling. AJNR Am J Neuroradiol 2007;28:155–158.

6. Henkes H, Fischer S, Weber W, et al. Endovascular coil occlusion of 1811 intracranial aneurysms: early angiographic and clinical results. Neurosurgery 2004;54:268–280; discussion 280–265.

7. Hwang JS, Hyun MK, Lee HJ, et al. Endovascular coiling versus neurosurgical clipping in patients with unruptured intracranial aneurysm: a systematic review. BMC Neurol 2012;12:99.

8. Jo KI, Yeon JY, Kim KH, et al. Predictors of thromboembolism during coil embolization in patients with unruptured intracranial aneurysm. Acta Neurochir (Wien) 2013;155:1101–1106.

9. Levy E, Koebbe CJ, Horowitz MB, et al. Rupture of intracranial aneurysms during endovascular coil-ing: management and outcomes. Neurosurgery 2001;49:807–811.

10. Park HK, Horowitz M, Jungreis C, et al. Periprocedural morbidity and mortality associated with endo-vascular treatment of intracranial aneurysms. AJNR Am J Neuroradiol 2005;26:506–514.

11. van Rooij WJ, Sluzewski M, Beute GN, Nijssen PC. Procedural complications of coiling of ruptured intracranial aneurysms: incidence and risk factors in a consecutive series of 681 patients. AJNR Am J Neuroradiol 2006;27:1498–1501.

536

A CONVERSATION

AN EXPLANATION

Hypothermia causes coma, and patients may present blue, pale, cold, and stiff. Clinically significant hypothermia is defined as a core body temperature of less than 35°C. (Some oral or tympanic thermometers do not record less than 35°C.)

In many patients, EKG manifestations are apparent and support the diagnosis. They include Osborne waves; PR, QRS, and QT prolongation; and atrial and ventricular dys-rhythmias.2,7 Osborn or J-waves are typically seen in patients with core temperatures

Comatose and accidental hypothermia

/ / / 61 / / /

Comatose and accidental hypothermia / / 537

less than 32°C but are larger and better recognized when the temperature is below 30°C (Fig. 61-1).

The causes of coma in accidental hypothermia are shown in Table 61-1. A marked reduction in cerebral function and metabolic rate is evident at core temperatures less than 30°C. Oxygen consumption is also reduced and this may actually be beneficial by protect-ing neurons from additional hypoxemia associated with airway collapse. Hypothermia is often associated with traumatic brain injury or alcohol intoxication, and these are condi-tions to consider.11 Ice submersion and water absorption may lead to severe hyponatre-mia (Chapter 81). A classification of hypothermia is shown in Table 61-2.

FIGURE 61-1 Admission EKG shows Osborn waves (arrowheads). They occur at the R-ST junction

(J point). Note sinus bradycardia and prolongation of the QRS interval and corrected QT interval

(QTc). With rewarming (29.4°C to 36.6°C), the Osborn waves diminish in amplitude and disap-

pear. The baseline tremor artifact is caused by shivering (arrows) and also resolves. From Krantz

and Lowery, with permission of New England Journal of Medicine.7

TABLE 61-1 Causes of Coma in accidental hypothermia

• Decreased cerebral metabolic rate• Multiple hemispheric contusions• Alcohol intoxication• Hyponatremia (ice submersion)

Table61-1

Table61-2



One cannot assess the absence of signs of life in a hypothermic patient, and rewarming should be started immediately. Generally, cardiopulmonary resuscitation is not initiated if the patient has been submerged in cold water for more than an hour with a core tempera-ture of 10°C or less. This could indicate ice formation in airways and a chest wall that can-not be compressed due to stiffness. The guidelines for cardiopulmonary resuscitation in emergency treatment in accidental hypothermia can be found at www.hypothermia.org and are shown in Figure 61-2. The most common problem remains supraventricular dysrhyth-mia, but it usually resolves with rewarming. Ventricular fibrillation is seen in patients with a core temperature less than 30°C. Resuscitation of cardiac arrhythmias is the most immedi-ate concern.9 Hypovolemia should be immediately corrected and potassium and glucose should be monitored. Warming is achieved through warming blankets, warm intravenous fluids, heated and humidified oxygen, and ventilation at 40°C to 42°C. Peritoneal lavage at 40°C to 42°C and fluids are an option. Gastric lavage, rectal lavage, or chemical heat packs are not recommended.8,10 Recently, extracorporeal membrane oxygenation (ECMO) has been tested in 59 patients with accidental hypothermia and resulted in 20% survival.9

The mortality of patients with accidental hypothermia who reach the intensive care unit remains very high.4 Hypothermia associated with accidental cold-water immersion is more severe than in other causes of hypothermia and has a mortality of 40%.3 Several poor predictive factors have been identified and include major hyperkalemia (>10 mmol/L), cardiac arrest before hospital admission, hypotension, elevated blood urea nitrogen, and need for mechanical ventilation and gastric intubation.3 Rewarming may take a full day but often these patients subsequently die. Nonetheless, awaking from coma may occur days after correction of hypothermia, and extreme caution is needed in neurologic prog-nostication. Poor prognosticating factors in a patient with profound hypothermia include fixed and dilated pupils, asystole at presentation, and marked acidosis.1,3,6

TABLE 61-2 Classification of hypothermia

ClassificationsCore Temperature

Own Ability to Rewarm Clinical Presentation

Mild 36°C–34°C Good Less alertModerate 34°C–30°C Limited Loss of consciousness (at 30°C shivering stops)Severe <30°C Unable Rigidity

Vital signs reduced or absent. Major risk of

mechanically stimulated ventricular fibrillation.Extreme <25°C Unable Spontaneous ventricular fibrillation

Cardiac arrest

http://www.hypothermia.org

Comatose and accidental hypothermia / / 539

A CONCLUDING NOTE

Neurologic examination can be of little use in the hypothermic patient. One should assume that all brainstem reflexes can be lost when the body temperature is less than 25°C. Perhaps due to the neuroprotective effects of hypothermia, comatose patients may have a better outcome than expected.

What is core temperature?

Passive rewarmingActive external rewarming

Active internal rewarmingsequence (below)

Warm IV fluids (43˚C)Warm humid oxygen(42–46˚C)Peritoneal lavage (KCI-free fluid)Extracorporeal rewarmingEsophageal rewarming tubes

Continue active internal rewarming untilCore temperature 35˚C Return of spontaneous circulation orResuscitative efforts cease

Continue CPRGive IV medications asindicated (but atlonger thanstandard intervals)Repeatdefibrillation forVF/FT as coretemperature rises

Continue CPRWithhold IVmedicationsLimit shocksfor VF/VT to 3maximumTransport tohospital

What is core temperature?

Start CPRDefibrillate VF/VT up to a total of3 shocks (200 J, 300 J, 360 J)IntubateVentilate with warm, humidoxygen (42–46˚C)Establish IVInfuse warm normal saline (43˚C)

Pulse/breathingabsent

Pulse/breathingpresent

<30˚C 30˚C

Active internal rewarming

<30˚C (severe hypothermia)

34–36˚C (mild hypothermia)

Passive rewarmingActive external rewarmingof truncal areas only

30–34˚C (moderate hypothermia)

Actions for all patientsRemove wet garments

Maintain horizontal positionAvoid rough movement and excess activityMonitor core temperatureMonitor cardiac rhythm

Protect against heat loss and wind chill (use blankets and insulating equipment)

Assess responsiveness, breathing, and pulse

FIGURE 61-2 Algorithm of management of hypothermia. Adapted from Department of Health and

Social Services, Division of Public Health, Section of Community Health and EMS. State of Alaska Cold Injuries Guidelines,5 Vassal et al.,10 Ruttman et al.,8 and Danzl.3 CPR = Cardiopulmonary

resuscitation, IV = Intravenous therapy, VF = Ventricular fibrillation, VT = Ventricular tachycardia


REFERENCES

1. Auerbach PS. Some people are dead when they’re cold and dead. JAMA 1990;264:1856–1857.2. Benezet-Mazuecos J, Ibanez B, Farre J. Severe hypothermia showing Osborn waves associated with tran-

sient atrial fibrillation and ST segment depression. Heart 2006;92:1666.3. Danzl DF. Accidental hypothermia. In: Auerbach PS, ed. Wilderness Medicine, 5th ed. St. Louis: Mosby,

2007.4. Dhillon S. Environmental hazards, hot, cold, altitude, and sun. Infect Dis Clin North Am 2012;26:707–723.5. Department of Health and Social Services, Division of Public Health, Section of Community Health and

EMS. State of Alaska Cold Injuries Guidelines. Juneau, 2003.6. Ko CS, Alex J, Jeffries S, Parmar JM. Dead? Or just cold: profoundly hypothermic patient with no signs

of life. Emerg Med J 2002;19:478–479.7. Krantz MJ, Lowery CM. Images in clinical medicine. Giant Osborn waves in hypothermia. N Engl J Med

2005;352:184.8. Ruttmann E, Weissenbacher A, Ulmer H, et al. Prolonged extracorporeal membrane oxygenation-assisted

support provides improved survival in hypothermic patients with cardiocirculatory arrest. J Thorac Cardiovasc Surg 2007;134:594–600.

9. Brugger H, Durrer B, Elsensohn F et al. Resuscitation of avalanche victims: Evidence-based guidelines of the International Commission for Mountain Emergency Medicine (ICAR MEDCOM): intended for physicians and other advanced life support personnel. Resuscitation. 2013;84:539–546.

10. Vassal T, Benoit-Gonin B, Carrat F, et al. Severe accidental hypothermia treated in an ICU: prognosis and outcome. Chest 2001;120:1998–2003.

11. Wilson E, Waring WS. Severe hypotension and hypothermia caused by acute ethanol toxicity. Emerg Med J 2007;24:e7.

541

A CONVERSATION

AN EXPLANATION

Carbon monoxide (CO) poisoning is common in the United States, with approximately 40,000 to 50,000 emergency department visits with at least a diagnostic suspicion.3,7 CO is odorless and colorless, and exposure can occur in inadequately ventilated areas, typically in fall or winter months. Use of gasoline-powered generators has been implicated.13 There are prodromal symptoms of confusion and headache, followed by seizures. The mecha-nism of CO poisoning is shown in Figure 62-1. CO has a high affinity to hemoglobin,

Comatose and Carbon monoxide inhalation

/ / / 62 / / /


estimated to be 200 times greater than that of oxygen at binding the iron atom of the hemoglobin molecule. Tissue hypoxemia leads to permanent damage, particularly in the brain with a high oxygen demand.

The causes of coma after CO poisoning are shown in Table 62-1. Hypoxemia is the main mechanism, and this explains the lesions found in vulnerable areas such as the basal ganglia, lentiform nucleus, globus pallidus, and cortex.7 CO poisoning is a known suicide method, and patients may have additionally self-administered drugs or alcohol. Multiple cerebral infarcts in watershed areas (e.g., white matter) may occur with profound shock. Rarely a delayed neurologic syndrome occurs, usually weeks to a month after exposure.6 In these patients, after a symptomatic interval, widespread demyelination leads to a rapid decrease in consciousness, posturing, spasticity, and coma. Resolution occurs in some patients, but with a parkinsonian syndrome.

COHb, or blood carboxyhemoglobin, is measured through multi-wavelength CO oximetry, and the concentration is stable for many days. Pulse oximeters overestimate the oxygen concentration.

FIGURE 62-1 Mechanism of carbon monoxide (CO) poisoning. Adapted from Weaver et al. with

permission of New England Journal of Medicine.14 PO2 = partial pressure of oxygen, PCO2 =

partial pressure of carbon dioxide.

TABLE 62-1 Causes of Coma in Carbon monoxide inhalation

• Anoxic-ischemic encephalopathy• Multiple cerebral infarcts• Drug or alcohol overdose (suicide attempt)• Diffuse demyelination (delayed onset)

Comatose and Carbon monoxide inhalation / / 543

MRI can either show white matter changes or are normal, depending on the expo-sure.3 There is preliminary evidence that single-photon emission computed tomography (SPECT) might be more sensitive than MRI in documenting lesions. Persistently abnor-mal SPECT studies one year after exposure are associated with a poor prognosis and major neuropsychological difficulties.2


CO poisoning is treated with 100% oxygen, which accelerates its elimination. Hyperbaric oxygen has been studied, but no definitive evidence exists that it improves outcome.1,5,8–12 Oxygen treatment through a high-flow reservoir face mask and treatment with hyperbaric oxygen have been tried with three-chamber sessions at intervals of six to 12 hours within a 24-hour period and may have an effect in the more severe cases. Although it remains a controversial treatment, transfer to a facility that offers hyperbaric oxygen should be considered. There is evidence that hyperbaric oxygen decreases the half-life of COHb to 15 to 30 minutes; however, as alluded to earlier, hypoxemia is far more important and may not be reflected by the level of COHb. Administration of 100% supplemental oxy-gen decreases the half-life of COHb from five hours on room air to 40 to 90 minutes. Additionally, 4.8% carbon dioxide to a nonrebreathing circuit provides normocapnia and further decreases the half-life of COHb. Many patients are admitted comatose or in extre-mis. The prognosis can be good in surviving noncomatose patients, with up to 75% of patients making a full recovery.4

A CONCLUDING NOTE

Immediate high-flow 100% oxygen should be administered. Uncertainty remains about the role of hyperbaric oxygen therapy but it should be provided if available. CO poisoning is not a rare cause of coma and has a high morbidity and mortality. The spectrum of outcome categories may vary from a persistent vegetative state to minimal short-term memory loss.

REFERENCES

1. Buckley NA, Isbister GK, Stokes B, Juurlink DN. Hyperbaric oxygen for carbon monoxide poisoning : a systematic review and critical analysis of the evidence. Toxicol Rev 2005;24:75–92.

2. Gale SD, Hopkins RO, Weaver LK, et al. MRI, quantitative MRI, SPECT, and neuropsychological find-ings following carbon monoxide poisoning. Brain Inj 1999;13:229–243.

3. Gutzman JA, Carbon monoxide poisoning. Crit Care Clin. 2012:28:537–548.


4. Hopkins RO, Woon FL. Neuroimaging, cognitive, and neurobehavioral outcomes following carbon monoxide poisoning. Behav Cogn Neurosci Rev 2006;5:141–155.

5. Juurlink DN, Stanbrook MB, McGuigan MA. Hyperbaric oxygen for carbon monoxide poisoning. Cochrane Database of Systematic Reviews 2000:CD002041.

6. Kondo A, Saito Y, Seki A, et al. Delayed neuropsychiatric syndrome in a child following carbon monox-ide poisoning. Brain Dev 2007;29:174–177.

7. Mokhlesi B, Leikin JB, Murray P, Corbridge TC. Adult toxicology in critical care: Part II: specific poison-ings. Chest 2003;123:897–922.

8. Olson KR. Hyperbaric oxygen or normobaric oxygen? Toxicol Rev 2005;24:151; discussion 159–160.9. Parkinson RB, Hopkins RO, Cleavinger HB, et al. White matter hyperintensities and neuropsychological

outcome following carbon monoxide poisoning. Neurology 2002;58:1525–1532.10. Seger D. The myth. Toxicol Rev 2005;24:155–156; discussion 159–160.11. Silver S, Smith C, Worster A. Should hyperbaric oxygen be used for carbon monoxide poisoning? CJEM

2006;8:43–46.12. Thom SR. Hyperbaric oxygen therapy for carbon monoxide poisoning : is it time to end the debates?

Toxicol Rev 2005;24:157–158; discussion 159–160.13. Van Sickle D, Chertow DS, Schulte JM, et al. Carbon monoxide poisoning in Florida during the 2004

hurricane season. Am J Prev Med 2007;32:340–346.14. Weaver LK, Hopkins RO, Chan KJ, et al. Hyperbaric oxygen for acute carbon monoxide poisoning. N

Engl J Med 2002;347:1057–1067.

545

A CONVERSATION

AN EXPLANATION

Most of the time, fever is a physiologic response to inflammation or infection. The thermoregulatory control center in the hypothalamus may fail if heat production exceeds heat dissipation, particularly if an insufficient amount of fluid is provided. Strenuous activity without fluid replenishment can cause body temperature to rise quickly. There is new evidence that metabolic acidosis can induce heatstroke by inhibiting heat loss.9 Risk factors for excessive heat exposure include obesity, medication (antidepressants,

Comatose and heatstroke/ / / 63 / / /


diuretics, antihypertensives, and antihistamines), stimulants (caffeine), and alcohol consumption.1,5 Upper respiratory illness or acute gastroenteritis within one week of strenuous exercise also fits well with dehydration as a major predisposing factor. Thermoregulation may also be impaired in a patient with spine injury, particularly cervi-cal cord injury.8 The risk of heatstroke (using relative humidity and air temperature) can be estimated (Fig. 63-1).

The causes of coma in heatstroke are shown in Table 63-1. The neurologic findings in heatstroke are a result of multiorgan failure. The clinical and laboratory manifestations are almost identical to a sepsis syndrome but not its pathophysiology.10 Rapid dehydration leads to decreased volume status, renal failure (if not already due to rhabdomyolysis), and eventually diffuse intravascular coagulation.11 A core temperature of 41°C is associ-ated with shock, tachycardia, tachypnea, cessation of shivering, and, finally, ventricular fibrillation.

Neuropathology in patients who died from heatstroke may show possible “heat-induced” changes. Neuronal loss is most striking in the Purkinje cells, substantia

Relative humidity (%)

40 45 50 55 60 65 70 75 80 85 90 95 100

136

130 137

124 130 137

119 124 131 137

114

109 114 118 124 129 136

119 124 130 137

105

101

97

94

91

88

85

85

85

85

83 84

83

83 84 84

82

82 82

89

81

87

89 91 93

91

95

95

98

98

97

100 100

100

100 103102 105 108 1129388

8886

86

9190

96949290

86 88 89

86 87

959384 84

81818080

89

93 95 97 100 103 106

106 110

109 113113

117

117

122 127 13296 99

100 102 106

101

110 114 119

112

124

116

129

121

121

135

126 131105 108

104 108 112 116 121 126 132

109 113 117 123 128 134

Heat index(apparent

temperature)

Extreme danger

Heat stroke or sunstrokehighly likely

With prolonged exposureand/or physical activity

Danger

Sunstroke, muscle cramps,and/or heat exhaustion likely

Extreme caution

Sunstroke, muscle cramps,and/or heat exhaustion possible

Caution

Fatigue possible

110

108

106

104

102

100

98

96

94

92

90

88

86

84

82

80

Air

tem

pera

ture

(˚F

)

FIGURE 63-1 Heat illness risk assessment chart. Source: National Oceanic and Atmospheric

Administration.

TABLE 63-1 Causes of Coma in heatstroke

• Anoxic-ischemic encephalopathy• Acute uremia• Acute hyperammonemia• Osmotic demyelination syndrome

Comatose and heatstroke / / 547

nigra, and thalamus. Down-beat nystagmus has been repeatedly noted in patients and indi-cates bilateral lesions in the flocculus, suggesting that the cerebellum is vulnerable to heat injury.2 Lesions in the dentate nucleus may explain the clinical findings of facial and buccal myoclonus in some patients. Central pontine myelinolysis associated with fluid and elec-trolyte shifts has been described.7 Most reports document normal CT and MRI findings in patients with heatstroke, but if changes are found, they are due to ischemia associated with hypovolemic shock.6


The manifestations are serious, and most patients are critically ill, if not moribund. Methods for physically cooling the skin using evaporation, conduction, or pharmaco-logic techniques are shown in Table 63-2.4 Immersion in ice-cold water produces shiv-ering and vasoconstriction and is ill advised. In the field, splashing lukewarm water, removal of clothing, and air fanning is important. Iced peritoneal lavage may not be superior to other less invasive methods. Outcome can be good if systemic manifesta-tions can be controlled. However, mortality is high, with over 20,000 to 30,000 deaths in most reported heat waves. Poor prognostic factors include being confined to bed, living alone, psychiatric illness, cardiovascular and pulmonary illness, and use of psy-chotropic medications.2 If the patient survives, neurologic recovery is often delayed but can be complete.

TABLE 63-2 Cooling methods for Patients with heatstroke

EVAPORATION TECHNIQUESWetting of the body surface during continuous fanning

Use of alcohol spongesCONDUCTION TECHNIQUESExternal–Tap water immersion–Application of ice packs over part or whole body

–Cooling blanketsInternal–Iced gastric lavage–Iced peritoneal lavagePHARMACOLOGIC TECHNIQUESDantrolene



A CONCLUDING NOTE

Neurologic presentation depends on the systemic manifestations of heatstroke. Neurologic complications may be caused by fluid shifts, acute renal failure, and hepatic failure. In-hospital mortality is high.

REFERENCES

1. Atha WF. Heat-related illness. Emerg Med Clin North Am. 2013:31:1097–1108.2. Bouchama A, Dehbi M, Mohamed G, et al. Prognostic factors in heat wave-related deaths: a meta-analysis.

Arch Intern Med 2007;167:2170–2176.3. Deleu D, El Siddig A, Kamran S, et al. Downbeat nystagmus following classical heat stroke. Clin Neurol

Neurosurg 2005;108:102–104.4. Hadad E, Rav-Acha M, Heled Y, Epstein Y, Moran DS. Heat stroke: a review of cooling methods. Sports

Med 2004;34:501–511.5. Hajat S, O’Connor M, Kosatsky T. Health effects of hot weather: from awareness of risk factors to effec-

tive health protection. Lancet 2010;375:856–863.6. McLaughlin CT, Kane AG, Auber AE. MR imaging of heat stroke: external capsule and thalamic T1

shortening and cerebellar injury. AJNR Am J Neuroradiol 2003;24:1372–1375.7. McNamee T, Forsythe S, Wollmann R, Ndukwu IM. Central pontine myelinolysis in a patient with clas-

sic heat stroke. Arch Neurol 1997;54:935–936.8. Steele SR, Martin MJ, Mullenix PS, Long WB, 3rd, Gubler KD. Fatal malignant hyperpyrexia in a cervi-

cal spine- injured patient. J Trauma 2005;58:375–377.9. Wright CL, Boulant JA. Carbon dioxide and pH effects on temperature-sensitive and -insensitive hypo-

thalamic neurons. J Appl Physiol 2007;102:1357–1366.10. Yan YE, Zhao YQ, Wang H, Fan M. Pathophysiological factors underlying heatstroke. Med Hypotheses

2006;67:609–617.11. Yeolekar ME, Athavale AM. Heat stroke: managing a tropical continuum. J Assoc Physicians India

2006;54:357–358.

549

A CONVERSATION

AN EXPLANATION

Patients with near-drowning are commonly found with hypothermia and may later develop marked hypoxemia due to pulmonary edema.6 The causes of coma after near-drowning are shown in Table 64-1. Anoxic-ischemic brain injury initially is a result of pulmonary failure2 (Fig. 64-1). Rapid onset of acute respiratory distress syndrome may result in problems with oxygenation. Vasoconstriction follows, and a systemic inflammatory response may cause a capillary leak syndrome and shock.12 Large amounts of ingested fluids may cause severe hyponatremia and contribute considerably to coma.

Comatose and Near-Drowning/ / / 64 / / /


Thus, patients may improve after correction of sodium values. Fungi in polluted waters may pose an additional risk. Aspergillosis infection may cause central nervous system infection as early as seven to 14 days after the accident.4,7 Alcohol or drugs may be important confounders, and some patients have had an injury before being thrown in the water or as a result of immersion. CT findings are normal, but MRI may show simi-lar patterns on diffusion-weighted images (DWI) as with any comatose survivor of an anoxic-ischemic brain injury (Fig. 64-2).

TABLE 64-1 Causes of Coma in Near-Drowning

• Anoxic-ischemic encephalopathy• Traumatic brain injury• Coexisting alcohol or drug intoxication• Hyponatremia• Central nervous system aspergillosis (late)

Aspiration

Bronchospasm

HypoxemiaAcidosis

Surfactantreduced

Fresh waterAlveolaredema

Salt water

FIGURE 64-1 Mechanism of lung injury according to fluid aspiration.2

FIGURE 64-2 Patient in minimally conscious state after near-drowning. MRI (DWI) shows typical

symmetric globus pallidus and caudate nucleus involvement together with scattered cortical

hyperintensities.

Comatose and Near-Drowning / / 551


Early treatment management of submersion involves a series of measures.1 A treatise on management has been recently published.12 A nasogastric tube is placed to decom-press the stomach.3,5,8,10 The initial blood gas is a marker for pulmonary edema, and a pH below 7 indicates a poor prognosis. Chest x-ray may show aspirated water. Septicemia is a feared complication and requires careful monitoring and blood cultures. Treatment of a near-drowned patient is focused on treating the pulmonary edema due to water aspi-ration. Most of the immediate problems include laryngospasm and other debris such as vomit, sand, or mud that may have been aspirated into the lungs.2 This all leads to inadequate oxygenation and intrapulmonary shunting, chemical pneumonitis, or adult respiratory distress syndrome. Although they are rare, it is important that cervical spine injuries are recognized. Cervical spine injuries are most often seen if submersion is asso-ciated with diving, a motor vehicle crash, or fall from height. In one series of over 2,000 submersion victims, only 11 patients had evidence of a cervical spine injury.14

To provide neuroprotection, barbiturate treatment has been tried, but without effect.9 This study was focused on children who presented flaccid and comatose; thus, it may still have a benefit in less severely affected patients.9 There is no evidence that monitoring of intracranial pressure would affect outcome. Many of the treatment para-digms for anoxic-ischemic injury or postresuscitation encephalopathy could apply here (Chapter 65), but the prognosis may be entirely different. Outcome in patients who were resuscitated for pediatric near-drowning was determined by the presence of the Glasgow Coma Score (GCS). Patients who arrived with a GCS of 3 did not survive neurologi-cally intact, with one third of the patients suffering severe brain damage. Serial neuro-logic examination in 44 children admitted to a pediatric intensive care unit found that patients who survived in a favorable neurologic condition all had purposeful movements 24 hours after the near-drowning.13 Any other neurologic abnormality present 24 hours after near-drowning could imply a later severe neurologic deficit and emphasizes that the first 24 hours in the drowning of children may determine outcome.11 Mortality after sub-mergence is high (50%), and patients submerged in cold water (<10°C) have a worse outcome. Factors that are highly predictive of fatal outcome are shown in Table 64-2, but neurologic details are missing in most studies.

A CONCLUDING NOTE

Near-drowning often leads to severe anoxic-ischemic injury to the brain. Near-drowning may have a bimodal prognosis—good with minimal sequelae or poor with a persistent


vegetative state, minimally conscious state, or death as outcome. Neurologic prognosis remains difficult to predict initially. However, patients who respond to localization of pain within 24 hours have a good chance of a full recovery.

REFERENCES

1. Burford AE, Ryan LM, Stone BJ, Hirshon JM, Klein BL. Drowning and near-drowning in chil-dren and adolescents: a succinct review for emergency physicians and nurses. Pediatr Emerg Care 2005;21:610–616.

2. Christe A, Aghayev E, Jackowski C, Thali MJ, Vock P. Drowning—post-mortem imaging findings by computed tomography. Eur Radiol 2008;18:283–290.

3. Falk JL, Escowitz HE. Submersion injuries in children and adults. Semin Respir Crit Care Med 2002;23:47–55.

4. Harries M. Near drowning. BMJ 2003;327:1336–1338.5. Hasibeder WR. Drowning. Curr Opin Anaesthesiol 2003;16:139–145.6. Lee LK, Mao C, Thompson KM. Demographic factors and their association with outcomes in pediatric

submersion injury. Acad Emerg Med 2006;13:308–313.7. Leroy P, Smismans A, Seute T. Invasive pulmonary and central nervous system aspergillosis after

near-drowning of a child: case report and review of the literature. Pediatrics 2006;118:e509–513.8. Lienhart HG, John W, Wenzel V. Cardiopulmonary resuscitation of a near-drowned child with a combi-

nation of epinephrine and vasopressin. Pediatr Crit Care Med 2005;6:486–488.9. Nussbaum E, Maggi JC. Pentobarbital therapy does not improve neurologic outcome in nearly drowned,

flaccid-comatose children. Pediatrics 1988;81:630–634.10. Papa L, Hoelle R, Idris A. Systematic review of definitions for drowning incidents. Resuscitation

2005;65:255–264.11. Pierro MM, Bollea L, Di Rosa G, et al. Anoxic brain injury following near-drowning in children.

Rehabilitation outcome: three case reports. Brain Inj 2005;19:1147–1155.

TABLE 64-2 Factors Predictive of Death or Survival with Severe Neurologic Sequelae in Submersion Victims in Non-icy Water

AT THE SCENESubmersion >25 minCardiopulmonary resuscitation >25 minInotropic medication to establish a perfusing rhythm

IN THE EMERGENCY DEPARTMENTCardiopulmonary resuscitation

Fixed and dilated pupils

Initial pH <7.00

ApneaGlasgow Coma Scale of 3Only localizes painful stimuli at 24 hAbnormal CT scan of the brain at 36 h


Comatose and Near-Drowning / / 553

12. Topjian AA, Berg RA, Bierens JJ, et al. Brain resuscitation in the drowning victim. Neurocrit Care 2012;17:441–467.

13. Varon J, Marik PE. Complete neurological recovery following delayed initiation of hypothermia in a victim of warm water near-drowning. Resuscitation 2006;68:421–423.

14. Watson RS, Cummings P, Quan L, Bratton S, Weiss NS. Cervical spine injuries among submersion vic-tims. J Trauma 2001;51:658–662.

554

A CONVERSATION

AN EXPLANATION

Neurons are able to tolerate only brief periods of interrupted blood flow. Neuronal oxy-gen stores are depleted after 20 seconds and adenosine triphosphate stores follow within 5 minutes. Eventually the NA/K pumps shut down, resulting in calcium and sodium influx. Calcium influx damages mitochondria, which in turn generate reactive oxygen species and trigger apoptotic cascades.

Comatose after Cardiopulmonary Resuscitation

/ / / 65 / / /

Comatose after Cardiopulmonary Resuscitation / / 555

During the immediate postresuscitation period, global cerebral blood flow and the metabolic rate of oxygen transiently increase for 15 to 30 minutes. Subsequently cerebral blood flow decreases, along with decreased metabolic rate of oxygen (delayed hypoperfu-sion phase). Between 90 minutes and 12 hours, the cerebral blood flow is approximately 50% of baseline value. The underlying mechanism of cerebral necrosis is ischemia. Pure hypoxia alone does not result in cerebral necrosis even with extreme levels (Pao2 <20 mm Hg).10,12 Reversible gamma-aminobutyric acid (GABA)ergic deficiency and synaptic dysfunction characterize pure hypoxia; therefore, respiratory arrest alone (Chapter 70) has a better outcome than when associated with cardiac arrest14.

Preferential areas of involvement are the frontoparietal cortex, hippocampus, basal ganglia, and cerebellum. The CA1 area of the hippocampus (Sommers’ sector) is par-ticularly affected by ischemia (Chapter 6). The location of lesions in the central nervous system reflects the selective vulnerability of tissues to global ischemia, high metabolic demand, and the presence of receptors for excitatory neurotransmitters in these areas.

The causes of coma after cardiopulmonary resuscitation are shown in Table 65-1. Physicians evaluating comatose patients in the emergency department or intensive care unit after successful cardiopulmonary resuscitation (CPR) should not overlook the pos-sibility that cardiac arrest may be a consequence of acute brain injury such as primary intraventricular hemorrhage, subarachnoid hemorrhage, massive drug ingestion, or envi-ronmental exposure. Loss of all brain function (brain death) may occur after prolonged resuscitation efforts.

Immediately after resuscitation, CT scans are normal, but changes can be seen in comatose patients after a few days. Early changes are also common in patients found pulseless for an uncertain period. These changes are diffuse cerebral swelling with effacement of basal cisterns and sulci or the presence of diffuse hemispheric hypoden-sities (Fig. 65-1). It may include infarcts in the basal ganglia, cerebellar hemispheres, or watershed areas. MRI (diffusion-weighted imaging [DWI]) may show the presence of widespread restricted diffusion abnormalities in the cortex, white matter, thalamus, and cerebellum (Fig. 65-2).13,17,20 Other areas typically involved in hypoxic-ischemic

TABLE 65-1 Causes of Coma after Cardiopulmonary Resuscitation

• Cortical laminar necrosis• Bithalamic ischemic injury• Hemispheric and brainstem injury (brain death)• Primary catastrophic brain injury resulting in cardiac arrest


FIGURE 65-1 CT scan with early edema (absent sulci) after CPR.

FIGURE 65-2 MRI (DWI) showing multiple areas of ischemia. Note white matter involvement on

ADC mapping.


encephalopathy are the striatum (caudate nucleus and putamen) and hippocampus. Diffuse cortical abnormalities are more important for prognosis than abnormalities in other locations.13,17 Reperfusion can also cause microhemorrhages in the basal ganglia.1,5 There have been earlier reports of delayed demyelination in anoxic-ischemic encepha-lopathy, similar to that in carbon monoxide poisoning, but it is rare (Chapter 62). MRI might be useful, but we have seen patients do very poorly with repeatedly normal MRI during their hospitalization. (MRI in persistently comatose patients over time will then show diffuse atrophy.)


Evidence-based guidelines are not available to assist in the management of the “postresus-citation” phase.11 The primary goals of treatment at this stage are hemodynamic resusci-tation and maintenance of adequate oxygenation. The patient is typically intubated and ventilated “in the field.” Hyperoxygenation with Pao2 goals of 100 to 150 mm Hg and normocapnia Pao2 40 to 45 mm Hg may be considered. (Rat models have demonstrated a reduction in volume of necrotic tissue if Pao2 levels are maintained >200 mm Hg.)10 Blood pressure temporarily increases in some patients, partly due to the effect of epineph-rine administered during resuscitative measures. As the cerebral autoregulation curve is right-shifted and microcirculatory disturbances are present, it could be advantageous to maintain normotension or some degree of hypertension and to increase tissue perfusion, but there is no clinical proof of such a measure.

Therapeutic hypothermia (Chapter 66) is currently used in comatose or stuporous patients after out-of-hospital CPR.3,6 In clinical trials, the interval to initiation of hypo-thermia has been two to three hours after ventricular fibrillation with core temperatures around 32°C to 34°C. Hypothermia is achieved with invasive or noninvasive cooling devices and maintained for 24 hours. Sedation and neuromuscular blocking agents are administered and gradual rewarming follows. Surface cooling can only be reliably achieved with a temperature-regulating device. Practical limitations of hypothermia include com-plications such as coagulopathy, electrolyte shifts, and cardiac arrhythmias. However, a short period of hypothermia results in few complications and is relatively safe.2,15

Generalized tonic-clonic seizures are uncommon and may be related to lidocaine administration during resuscitation. A more serious concern is the appearance of myo-clonic status epilepticus. Intermittent or continuous, synchronous or asynchronous jerky movements affect the face, trunk, and limbs.19 These myoclonic jerks can be very forceful, interfere with mechanical ventilation, and be a source of distress for family members. Myoclonic status epilepticus is difficult to treat and does not respond to conventional


antiepileptic drugs. Under these circumstances, propofol, levetiracetam, or as a last resort neuromuscular-blocking agents are more useful.16

Immediately following resuscitation, the EEG may show marked electrographic sup-pression or more distinctive patterns (e.g., burst suppression), and these patterns tend to evolve after 24 hours.8,21 Their value for prognostication remains uncertain. Median nerve somatosensory-evoked potentials (SSEP) have been used in the prediction of recovery after cardiac arrest. If the N20 (cortical) potential is bilaterally absent in the presence of preserved potentials in the cervical cord, the test has a specificity of 100% for poor outcome.9,18 Other clinical and laboratory criteria that predict poor prognosis with high certainty have been identified and a recent guideline has been published (Fig. 65-3).18 The value of neuroimaging in prognostication is still unresolved.7 These guidelines only apply to patients not treated with hypothermia, which may still be 50% of patients admit-ted to the hospital, and therefore could be different after utilization of therapeutic hypo-thermia (Chapter 66). A careful examination remains important, and the FOUR score is a much better predictor than the Glasgow Coma Scale score.4 When these clinical and

Coma

Excludemajor

confounders

No brain stem reflexes at any time

(pupil, cornea, oculocephalic,cough)

Day 1 Myoclonus

Status Epilepticus

Day 1–3 Serum NSE > 33 g/L

Day 3 Absent pupil or corneal

reflexes; extensor or absentmotor response

Day 3SSEP

absent N20 responses

No

Or

Or

Or

Or

Indeterminate outcome

Yes

Yes

Yes

Yes

Yes

FPR0%

(0–8.8)

FPR0%

(0–3)

FPR0%

(0–3)

FPR0.7%(0–3)

Brain deathtesting

Pooroutcome

Pooroutcome

Pooroutcome

Pooroutcome

FIGURE 65-3 The American Academy of Neurology guidelines for prognostication in comatose

patients following CPR. From Wijdicks et al.18 with permission. NSE = Neuron specific enolase,

SSEP = Somatosensory Evoked Potentials


SSEP findings are found, physicians should be pessimistic for recovery. In patients with protracted awakening, quality of life may be affected, but cognitive decline in patients returning home is less than 10%.8

A CONCLUDING NOTE

Hypothermia is an emerging therapy for comatose patients resuscitated for ventricular fibrillation. The value of other supportive care measures (e.g., blood pressure augmen-tation) is less certain. Poor prognosis in comatose patients after CPR can be reliably predicted.

REFERENCES

1. Arbelaez A, Castillo M, Mukherji SK. Diffusion-weighted MR imaging of global cerebral anoxia. AJNR Am J Neuroradiol 1999;20:999–1007.

2. Bernard SA, Buist M. Induced hypothermia in critical care medicine: a review. Crit Care Med 2003;31:2041–2051.

3. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557–563.

4. Fugate JE, Rabinstein AA, Claassen DO, White RD, Wijdicks EF. The FOUR score predicts outcome in patients after cardiac arrest. Neurocrit Care 2010;13:205–210.

5. Fujioka M, Okuchi K, Sakaki T, et al. Specific changes in human brain following reperfusion after cardiac arrest. Stroke 1994;25:2091–2095.

6. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neuro-logic outcome after cardiac arrest. N Engl J Med 2002;346:549–556.

7. Hahn DK, Geocadin RG, Greer DM. Quality of evidence in studies evaluating neuroimaging for neuro-logic prognostication in adult patients resuscitated from cardiac arrest. Resuscitation. 2014:85:165–172.

8. Horsted TI, Rasmussen LS, Meyhoff CS, Nielsen SL. Long-term prognosis after out-of-hospital cardiac arrest. Resuscitation 2007;72:214–218.

9. Logi F, Fischer C, Murri L, Mauguiere F. The prognostic value of evoked responses from primary somatosensory and auditory cortex in comatose patients. Clin Neurophysiol 2003;114:1615–1627.

10. Miyamoto O, Auer RN. Hypoxia, hyperoxia, ischemia, and brain necrosis. Neurology 2000;54:362–371.11. Nolan JP, Neumar RW, Adrie C, et al. Post-cardiac arrest syndrome: epidemiology, pathophysiology,

treatment, and prognostication. A Scientific Statement from the International Liaison Committee on Resuscitation; the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; the Council on Stroke. Resuscitation 2008;79:350–379.

12. Sadove MS, Yon MK, Hollinger PH, Johnston KS, Phillips FL. Severe prolonged cerebral hypoxic epi-sode with complete recovery. JAMA 1961;175:1102–1104.

13. Singhal AB, Topcuoglu MA, Koroshetz WJ. Diffusion MRI in three types of anoxic encephalopathy. J Neurol Sci 2002;196:37–40.

14. Sloper JJ, Johnson P, Powell TP. Selective degeneration of interneurons in the motor cortex of infant monkeys following controlled hypoxia: a possible cause of epilepsy. Brain Res 1980;198:204–209.

15. Wijdicks EFM. Induced hypothermia in neurocatastrophes: feeling the chill. Rev Neurol Dis 2004;1:10–15.

16. Wijdicks EFM. Propofol in myoclonus status epilepticus in comatose patients following cardiac resusci-tation. J Neurol Neurosurg Psychiatry 2002;73:94–95.


17. Wijdicks EFM, Campeau NG, Miller GM. MR imaging in comatose survivors of cardiac resuscitation. AJNR Am J Neuroradiol 2001;22:1561–1565.

18. Wijdicks EFM, Hijdra A, Young GB, Bassetti CL, Wiebe S. Practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;67:203–210.

19. Wijdicks EFM, Parisi JE, Sharbrough FW. Prognostic value of myoclonus status in comatose survivors of cardiac arrest. Ann Neurol 1994;35:239–243.

20. Wijman CA, Mlynash M, Caulfield AF, et al. Prognostic value of brain diffusion-weighted imaging after cardiac arrest. Ann Neurol 2009;65:394–402.

21. Young GB. The EEG in coma. J Clin Neurophysiol 2000;17:473–485.

561

A CONVERSATION

AN EXPLANATION

On average, 50% of patients who had out-of-hospital cardiac arrest and had resumption of circulation are entered into a therapeutic hypothermia protocol.7 The utilization of hypothermia varies greatly throughout the world but in some countries it is up to 80% of patients who had a successful cardiac resuscitation.

Comatose after Therapeutic hypothermia

/ / / 66 / / /


This intervention has dramatically changed the landscape of outcome assessment—certainly for neurologists. Consultants are now suddenly faced with examining a coma-tose patient after a major intervention with a number of confounders that all seem to converge into a difficult to assess clinical condition. Patients who are comatose following cardiopulmonary resuscitation most likely have associated kidney and liver injury due to prolonged shock and have now also been treated with varying (some very high) IV doses of opioids, neuromuscular junction blockers, and benzodiazepines. Even after rewarming of the patient, these drugs are expected to linger and cause difficulty in assessment. This situation is not comparable to the typical assessment of coma after anoxic-ischemic brain injury as discussed in the prior chapter, and there should be extreme caution.15

The causes of coma after therapeutic hypothermia (Table 66-1) are more or less simi-lar to any type of anoxic-ischemic injury, but using both opioids and benzodiazepines in a cooled patient with marked liver function abnormalities may complicate assessment. Clearance of fentanyl and propofol is significantly lower in therapeutic hypothermia, but midazolam levels seem to be relatively unaffected.1

Continuous EEG monitoring has complicated assessment even further, particularly because now abnormalities are seen that were not known before. Seizures and nonconvul-sive status epilepticus have been seen in approximately 10% to 15% of patients. The risk of seizures may clearly increase during rewarming. The significance of these abnormal EEG patterns is not known, but they must be considered a worrisome observation if it emerges during hypothermia (note that hypothermia is often an effective treatment for seizures).11 Clinically, there is still close to 100% mortality in patients with myoclonus status epilepticus, although occasional cases have been described with post-arrest improvement. It is unclear whether the reported patients had profound myoclonus, subtle twitching, seizures, or both.


There is general understanding that therapeutic hypothermia improves outcome and cogni-tive outcomes are better than expected.4 Hypothermia does not delay awakening but it is simply a consequence of high-dose IV infusions of CNS depressants.6 It has little or no effect on evoked potentials.2 A general prognosis can be given only if the patient continues to be normothermic and there is no evidence of a lingering effect of sedation or paralyzing drugs. The major concerns with hypothermia are summarized in Figure 66-1. Two new trials found

TABLE 66-1 Causes of Coma after Therapeutic hypothermia

• Anoxic-ischemic cortical damage• Lingering benzodiazepines and opioids• Coexisting severe liver and kidney failure• Status epilepticus during rewarming

Comatose after Therapeutic hypothermia / / 563

that 1) prehospital cooling was not effective and 2) no difference was found between 33°C and 36°C cooling targets.10

Prognosis after therapeutic hypothermia can be assessed, and in the vast majority of patients the presence of myoclonus status epilepticus before, during, and after hypother-mia remains a poor prognosticating feature.5,9 Treating seizures during hypothermia does not result in better outcome. A burst-suppression pattern, however, in general cannot dis-criminate between good and poor outcome in this category of patients.3 Brainstem injury also remains difficult to assess, and errors have been made in determining this more severe category of patients. The EEG can markedly vary but can yield important prog-nostic information.12–14 A reactive theta coma may result in good outcome. A nonreactive background on EEG indicates a poor prognosis.

A CONCLUDING NOTE

Assessment and prognostication may have changed since the introduction of therapeutic hypothermia largely due to use of new IV drugs. Frequent use of EEG monitoring detects abnormalities of uncertain significance.8 The ideal cooling target is now unknown but can be closer to 36°C.

REFERENCES

1. Bjelland TW, Klepstad P, Haugen BO, Nilsen T, Dale O. Effects of hypothermia on the disposition of morphine, midazolam, fentanyl, and propofol in intensive care unit patients. Drug Metab Dispos 2013;41:214–223.

2. Bouwes A, Binnekade JM, Zandstra DF, et al. Somatosensory evoked potentials during mild hypother-mia after cardiopulmonary resuscitation. Neurology 2009;73:1457–1461.

Clearance of benzodiazipinesOpioids

Coronary perfusionCardiac output

Cardiac arrhythmias

PneumoniaAtelectasis

Insulin secretionHyperglycemia

Cold diuresisHypovolemia

FIGURE 66-1 Effects of therapeutic hypothermia. From reference 16.


3. Crepeau AZ, Rabinstein AA, Fugate JE, et al. Continuous EEG in therapeutic hypothermia after cardiac arrest: prognostic and clinical value. Neurology 2013;80:339–344.

4. Fugate JE, Moore SA, Knopman DS, et al. Cognitive outcomes of patients undergoing therapeutic hypo-thermia after cardiac arrest. Neurology 2013;81:40-45.

5. Fugate JE, Wijdicks EFM, Mandrekar J, et al. Predictors of neurologic outcome in hypothermia after cardiac arrest. Ann Neurol 2010;68:907–914.

6. Fugate JE, Wijdicks EFM, White RD, Rabinstein AA. Does therapeutic hypothermia affect time to awak-ening in cardiac arrest survivors? Neurology 2011;77:1346–1350.

7. Holzer M, Bernard SA, Hachimi-Idrissi S, et al. Hypothermia for neuroprotection after cardiac arrest: sys-tematic review and individual patient data meta-analysis. Crit Care Med 2005;33:414–418.

8. Kawai M, Thapalia U, Verma A. Outcome from therapeutic hypothermia and EEG. J Clin Neurophysiol 2011;28:483–488.

9. Lucas JM, Cocchi MN, Salciccioli J, et al. Neurologic recovery after therapeutic hypothermia in patients with post-cardiac arrest myoclonus. Resuscitation 2012;83:265–269.

10. Mearns BM. Therapeutic hypothermia after out-of-hospital cardiac arrest. Nature Rev Cardiol 2014; in press.

11. Rabinstein AA, Wijdicks EFM. The value of EEG monitoring after cardiac arrest treated with hypother-mia. Neurology 2012;78:774–775.

12. Rossetti AO, Logroscino G, Liaudet L, et al. Status epilepticus: an independent outcome predictor after cerebral anoxia. Neurology 2007;69:255–260.

13. Rossetti AO, Oddo M, Liaudet L, Kaplan PW. Predictors of awakening from postanoxic status epilepti-cus after therapeutic hypothermia. Neurology 2009;72:744–749.

14. Rossetti AO, Urbano LA, Delodder F, Kaplan PW, Oddo M. Prognostic value of continuous EEG moni-toring during therapeutic hypothermia after cardiac arrest. Crit Care 2010;14:R173.

15. Wijdicks EFM, Hijdra A, Young GB, Bassetti CL, Wiebe S. Practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;67:203–210.

16. Wijdicks EFM. Neurologic Complications of Critical Illness. Contemporary Neurology Series. Oxford University Press, 2009.

565

A CONVERSATION

AN EXPLANATION

Intentional hangings may be classified as complete (suspended body) or incomplete (feet touching the ground).11,14 In near-hangings (a similar connotation as in near-drowning), patients are found with a trace of breathing and a pulse. Often, strangling injury is noted (Fig. 67-1). Depending on time of suspension and body drop, laryngotracheal, neck, and spinal cord injury can occur.3 Pulmonary edema may occur.13 Accidental strangulation injuries do occur commonly in children less than 1 year (e.g., playgrounds).12

Comatose after Near-hanging/ / / 67 / / /


The causes of coma after hanging are shown in Table 67-1. A lesion at the upper medulla-pons may become apparent due to sudden kinking forces, but more commonly lesions are due to severe anoxic-ischemic injury. Direct carotid artery injury may occur, causing cerebral infarcts. Status epilepticus has been reported in a single case.10 Neck fracture in near-hanging is uncommon because a hangman fracture (fracture through the arch of the second cervical vertebra) often leads to cardiac arrest and the patient arrives dead. CT scan in near-hanging may show early cerebral swelling from anoxic injury, but MRI may be far more sensitive in demonstrating these lesions.1,2,4 Bilateral signal changes in lentiform nuclei and medial thalami may occur (Fig. 67-2).4,7 Typical findings on MRI also include vocal cord and traumatic lymph node hemorrhages.15


The treatment of near-hanging is supportive. Therapeutic hypothermia—similar as in survivors of cardiac arrest—has been employed, but experience is limited to single cases.6 The injury in suicidal hanging is obviously different than in executional-type hangings because the body does not fall from a great height, carotid arteries are rarely lacerated, and the larynx is seldom injured. In many cases of suicidal hangings, alcohol or drugs are confounding factors. It is a common misunderstanding that outcome is poor in these

FIGURE 67-1 Evidence of strangling injury on the neck.

TABLE 67-1 Causes of Coma after Near-hanging

• Cortical laminar necrosis• Bithalamic necrosis• Pontine-medulla injury• Bilateral carotid occlusions and hemispheric infarcts• Status epilepticus

Comatose after Near-hanging / / 567

patients—including those with abnormalities on MRI—and even patients with no motor response to pain or eye opening to pain and fixed pupils have surprisingly returned home with few neurologic deficits. Poor prognostic factors are a circumferential ligature mark (indicator of more severe anoxic injury to the brain), cardiopulmonary arrest at the scene, comatose with no motor response, and hanging time of more than five minutes, but again, exceptional recoveries have been reported.8 In a recent series, 32% of patients comatose with no motor response of 3 returned to independent living.9 In the largest experience of 63 patients, additional indicators of poor outcome were shock, Injury Severity Score more than 15, and “anoxia on CT.”11 There was no apparent benefit of therapeutic hypo-thermia in 16 survivors of near-hanging and cardiac arrest.5

A CONCLUDING NOTE

Patients who survive a suicidal hanging attempt can make a favorable recovery, and prog-nostication is uncertain due to little available clinical experience. This is different from prognostication in patients with cardiac arrest. Neuroimaging—despite abnormalities—may not be predictive of outcome.

REFERENCES

1. Bianco F, Floris R. Computed tomography abnormalities in hanging. Neuroradiology 1987;29:297–298.2. Brancatelli G, Sparacia G, Midiri M, et al. Brain damage in hanging: a new CT finding. Neuroradiology

2000;42:209–210.3. Kaki A, Crosby ET, Lui AC. Airway and respiratory management following non-lethal hanging. Can

J Anaesth 1997;44:445–450.

FIGURE 67-2 Bithalamic injury on DWI MRI.


4. Kalita J, Mishra VN, Misra UK, Gupta RK. Clinicoradiological observation in three patients with sui-cidal hanging. J Neurol Sci 2002;198:21–24.

5. Lee BK, Jeung KW, Lee HY, Lim JH. Outcomes of therapeutic hypothermia in unconscious patients after near-hanging. Emerg Med J 2012;29:748–752.

6. Legriel S, Bouyon A, Nekhili N, et al. Therapeutic hypothermia for coma after cardiorespiratory arrest caused by hanging. Resuscitation 2005;67:143–144.

7. Matsuyama T, Okuchi K, Seki T, et al. Magnetic resonance images in hanging. Resuscitation 2006;69:343–345.

8. Matsuyama T, Okuchi K, Seki T, Murao Y. Prognostic factors in hanging injuries. Am J Emerg Med 2004;22:207–210.

9. Penney DJ, Stewart AH, Parr MJ. Prognostic outcome indicators following hanging injuries. Resuscitation 2002;54:27–29.

10. Pesola GR, Westfal RE. Hanging-induced status epilepticus. Am J Emerg Med 1999;17:38–40.11. Salim A, Martin M, Sangthong B, et al. Near-hanging injuries: a 10-year experience. Injury

2006;37:435–439.12. Sep D, Thies KC. Strangulation injuries in children. Resuscitation 2007;74:386–391.13. Viswanathan S, Muthu V, Remalayam B. Pulmonary edema in near hanging. J Trauma Acute Care Surg

2012;72:297–301.14. Wahlen BM, Thierbach AR. Near-hanging. Eur J Emerg Med 2002;9:348–350.15. Yen K, Thali MJ, Aghayev E, et al. Strangulation signs: initial correlation of MRI, MSCT, and forensic

neck findings. J Magn Reson Imaging 2005;22:501–510.

569

A CONVERSATION

AN EXPLANATION

Fat embolization is a neurologic entity that is hard to diagnose, because it may occur unexpectedly, it is rare, and there may be no specific clinical sign that points in that direction. It usually occurs after a major trauma. Mostly on the same day, the patient’s condition deteriorates, and therefore other causes (e.g., delayed cerebral hematoma or acute subdural hematoma) are more often considered. Fat embolization may also occur days after the initial impact in a recovering patient. Cotton-wool spots, petechial

Comatose after Fat Embolism Syndrome

/ / / 68 / / /


hemorrhages, and intravascular fat globules may be seen in the fundi, but only in patients with widespread skin petechiae and thrombocytopenia. Fat embolization syndrome can be recognized by tachycardia, fever, and increased erythrocyte sedimentation rate, but also a petechial skin rash (Fig. 68-1). Fat embolization syndrome characteristically shows a gradual worsening of a patient several hours after the incident and lapse into deep unresponsive coma. It may be preceded by agitation or fluctuating responsiveness that often is misinterpreted as a reaction to opioids given for pain management of the fracture.

Fat globules can enter the peripheral microcirculation and get caught by lung tis-sue or can simply squeeze in, pass, and enter the systemic and cerebral circulation. This embolization may be facilitated by a high intramedullary pressure in the fractured bone. It may also be a consequence of intramedullary nailing.

Causes of coma in fat embolization are shown in Table 68-1. Traumatic brain injury needs to be excluded and, most commonly, delayed cerebral contusions have to be con-sidered.2,5,7 Fat embolization is often not recognized and failure to awaken after surgery may be attributed to hypotension or hypoxemia. Some of these patients may also develop paroxysmal sympathetic hyperactivity syndrome and this manifestation is explained by multifocal lesions in the thalamus and brainstem. This diencephalic-mesencephalic dysfunction leads to autonomic nervous system dysregulation.

FIGURE 68-1 Petechial skin rash.

TABLE 68-1 Fat Embolism Syndrome

• Multifocal cortical, white matter, and brainstem lesions (infarcts or edema)• Opioid overdose for treatment of fracture• Coexisting traumatic delayed contusions• Nonconvulsive status epilepticus

Comatose after Fat Embolism Syndrome / / 571

Clinical criteria for fat embolization are shown in Table 68-2. Neuropathologic stud-ies in patients with cerebral fat embolization involvement have demonstrated fat droplets in arteries supplying both white and gray matter and multiple microinfarcts. This finding can now be demonstrated on MRI and it is diagnostic when it shows a “starfield” or starry sky pattern (Fig. 68-2). These are scattered foci of restricted diffusion on DWI sequences and they may start as small lesions becoming more confluent in the following days.4,8

TABLE 68-2 Fat Embolism Syndrome

Major criteria Petechial rash

Respiratory symptoms—tachypnea, dyspnea, bilateral inspiratory

crepitations, hemoptysis, bilateral diffuse patchy shadowing on chest x-ray

Neurologic—confusion, drowsiness, comaMinor criteria Tachycardia >120 bpm

Pyrexia >39.4°C

Retinal changes—fat or petechiae

Renal changes—anuria or oliguria

JaundiceLaboratory Thrombocytopenia (>50% decrease of admission value)

Sudden decrease in hemoglobin level (>20% of admission value)

High erythrocyte sedimentation rate (>70 mm/h)

Macroglobulinemia

Fat in sputum


FIGURE 68-2 MRI showing specks of edema or infarction in a “starfield” pattern.



There is no good treatment, and management is largely supportive. Opioids, beta block-ers, gabapentin, and alpha-1 agonists can manage the paroxysmal sympathetic hyperac-tivity syndrome. Corticosteroids have a role in preventing fat embolization syndrome, but there is no evidence they improve outcome or reduce edema after fat emboli have been dispersed. Prognosis can be very good. After reviewing all these cases, it appears that approximately two thirds of the patients who became comatose from cerebral fat embolization made very good recoveries.3

A CONCLUDING NOTE

Cerebral fat embolization syndrome can occur with any long-bone fracture or high-velocity gunshot wounds.3,6 It may not be preceded by pulmonary edema. Even comatose patients with MRI abnormalities may recover well.

REFERENCES

1. Gurd AR. Fat embolism: an aid to diagnosis. J Bone Joint Surg Br 1970;52:732–737.2. Husebye EE, Lyberg T, Roise O. Bone marrow fat in the circulation: clinical entities and pathophysiologi-

cal mechanisms. Injury 2006;37 Suppl 4:S8–18.3. Mittal MK, Burrus TM, Campeau NG. Good recovery following cerebral fat embolization with paroxys-

mal hyperactivity syndrome. Neurology 2013;81:e107–109.4. Parizel PM, Demey HE, Veeckmans G, et al. Early diagnosis of cerebral fat embolism syndrome by

diffusion-weighted MRI (starfield pattern). Stroke 2001;32:2942–2944.5. Robert JH, Hoffmeyer P, Broquet PE, Cerutti P, Vasey H. Fat embolism syndrome. Orthop Rev

1993;22:567–571.6. Samarasekera S, Mazibrada G. Shot in the foot. Pract Neurol 2012;12:382–383.7. Sinha P, Bunker N, Soni N. Fat embolism—An update. Curr Anaesthesia Critical Care 2010;21:277–281.8. Takahashi M, Suzuki R, Osakabe Y, et al. Magnetic resonance imaging findings in cerebral fat embo-

lism: correlation with clinical manifestations. J Trauma 1999;46:324–327.

573

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AN EXPLANATION

Iatrogenic gas embolization is rare; some have estimated the incidence at approximately 3 per 100,000 hospitalizations.2 When it is clinically recognized, it is associated in 25% of cases with central venous catheterization and during accidental removal, manipulation or insertion.6 This is because—as a result of respiration—the potential for negative pres-sure exists in the thoracic vessels. It has also been described in biopsies including pleural

Comatose and air Embolism/ / / 69 / / /


puncture, transthoracic biopsy, or bronchoscopy and endoscopic retrograde cholangio-pancreatography (ERCP).1 Massive air embolization has been reported after cesarean section. 4 Classically, air embolization has been noted with neurosurgery in a sitting posi-tion, when this position is required during spine surgery. Air embolism is not expected as a complication of interventional radiology (i.e., enterography or coronary angiogram) and during massive blood transfusion.

Lodging of air in multiple arteries—after travel through the lungs or a patent fora-men ovale (present in 30% of normal individuals)—results in acute hypoxemia and hypercapnia. The acute changes in right ventricular pressure lead to right heart strain and failure, decreased cardiac output, right ventricular ischemia, and arrhythmia. This often leads to systemic circulatory collapse. Arterial air embolization can result in marked cardiac ischemia and ST elevation, and myocardial infarction may be seen in about 20% of the patients. The causes of coma after air emboli to the brain are shown in Table 69-1.

The diagnosis of air embolism requires, first, the recognition of a highly unusual situation and, second, a recent procedure that may have introduced air into the vascular system. Most of the neurologic symptoms—similar to those in fat embolization—are acute coma, often with a presenting seizure.3 Patients may eventually have ischemic strokes in the territory involved. There may also be an arterial air embolism causing a spinal cord injury. Systemic injury activates coagulation cascades and causes diffuse intravascular coagulation. Cerebral air is often detected.7,9 CT scan of the brain eas-ily detects air as black (intravascular) spots (Fig. 69-1). A chest x-ray is often abnor-mal after a venous air embolization and patients develop an acute respiratory distress syndrome.

FIGURE 69-1 CT showing massive air.

Comatose and air Embolism / / 575


If a venous air embolism is strongly suspected, emergency management includes stop-ping air entry. A serious attempt at aspiration of the air from the right ventricle if a central catheter is being used should be tried while placing the patient in Trendelenburg and left lateral decubitus position (Durants maneuver). This positioning allows the entrapped air in the heart to stay within the apex of the ventricle. Ventilation with 100% oxygen cor-rects hypoxemia but also increases the diffusion gradient for nitrogen out of the bubbles. This may have to be followed with further stabilization, and that includes inotropic sup-port. If available, patients should be moved to a hyperbaric tank for a “dive” (Fig. 69-2). Most conventional hyperbaric chambers use 282 kPa, and this will result in significant spherical gas bubble volume reduction of up to 50%. Improving bubble passage through the microcirculation will reduce ischemia.

Hyperbaric oxygen provides oxygen at higher pressures, and recipients of hyperbaric oxygen have a better outcome.5,9 The best series published is by Moon and Gorman.8 In their series of 441 patients, 78% had full recovery, and 10% had residual deficit. Of the

TABLE 69-1 Causes of Coma in air Embolization

• Multiple cerebral infarcts• Cortical injury from shock• Diffuse intravascular coagulation• Nonconvulsive status epilepticus

4

Design of an hyperbaric oxygentherapy session

3

Pre

ssu

re (

AT

A)

2

1

00 15 30 45 60 75 90

Time (min)

105 120 135 155 168

FIGURE 69-2 Hyperbaric chamber protocol. Adapted from reference 8.


288 patients not treated with hyperbaric oxygen, 26% recovered fully, and 21% had resid-ual deficits.

Poor outcome can be expected when the air bubble volume is more than 500 cc. In most instances, patients remain comatose and care is withdrawn. Independent predictors for one-year mortality are age or acute renal failure.2 Long-term sequelae are expectedly related to a duration of mechanical ventilation or the presence of focal motor deficits.2

A CONCLUDING NOTE

Air embolization is probably more common than recognized. Acute use of hyperbaric therapy may improve outcome, but most hospitals do not have this capability.

REFERENCES

1. Al-Ali WM, Browne T, Jones R. A case of cranial air embolism after transthoracic lung biopsy. Am J Respir Crit Care Med 2012;186:1193–1195.

2. Bessereau J, Genotelle N, Chabbaut C, et al. Long-term outcome of iatrogenic gas embolism. Intensive Care Med 2010;36:1180–1187.

3. Burrell JR, Hayes M, Thanakrishnan G, Peters M. Coma and seizures due to gas emboli following extuba-tion. J Clin Neurosci 2009;16:344–345.

4. Davis FM, Glover PW, Maycock E. Hyperbaric oxygen for cerebral arterial air embolism occurring during caesarean section. Anaesth Intensive Care 1990;18:403–405.

5. Diethrich EB, Koopot R, Maze A, Dyess N. Successful reversal of brain damage from iatrogenic air embo-lism. Surg Gynecol Obstet 1982;154:572–575.

6. Grace DM. Air embolism with neurologic complications: a potential hazard of central venous catheters. Can J Surg 1977;20:51–53.

7. Hodics T, Linfante I. Cerebral air embolism. Neurology 2003;60:112.8. Moon RE, Gorman DF. Treatment of the decompression disorders. In: Brubakk AO, Neuman TS, eds.

Bennett and Elliott’s Physiology and Medicine of Diving, 5th ed. London: Saunders Ltd., 2003:506–541.9. Muth CM, Shank ES. Gas embolism. N Engl J Med 2000;342:476–482.

577

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AN EXPLANATION

Acute severe asthma unfortunately has a high mortality rate.1 Sudden asphyxic asthma is a subtype with a far more intense bronchoconstriction that may evolve within hours.5,9 With quick intervention, recovery is possible, but many patients suffer respiratory arrest that is not always witnessed, followed by cardiac arrest. Clinically significant hypoxemia, defined as an arterial Po2 of less than 30 mm Hg, does not necessarily cause neurologic deficit and is tentatively explained by the fact that hypoxemia does not lead to a release of

Comatose and Status asthmaticus

/ / / 70 / / /


excitatory amino acids.3,4,8 Recovery from hypoxemia alone may be due to repair of the hypoxemic synaptic alterations.10 The deep gray matter is far more susceptible to anoxia than the cortex, and in severe hypoxemia these areas are typically involved. Hypoxemia often involves the globus pallidus and lentiform nucleus.

The causes of coma in status asthmaticus are shown in Table 70-1. In most instances, anoxic-ischemic brain injury is expected. Marked hypercarbia with hypoxemia could cause impaired consciousness and deep coma in some patients and is fully reversible. Treatment with bronchodilators, particularly theophylline, should be considered as a potential cause of recurrent seizures.6 Toxicity of theophylline may occur with errors in administration, and this may be a reason for impaired consciousness if serum levels are not monitored.

CT scan abnormalities may show dramatic changes (Fig. 70-1). Severe hypoxemia with shock or cardiac arrest may result in diffuse cerebral edema, similar to survivors of cardiopulmonary resuscitation (Fig. 70-2). There may be more subtle abnormalities (Fig. 70-3).

TABLE 70-1 Causes of Coma in Status asthmaticus

• Anoxic-ischemic cortical injury• Severe hypercarbia• Theophylline toxicity• Drug-associated seizures

FIGURE 70-1 CT scan with multiple hypodensities including globus pallidus in a patient with

status asthmaticus. The prognosis was poor in this patient.

Comatose and Status asthmaticus / / 579


Patients with status asthmaticus are treated with high concentrations of intravenous oxy-gen, continuous nebulization of beta agonists, and intravenous corticosteroids. Isoflurane therapy has been recently suggested.2,7 Repeat infusions with potassium chloride are required because hypokalemia is common and exaggerated by fluid resuscitation and the use of beta-agonist bronchodilators. Mechanical ventilation is needed in most patients. ECMO may be a last effort, but it may not necessarily change outcome.11 Outcome is determined by the degree of hypoxemia. The neurologic prognostication of patients in whom the anoxic component of the acute brain injury is far greater than an ischemic

FIGURE 70-2 Diffuse cerebral edema in severe asphyxia. The outcome was poor.

FIGURE 70-3 Hippocampal abnormalities. The outcome was indeterminate.


component remains problematic. CT scan abnormalities can be alarming and prognosis can be poor. However, similar to other instances of respiratory failure in young individu-als, favorable recovery despite abnormal MRI findings have been described.

A CONCLUDING NOTE

Status asthmaticus may lead to hypoxemic asphyxia. CT scan can show diffuse cerebral edema with sparing of the cerebellum, which would indicate future disability. The prog-nosis—in the absence of diffuse MRI abnormalities—can be good. Prolonged time of observation for neurologic recovery should be allowed.

REFERENCES

1. Carroll CL, Sala KA. Pediatric status asthmaticus. Crit Care Clin 2013;29:153–166.2. Cooper MK, Bateman ST. Cisatracurium in “weakening doses” assists in weaning from sedation and

withdrawal following extended use of inhaled isoflurane. Pediatr Crit Care Med 2007;8:58–60.3. de Courten-Myers GM, Yamaguchi S, Wagner KR, Ting P, Myers RE. Brain injury from marked hypoxia

in cats: role of hypotension and hyperglycemia. Stroke 1985;16:1016–1021.4. Miyamoto O, Auer RN. Hypoxia, hyperoxia, ischemia, and brain necrosis. Neurology 2000;54:362–371.5. Phipps P, Garrard CS. The pulmonary physician in critical care. 12: Acute severe asthma in the intensive

care unit. Thorax 2003;58:81–88.6. Ream RS, Loftis LL, Albers GM, et al. Efficacy of IV theophylline in children with severe status asthmati-

cus. Chest 2001;119:1480-1488.7. Shankar V, Churchwell KB, Deshpande JK. Isoflurane therapy for severe refractory status asthmaticus in

children. Intensive Care Med 2006;32:927–933.8. Simon RP. Hypoxia versus ischemia. Neurology 1999;52:7–8.9. Stein R, Canny GJ, Bohn DJ, Reisman JJ, Levison H. Severe acute asthma in a pediatric intensive care

unit: six years’ experience. Pediatrics 1989;83:1023–1028.10. Yu MC, Bakay L, Lee JC. Effects of hypoxia and hypercapnic hypoxia on the ultrastructure of central

nervous synapses. Exp Neurol 1973;40:114–125.11. Zabrocki LA, Brogan TV, Statler KD, et al. Extracorporeal membrane oxygenation for pediatric respira-

tory failure: Survival and predictors of mortality. Crit Care Med 2011;39:364–370.

581

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AN EXPLANATION

Many patients with end-stage renal disease have had prior diabetes and vascular complica-tions, have poor cardiac function, and have a constant risk of uremia-associated bleeding. Hypertension is a common comorbid finding strongly associated with increased intra-vascular volume, increased sympathetic nervous system activity, and increased erythro-poietin, among other mechanisms. However, blood pressure may gradually decrease in the interdialysis period, and hypotension may become profound after substantial fluid

Comatose and Acute Uremia/ / / 71 / / /

582 / / The ComATose PATienT

removal. The presence of autonomic failure in many patients prevents blood pressure increase, but there is also an inability to compensate with increasing cardiac output or vasoconstriction. Acute renal failure is also a common complication in surgical, critically ill patients, or patients hospitalized for congestive heart failure.6,14

Acute renal failure is an indication for dialysis in many patients, and at that juncture, neurologic signs are found such as asterixis and multifocal myoclonus.2,3 Asterixis can be seen before a decrease in level of consciousness. (Asterixis, from the Greek “a-sterixis,” is best translated as no steadiness.) It is asynchronous and asymmetrical. Asterixis can also be demonstrated by puckering of the lips by the patient and protru-sion of the tongue. Worsening uremia may result in uncontrollable aggressive behavior with difficulty in restraining the patient, followed by gradual drowsiness, eye closure, and lying immobile with rapid or periodic breathing patterns. The development of sig-nificant pitting edema and a chest x-ray showing interstitial pulmonary edema are also useful clinical signs.

The causes of coma in acute uremia are shown in Table 71-1. The pathophysi-ology of uremic encephalopathy remains unclear and is likely a combination of accumulation of neurotoxins such as uric acid, amino acids, myoinositol, and gua-nidino compounds.8,9,11 Because blood levels of parathyroid hormone, insulin growth hormone, glucagon, and gastrin are elevated, these hormones could also be impli-cated. Abnormalities in brain dopamine and serotonin may play a role in the more severe cases of uremic encephalopathy. Impaired consciousness can also be due to recent administration of drugs that, in the setting of acute renal failure, accumulate and reach toxic levels.1,4

Thrombotic complications are equally common and explained by a hypercoagu-lable state in end-stage renal disease. Some of the main culprits are the presence of a lupus anticoagulant, increased platelet aggregation, decreased protein C, and increased homocysteine. Poor platelet function may increase the risk of a subdural hematoma.13 Uncontrolled hypertension may result in a hypertensive encephalopathy with character-istic MR findings.

TABLE 71-1 Causes of Coma in Acute Uremia

• Uremic encephalopathy due to uremic neurotoxins• Multiple watershed cerebral infarcts due to hypotension• Bilateral subdural hematoma• Posterior reversible encephalopathy syndrome

Comatose and Acute Uremia / / 583

The EEG is nonspecific but may show an excess of delta and theta waves and often bilateral sharp-wave complexes that are occasionally misinterpreted as nonconvulsive status epilepticus12 (Fig. 71-1). Equally frequent are triphasic waves. Nonetheless, non-convulsive status epilepticus has been sporadically reported.7 CT scan or MRI remains normal, but a recent study in a patient after first dialysis found an increased apparent dif-fusion coefficient in normal-appearing white and gray matter consistent with interstitial brain edema.5 This finding suggests a reverse urea effect due to a urea gradient resulting in water inflow to the brain.


Hemodialysis will improve the laboratory values fairly rapidly, but the recovery of level of consciousness is often protracted. Generally, the serum level of urea and creatinine cor-relates poorly with uremic encephalopathy; thus, failure to improve rapidly can be seen with rapid improvement of the renal indices. Renal replacement therapy can adequately benefit patients and may serve as a bridge to renal transplantation. Long-term outcome of patients with uremic encephalopathy remains poor due to considerable associated medi-cal comorbidity. Severe myoclonus responds well to dexmedetomidine.10

FIGURE 71-1 EEG epoch of a patient with a severe uremic encephalopathy shows generalized

slowing and quasi-periodic sharp waves maximal over the right and midparietal regions. The

arrows indicate occurrence of mouth movements time-locked to higher-amplitude discharges.


A CONCLUDING NOTE

Uremic encephalopathy is a common cause of impaired consciousness because renal failure is a common complication in hospitalized patients. The sudden onset of pitting edema, and pulmonary infiltrate in a patient with diabetes may indicate acute renal fail-ure, and impaired consciousness may be caused by a profound uremia.

REFERENCES

1. Abanades S, Nolla J, Rodriguez-Campello A, et al. Reversible coma secondary to cefepime neurotoxicity. Ann Pharmacother 2004;38:606–608.

2. Brouns R, De Deyn PP. Neurological complications in renal failure: a review. Clin Neurol Neurosurg 2004;107:1–16.

3. Burn DJ, Bates D. Neurology and the kidney. J Neurol Neurosurg Psychiatry 1998;65:810–821.4. Chatellier D, Jourdain M, Mangalaboyi J, et al. Cefepime-induced neurotoxicity: an underestimated

complication of antibiotherapy in patients with acute renal failure. Intensive Care Med 2002;28:214–217.5. Chen CL, Lai PH, Chou KJ, et al. A preliminary report of brain edema in patients with uremia at first

hemodialysis: evaluation by diffusion-weighted MR imaging. AJNR Am J Neuroradiol 2007;28:68–71.6. Chittineni H, Miyawaki N, Gulipelli S, Fishbane S. Risk for acute renal failure in patients hospitalized for

decompensated congestive heart failure. Am J Nephrol 2007;27:55–62.7. Chow KM, Wang AY, Hui AC, et al. Nonconvulsive status epilepticus in peritoneal dialysis patients. Am

J Kidney Dis 2001;38:400–405.8. Deguchi T, Isozaki K, Yousuke K, Terasaki T, Otagiri M. Involvement of organic anion transporters in

the efflux of uremic toxins across the blood-brain barrier. J Neurochem 2006;96:1051–1059.9. Mahoney CA, Arieff AI. Uremic encephalopathies: clinical, biochemical, and experimental features. Am

J Kidney Dis 1982;2:324–336.10. Nomoto K, Scurlock C, Bronster D. Dexmedetomidine controls twitch-convulsive syndrome in the

course of uremic encephalopathy. J Clin Anesth 2011;23:646–648.11. Schmidt M, Sitter T, Lederer SR, Held E, Schiffl H. Reversible MRI changes in a patient with uremic

encephalopathy. J Nephrol 2001;14:424–427.12. Seifter JL, Samuels MA. Uremic encephalopathy and other brain disorders associated with renal failure.

Semin Neurol 2011;31:139–143.13. Sood P, Sinson GP, Cohen EP. Subdural hematomas in chronic dialysis patients: significant and increas-

ing. Clin J Am Soc Nephrol 2007;2:956–959.14. Sykes E, Cosgrove JF. Acute renal failure and the critically ill surgical patient. Ann R Coll Surg Engl

2007;89:22–29.

585

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AN EXPLANATION

Clinically, a hypertensive crisis is recognized by the presence of high systolic and diastolic blood pressures (mean arterial blood pressure >140 mm Hg), acute left ventricular strain, and papilledema (Fig. 72-1).3 The neuro-ophthalmological signs are valuable, but hemor-rhages and cotton-wool spots are not easily recognized and in a nondilated pupil escape the examiner.3 Acute hypertensive crisis is an underappreciated cause of rapid-onset impaired consciousness. An acute hypertensive crisis leading to brain injury has been termed posterior reversible encephalopathy syndrome (PRES).

Comatose and hypertensive Crisis

/ / / 72 / / /


The causes of coma in PRES are shown in Table 72-1. Triggering conditions are shown in Table 72-2.7,13,16 Breakthrough edema is the most accepted explanation.17 Hypertension, particularly when rapidly increasing, acutely disrupts the blood–brain barrier, causing extravasation (a transudate or vasogenic edema). Coma in PRES can be due to several lesions that can interrupt the arousal system. It includes the presence of multiple gray–white matter patches of vasogenic edema20, pontine involvement,4,5,15,17 or a predominantly anterior involvement.6,8,18 Edema of the cerebellum can result in an acute obstructive hydrocephalus, but global edema has been reported.1,11 Seizures or a prolonged postictal state could be a presenting clinical feature.9

FIGURE 72-1 Cotton-wool spots and papilledema in acute hypertensive emergency.

TABLE 72-1 Causes of Acute hypertensive Crisis (PRes)

• Diffuse white matter edema• Bithalamic edema• Pontine edema• Cerebellar edema with acute hydrocephalus

Comatose and hypertensive Crisis / / 587

FIGURE 72-2 CT showing PRES with some petechial hemorrhages.

TABLE 72-2 Conditions Associated With Acute hypertensive Crisis (PRes)

Toxemia of pregnancyDrugsCyclosporineTacrolimusInterferon-alphaFludarabineCisplatinGemcitabineErythropoietinIfosfamide

Uncontrolled essential hypertensionSecondary hypertensionSystemic lupus erythematosusAcute glomerulonephritisHypertension with chronic renal failure

OthersSeptic shockHemolytic-uremic syndromeHepatorenal syndromeAcute intermittent porphyriaThrombotic thrombocytopenic purpura

Data from references 2,14,16,21,22.


CT scan will demonstrate hypodensities in the posterior regions and there may be petechial hemorrhages. On MRI Hyperintensities on T2-weighted images with an increase in apparent diffusion coefficient (ADC) suggest cerebral vasogenic edema. It has been convincingly argued that the term “PRES” is a misnomer, but it is hard to eliminate from the medical lexicon.9 In most cases, it is not exclusively posterior(Fig. 72-3), it may not be reversible, and it could result in cerebral infarction and sequelae.7,10,12,21 Recurrence has been reported. In newly presenting cases, a renal artery stenosis should be sought and can be documented by MRA (Fig. 72-4).


Acute control of blood pressure using labetalol, hydralazine, or intravenous nicardipine is warranted. It is prudent to decrease the mean arterial pressure by 20% acutely or to

FIGURE 72-3 MRI showing multiple areas of edema in PRES (pons, cerebellum, unilateral

parieto-occipital, posterior regions).

Comatose and hypertensive Crisis / / 589

aim for a diastolic pressure of 100 mm Hg or less.19,22 One concern is the development of a relative hypotension, but it remains unproven whether permanent cerebral infarcts in PRES—when they occur— are a consequence of a steep decline in blood pressure. Aggressive management of seizures with intravenous loading with (phos)phenytoin (20 mg/kg) is warranted. Ventriculostomy may be needed in patients with cerebellar edema and obstructive hydrocephalus.1 Many patients recover in a protracted way that may take weeks, initially with marked fluctuations in consciousness.

A CONCLUDING NOTE

Hypertensive surges (mean arterial pressures more than 140 mm Hg), cotton-wool spots, and evidence of left ventricular hypertrophy are early clinical clues for acute hyperten-sive encephalopathy. PRES on MRI may have multiple appearances (frontal, parietal, thalamus, pons, and cerebellar) and rarely shows vasogenic edema in the posterior regions alone.

REFERENCES

1. Adamson DC, Dimitrov DF, Bronec PR. Upward transtentorial herniation, hydrocephalus, and cerebel-lar edema in hypertensive encephalopathy. Neurologist 2005;11:171–175.

2. Bartynski WS, Boardman JF, Zeigler ZR, Shadduck RK, Lister J. Posterior reversible encephalopathy syndrome in infection, sepsis, and shock. AJNR Am J Neuroradiol 2006;27:2179–2190.

3. Bell ML, Wijdicks EFM. The triumvirate of acute hypertension. Neurology 2005;65:E5.4. Casey SO, Truwit CL. Pontine reversible edema: a newly recognized imaging variant of hypertensive

encephalopathy? AJNR Am J Neuroradiol 2000;21:243–245.5. Cruz-Flores S, de Assis Aquino Gondim F, Leira EC. Brainstem involvement in hypertensive encepha-

lopathy: clinical and radiological findings. Neurology 2004;62:1417–1419.

FIGURE 72-4 High-grade left renal artery stenosis.


6. Gokce M, Dogan E, Nacitarhan S, Demirpolat G. Posterior reversible encephalopathy syndrome caused by hypertensive encephalopathy and acute uremia. Neurocrit Care 2006;4:133–136.

7. Hagemann G, Ugur T, Witte OW, Fitzek C. Recurrent posterior reversible encephalopathy syndrome (PRES). J Hum Hypertens 2004;18:287–289.

8. Hinchey J, Chaves C, Appignani B, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med 1996;334:494–500.

9. Kozak OS, Wijdicks EFM, Manno EM, Miley JT, Rabinstein AA. Status epilepticus as initial manifesta-tion of posterior reversible encephalopathy syndrome. Neurology 2007;69:894–897.

10. Lamy C, Oppenheim C, Meder JF, Mas JL. Neuroimaging in posterior reversible encephalopathy syn-drome. J Neuroimaging 2004;14:89–96.

11. Lee VH, Temes RE, John S, et al. Posterior reversible leukoencephalopathy syndrome presenting with global cerebral edema and herniation. Neurocrit Care 2013;18:81–83.

12. Lee VH, Wijdicks EFM, Manno EM, Rabinstein AA. Clinical spectrum of reversible posterior leukoen-cephalopathy syndrome. Arch Neurol 2008;65:205–210.

13. Magnano MD, Bush TM, Herrera I, Altman RD. Reversible posterior leukoencephalopathy in patients with systemic lupus erythematosus. Semin Arthritis Rheum 2006;35:396–402.

14. McKinney AM, Short J, Truwit CL, et al. Posterior reversible encephalopathy syndrome: incidence of atypical regions of involvement and imaging findings. AJR Am J Roentgenol 2007;189:904–912.

15. Meylaerts L, Ooms V, Lyra S, et al. Hypertensive brain stem encephalopathy in a patient with chronic renal failure. Clin Nephrol 2006;65:138–140.

16. Mirza A. Posterior reversible encephalopathy syndrome: a variant of hypertensive encephalopathy. J Clin Neurosci 2006;13:590–595.

17. Schiff D, Lopes MB. Neuropathological correlates of reversible posterior leukoencephalopathy. Neurocrit Care 2005;2:303–305.

18. Schwartz RB, Mulkern RV, Gudbjartsson H, Jolesz F. Diffusion-weighted MR imaging in hypertensive encephalopathy: clues to pathogenesis. AJNR Am J Neuroradiol 1998;19:859–862.

19. Slama M, Modeliar SS. Hypertension in the intensive care unit. Curr Opin Cardiol 2006;21:279–287.20. Stevens CJ, Heran MK. The many faces of posterior reversible encephalopathy syndrome. Br J Radiol

2012;85:1566–1575.21. Stott VL, Hurrell MA, Anderson TJ. Reversible posterior leukoencephalopathy syndrome: a misnomer

reviewed. Intern Med J 2005;35:83–90.22. Vaughan CJ, Delanty N. Hypertensive emergencies. Lancet 2000;356:411–417.

591

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AN EXPLANATION

Fulminant hepatic failure is a comparatively rare disorder, but there are approximately 2.000 cases in the United States and mortality is high.14,15 The mechanism of neurologic deterioration in fulminant hepatic failure is the development of cerebral edema and not ammonia-induced encephalopathy. The clinical features of fulminant hepatic failure—in the worst possible course of events—could include a rapid onset of diffuse brain edema and loss of upper brainstem reflexes with extensor posturing.

Comatose and Fulminant hepatic Failure

/ / / 73 / / /


The causes of coma in fulminant hepatic failure are shown in Table 73-1. Increasing ammonia levels initially cause hepatic encephalopathy, but further worsening of the patient is from cerebral edema. The development of cerebral edema in the later phases has been explained by the “glutamine-ammonia” hypothesis or the “cerebral vasodila-tion” hypothesis.6,7 Excess ammonia is detoxified in the brain to glutamine, which has a marked osmotic effect on astrocytes and is one of the first triggers in the development of cerebral edema. A significant glutamine overload will lead to oxidative nitrosative stress followed by the development of anaerobic glycolysis.3–5,12 However, there is also evidence of increased cerebral blood flow, likely a result of activation of vasodilatory components. This cerebral vasodilatation hypothesis is explained by increased production of prosta-glandins or the expression of the gene for cyclooxygenase in patients with markedly ele-vated blood ammonia levels. The increased ammonia levels may also produce increased neuronal nitric oxide synthases (nNOS) and NO production.

Brain edema can be documented on CT but mostly in patients with higher grades of encephalopathy (e.g., comatose and a need for mechanical ventilation). CT scan may show that the sylvian fissure and sulci have become obliterated (Fig. 73-1). Marked hypo-natremia or hypoglycemia may occur and could cause further worsening of the patient’s condition.


Mortality may be as high as 90%.9 Fatality is a result not only of progressive brain edema but also an inability to find a suitable liver donor in time. There is active research on the development of an artificial liver, but with yet insufficient success. Currently, the only treatment of fulminant hepatic failure is liver transplantation. Predictive models have been tested and may help select appropriate candidates for transplantation.13 Patients are listed immediately, and then it becomes a challenge to shepherd these patients to liver transplantation.10

Monitoring of intracranial pressure (ICP) is urgent. The management of patients with fulminant hepatic failure involves the reduction of ICP using both standard therapies such

TABLE 73-1 Causes of Coma in Fulminant hepatic Failure

• Hyperammonemia (early)• Brain edema with upper brainstem compression (late)• Hyponatremia• Hypoglycemia

Comatose and Fulminant hepatic Failure / / 593

as mannitol, hypertonic saline (preferred due to less negative effect on kidney function), and hyperventilation (Fig. 73-2).17 Fortunately, the number of intracranial hematomas due to ICP monitor placement is low (5% to 10%), and this should not affect the decision to place such a device.2,10,16,17 Off-label recombinant activated factor VII and prothrombin complex concentrate (PCC) are important new developments in countering coagulopa-thy in fulminant hepatic failure.1 Propofol decreases cerebral metabolic rate and may be useful in rapidly reducing the ICP in certain patients.18 An additional trial of therapeutic hypothermia may be able to control ICP, but there is little experience.6–8 These measures may reduce the need for barbiturates, which is now considered a last-resort measure to control ICP. However, improvement of severe cerebral edema, once present with oblit-eration of basal cisterns, is uncommon.

FIGURE 73-1 CT scans in a comatose patient with fulminant hepatic failure showing ICP monitor

and diffuse cerebral edema.


A CONCLUDING NOTE

There is a transition of physiological brain dysfunction (increased ammonia) to struc-tural injury (cerebral edema) in fulminant hepatic failure. Liver transplantation is the only life-saving measure in many patients with fulminant hepatic failure. Biologic liver support systems remain an uncertain proposition.11

REFERENCES

1. Atkison PR, Jardine L, Williams S, et al. Use of recombinant factor VIIa in pediatric patients with liver failure and severe coagulopathy. Transplant Proc 2005;37:1091–1093.

2. Bernuau J, Durand F. Intracranial pressure monitoring in patients with acute liver failure: a questionable invasive surveillance. Hepatology 2006;44:502–504.

3. Blei AT. The pathophysiology of brain edema in acute liver failure. Neurochem Int 2005;47:71–77.4. Butterworth RF. Molecular neurobiology of acute liver failure. Semin Liver Dis 2003;23:251–258.5. Desjardins P, Du T, Jiang W, Peng L, Butterworth RF. Pathogenesis of hepatic encephalopathy and brain

edema in acute liver failure: role of glutamine redefined. Neurochem Int 2012;60:690–696.6. Jalan R, Olde Damink SW, Deutz NE, Hayes PC, Lee A. Moderate hypothermia in patients with acute

liver failure and uncontrolled intracranial hypertension. Gastroenterology 2004;127:1338–1346.7. Jalan R, Rose C. Hypothermia in acute liver failure. Metab Brain Dis 2004;19:215–221.8. Lee WM. Acute liver failure. Semin Respir Crit Care Med 2012;33:36–45.9. Mohsenin V. Assessment and management of cerebral edema and intracranial hypertension in acute liver

failure. J Crit Care 2013;28:783–791.10. Raghavan M, Marik PE. Therapy of intracranial hypertension in patients with fulminant hepatic failure.

Neurocrit Care 2006;4:179–189.11. Ryan JM, Tranah T, Mitry RR, Wendon JA, Shawcross DL. Acute liver failure and the brain: a look

through the crystal ball. Metab Brain Dis 2013;28:7–10.12. Sathyasaikumar KV, Swapna I, Reddy PV, et al. Fulminant hepatic failure in rats induces oxidative stress

differentially in cerebral cortex, cerebellum and pons medulla. Neurochem Res 2007;32:517–524.13. Schmidt LE, Larsen FS. MELD score as a predictor of liver failure and death in patients with

acetaminophen-induced liver injury. Hepatology 2007;45:789–796.

Stupor or coma

CaminoICP monitor

Propofol200 mg/kg/min

Hypothermia (33˚C)

Pentobarbital 0.2–1.0 mg/kg 1 hr

ICP >20 mm HgICP surges

CPP <60 mm Hg

FIGURE 73-2 ICP treatment options in fulminant hepatic failure.

Comatose and Fulminant hepatic Failure / / 595

14. Shawcross DL, Wendon JA. The neurological manifestations of acute liver failure. Neurochem Int 2012;60:662–671.

15. Stadlbauer V, Jalan R. Acute liver failure: liver support therapies. Curr Opin Crit Care 2007;13:215–221.16. Vaquero J, Chung C, Blei AT. Cerebral blood flow in acute liver failure: a finding in search of a mecha-

nism. Metab Brain Dis 2004;19:177–194.17. Wendon JA, Larsen FS. Intracranial pressure monitoring in acute liver failure. A procedure with clear

indications. Hepatology 2006;44:504–506.18. Wijdicks EFM, Nyberg SL. Propofol to control intracranial pressure in fulminant hepatic failure.

Transplant Proc 2002;34:1220–1222.

596

A CONVERSATION

AN EXPLANATION

Ammonia is produced in the intestinal tract, absorbed into the portal bloodstream, shunted past the cirrhotic liver into hepatic veins, passed through arterial blood, and passed through the blood–brain barrier. Ammonia depresses oxidate metabolism, resulting in increased lactate levels; however, changes in glutamatergic and gamma-aminobutyric acid (GABA) transmission have been implicated. Encephalopathy is more severe and preva-lent when a portosystemic shunt exists (or has been created by transjugular intrahepatic

Comatose and Chronic Liver Disease

/ / / 74 / / /

Comatose and Chronic Liver Disease / / 597

portal systemic shunts [TIPS]). However, failure to correlate serum ammonia (venous or arterial) levels to the degree of encephalopathy suggests that other critical factors may be operative. Toxins such as nitric oxide, oxygen-based free radicals, or other proinflam-matory cytokines have been suggested, also because sepsis is a well-known precipitant.5 Levels of inflammatory markers (e.g., IL-6, C-reactive protein) are increased.14

Clinical examination in chronic liver disease is fairly typical. All patients are jaundiced and often febrile. Patients with early hepatic encephalopathy have more subtle findings, with slowing of reaction times and minimal asterixis, but findings get considerably worse as ammonia levels increase. Downward (often dysconjugate) gaze, ocular bobbing (see video clip on eye movements in coma in Chapter 3), and brisk oculocephalic responses can be seen. Hepatic encephalopathy progresses in stages. The clinical signs of these stages are summarized in Table 74-1.

The causes of coma in a patient with chronic liver disease are shown in Table 74-2. Next to hyperammonemia, severe sodium derangements can be seen. Other condi-tions that should be considered in prior alcoholics are bilateral subdural hematoma and multiple contusional hematomas from falling. There is always the concern of fulminant bacterial meningitis and, if no severe coagulopathy is present, cerebrospinal fluid (CSF) examination should be performed. Hyperammonemic coma may also be due to inborn errors, but then no liver function abnormalities exist 6

TABLE 74-1 stages of hepatic encephalopathy

Stage Signs Findings

I Apathy, anxiety, restlessness, short attention span,

inverted sleep pattern, and impaired calculations

Impaired handwriting, tremor, slowed

coordinationII Personality change and disorientation, poor recall Asterixis, ataxia, and dysarthriaIII Delirium, stupor, seizures Myoclonus, marked hyperreflexiaIV Coma Decorticate or decerebrate responses, brisk

oculocephalic responses

TABLE 74-2 Causes of Coma in Chronic Liver Disease

• Hyperammonemia• Hyponatremia• Hypernatremia• Bacterial meningitis• Bilateral subdural hematomas


MRI has been used to further clarify the underlying pathophysiology. T1-signal changes in globus pallidus on MRI are characteristic of chronic liver disease (Fig. 74-1). Elevated manganese levels correlate with this signal on MRI, but more recently, low-grade cerebral edema was documented in diffusion-sensor MRI.8 Regional brain apparent diffusion coefficient (ADC) values did increase in patients with grade I and II hepatic encephalopathy, possibly reflecting increased brain water content, and suggested that brain edema may also play a role in the more chronic forms of liver failure.12 MR spec-troscopy has found reproducible spectral appearances with abnormalities in the gluta-mate/glutamine composite. However, its role in monitoring liver function has not been established.13,15 Recent insights into regional differences are of interest. Positron emission tomography (PET) and MR studies found that most of the “ammonia burden” was pres-ent in the basal ganglia, thalamus, and cerebellum.1


When serum ammonia levels decrease, hepatic encephalopathy improves; therefore, treatment is directed toward reducing ammonia burden. Use of protein-free cathartics to clean protein from the gastrointestinal tract, vitamin supplementation, and use of neo-mycin, lactulose, and metronidazole or rifaximin to decrease ammonia absorption are all mainstays of management (Fig. 74-2).2,4,16 An evidence-based review concluded that flumazenil transiently improved the clinical signs of hepatic encephalopathy11 but there is no impact on outcome. It can temporarily improve communication with the patient, which may help in discussions of care (e.g., consent for surgery). A recent trial confirmed

FIGURE 74-1 Sagittal MRI showing a globus pallidus signal associated with chronic liver disease.

Comatose and Chronic Liver Disease / / 599

significant improvement with use of rifaximin. In 22% of patients with hepatic encepha-lopathy, a major improvement was noted that also reduced hospitalization.3 Models for outcome have been developed, but they are based on laboratory data, suggesting that encephalopathy is not a factor in outcome. The development of intracerebral hematoma has an impact on outcome.7 One such model is the Model for End-Stage Liver Disease (MELD) score (using International Normalized Ratio [INR], bilirubin, and creatinine) (a calculator is available at www.unos.org).9

A CONCLUDING NOTE

Portosystemic shunting is the main mechanism in hepatic encephalopathy. Serum ammo-nia levels do not correlate well with depth of coma, but treatment is directed at reducing the ammonia burden. Coma remains an important predictor of outcome.10 Eye move-ment abnormalities and abnormal motor responses may occur in patients with a severe hepatic encephalopathy, and these signs can be reversible.

REFERENCES

1. Ahl B, Weissenborn K, van den Hoff J, et al. Regional differences in cerebral blood flow and cerebral ammonia metabolism in patients with cirrhosis. Hepatology 2004;40:73–79.

2. Baker DE. Rifaximin: a nonabsorbed oral antibiotic. Rev Gastroenterol Disord 2005;5:19–30.3. Bass NM, Mullen KD, Sanyal A, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med

2010;362:1071–1081.4. Cordoba J, Lopez-Hellin J, Planas M, et al. Normal protein diet for episodic hepatic encephalopa-

thy: results of a randomized study. J Hepatol 2004;41:38–43.

Fluid management Albumin, saline

IV steroids

AntibioticsTreatment of varices

Liver transplantation

LactuloseRitaxime

MetronidazoleVancomycin

Inotropes,vasopression analogue

Blood pressuremanagement

Management ofstress response

Control ofhyperammonemia

Replacement

Control of predisposingfactors

FIGURE 74-2 Management of the comatose patient with worsening chronic liver disease.

http://www.unos.org


5. Ferenci P, Lockwood A, Mullen K, et al. Hepatic encephalopathy—definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 2002;35:716–721.

6. Gaspari R, Arcangeli A, Mensi S, et al. Late-onset presentation of ornithine transcarbamylase deficiency in a young woman with hyperammonemic coma. Ann Emerg Med 2003;41:104–109.

7. Hoya K, Tanaka Y, Uchida T, et al. Intracerebral hemorrhage in patients with chronic liver disease. Neurol Med Chir (Tokyo) 2012;52:181–185.

8. Kale RA, Gupta RK, Saraswat VA, et al. Demonstration of interstitial cerebral edema with diffusion ten-sor MR imaging in type C hepatic encephalopathy. Hepatology 2006;43:698–706.

9. Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in patients with end-stage liver disease. Hepatology 2001;33:464–470.

10. Lehner S, Stemmler HJ, Muck A, Braess J, Parhofer KG. Prognostic parameters and risk stratification in intensive care patients with severe liver diseases. J Gastrointestin Liver Dis 2010;19:399–404.

11. Lock BG, Pandit K. Evidence-based emergency medicine/systematic review abstract. Is flumazenil an effective treatment for hepatic encephalopathy? Ann Emerg Med 2006;47:286–288.

12. Lodi R, Tonon C, Stracciari A, et al. Diffusion MRI shows increased water apparent diffusion coefficient in the brains of cirrhotics. Neurology 2004;62:762–766.

13. Ross BD, Jacobson S, Villamil F, et al. Subclinical hepatic encephalopathy: proton MR spectroscopic abnormalities. Radiology 1994;193:457–463.

14. Shawcross DL, Wright G, Olde Damink SW, Jalan R. Role of ammonia and inflammation in minimal hepatic encephalopathy. Metab Brain Dis 2007;22:125–138.

15. Taylor-Robinson SD, Buckley C, Changani KK, Hodgson HJ, Bell JD. Cerebral proton and phosphorus-31 magnetic resonance spectroscopy in patients with subclinical hepatic encephalopathy. Liver 1999;19:389–398.

16. Wright G, Jalan R. Management of hepatic encephalopathy in patients with cirrhosis. Best Pract Res Clin Gastroenterol 2007;21:95–110.

601

A CONVERSATION

AN EXPLANATION

Acute thyroid dysfunction—in both ways—has a protean clinical presentation, but coma is uncommon. Risk factors for hypothyroidism have been identified. Mostly, it is due to autoimmune thyroiditis, but hypothalamic and pituitary disorders should also be con-sidered. Prior neck radiotherapy has been implicated.17 Hypothyroidism is more com-mon in woman, increasing with age, and is most commonly associated with autoimmune thyroiditis (Hashimoto’s disease). Antimicrosomal or antithyroid antibodies are present

Comatose and Thyroid Disease/ / / 75 / / /


in more than 95% of patients.2,9,11–13,15,17 Recognition of certain clinical signs is impor-tant, including a baseline bradycardia, a slowed relaxation of tendon reflexes, diminished sweating, puffiness, hair loss, and dry cracked skin (Fig. 75-1).

At the other end of the spectrum of thyroid disease is acute hyperthyroidism. The thy-roid gland can be enlarged and firm, although not painful. Reported cases with a so-called “thyroid storm” have shown a certain pattern of signs and symptoms. Very few patients have a history of hyperthyroidism, but they can quite suddenly present with delirium, tachycardia, and hyperthermia with excessive sweating. Thyroid storm and acute hypo-thyroidism may be almost identical in presentation in elderly patients. Paradoxically, hyperthyroidism may cause the elderly to become withdrawn and impervious to any-thing happening in their surroundings.7,16

The causes of coma due to thyroid disease are shown in Table 75-1. The functional basis of coma or impaired consciousness in hypothyroidism has not been elucidated. Thyroid hormone has an effect on cerebral neuronal activity, but the T3 receptors are mostly concentrated in the limbic system and amygdala, with fewer located in the

FIGURE 75-1 Clinical features of hypothyroidism. Note facial puffiness, hair thinning at hairline,

tiny eyelashes, and dry flaking skin.

Comatose and Thyroid Disease / / 603

brainstem. Both reduced and increased brain metabolism have been reported in hypo-thyroid and hyperthyroid patients with positron emission tomography, but these find-ings correlate with depression and anxiety, not abnormal consciousness.5,14 Other major confounders are hyponatremia (initially causing muscle cramps) and hypoglycemia. It is much less likely that a pituitary mass or hypothalamic tumor may be the primary cause of thyroid dysfunction, and its mass effect may cause coma. Pituitary apoplexy may be a cause of hypothyroidism but it more commonly causes secondary adrenocor-ticotropic hormone deficiency. More recently, a Hashimoto’s encephalopathy has been recognized as a pathologically defined entity with perivascular, nonvasculitic, lympho-cytic infiltration in brain, meninges, cortex, basal ganglia, thalami, and hippocampus. This rare disorder may be difficult to detect because thyroid function may be clini-cally and biochemically normal. Other names—with more explanatory titles—such as steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT) or nonvasculitic autoimmune meningoencephalitis (NAIM) have been proposed.4 The laboratory findings include increased or high normal serum thyrotropin levels and increased thyroid peroxidase antibodies.6,8 Periventricular white matter lesions may be found on MRI (Fig. 75-2).3


A dramatic response in patients with myxedema can be expected with high-dose meth-ylprednisolone (five days of 500 mg/d) and a 500-µg loading dose of thyroxine followed by approximately 125 µg thyroxine (1.8 µg/kg) daily.13 Treatment of the thyroid storm is with a large loading dose of propylthiouracil followed by administration of iodide to block thyroid hormone synthesis (Table 75-2).1,10

TABLE 75-1 Causes of Coma in Thyroid Disease

• Decreased cerebral metabolism (hypothyroidism)• Diffuse white matter edema and demyelination• Hypoglycemia or hyponatremia (hypothyroidism)• Hypothalamic mass (hypothyroidism)• Hyperthermia (hyperthyroidism)• Hypernatremia (hyperthyroidism)• Hashimoto’s encephalopathy


FIGURE 75-2 MRI showing an acute leukoencephalopathy in Hashimoto’s encephalopathy (A)

and with resolution of abnormalities (B).

Comatose and Thyroid Disease / / 605

A CONCLUDING NOTE

Unexplained tachycardia or bradycardia associated with concomitant temperature changes in a comatose patient could point to thyroid disease. Abnormal relaxation in ten-don reflexes in a patient with dry, puffy skin is the most important clue. Thyroid storm is far more difficult to recognize, but should be considered in any patient with a febrile delirium progressing to coma.

REFERENCES

1. Beynon J, Akhtar S, Kearney T. Predictors of outcome in myxoedema coma. Crit Care 2008;12:111.2. Canton A, de Fabregas O, Tintore M, et al. Encephalopathy associated to autoimmune thyroid disease: a

more appropriate term for an underestimated condition? J Neurol Sci 2000;176:65–69.3. Castillo P, Woodruff B, Caselli R, et al. Steroid-responsive encephalopathy associated with autoimmune

thyroiditis. Arch Neurol 2006;63:197–202.4. Chong JY, Rowland LP, Utiger RD. Hashimoto encephalopathy: syndrome or myth? Arch Neurol

2003;60:164–171.5. Constant EL, de Volder AG, Ivanoiu A, et al. Cerebral blood flow and glucose metabolism in hypothy-

roidism: a positron emission tomography study. J Clin Endocrinol Metab 2001;86:3864–3870.6. Duffey P, Yee S, Reid IN, Bridges LR. Hashimoto’s encephalopathy: postmortem findings after fatal sta-

tus epilepticus. Neurology 2003;61:1124–1126.7. Feroze M, May H. Apathetic thyrotoxicosis. Int J Clin Pract 1997;51:332–333.8. Ferracci F, Moretto G, Candeago RM, et al. Antithyroid antibodies in the CSF: their role in the patho-

genesis of Hashimoto’s encephalopathy. Neurology 2003;60:712–714.9. Gupta KJ. Myxedema coma: a sleeping grant in clinical practice Am. J Med 2013:126:e3–e4.

10. Mathew V, Misgar RA, Ghosh S, et al. Myxedema coma: a new look into an old crisis. J Thyroid Res 2011;2011:493462.

TABLE 75-2 emergency management in Acute Thyroid Disease

HYPOTHYROIDISM (MYXEDEMA COMA)

• Fluid resuscitation with 0.9% saline or albumin• 500 µg thyroxine IV• 100 mg hydrocortisone• Heating blankets

HYPERTHYROIDISM (THYROID STORM)

• Propylthiouracil (600 mg loading) 100–200 mg (q6–8h) per nasogastric tube• Methimazole 10–20 mg (q8–12h)• Propranolol 20–40 mg (q6h)• Potassium iodide (5 drops saturated solution of potassium chloride q6h)

HASHIMOTO’S ENCEPHALOPATHY

• 1 g methylprednisolone for 5 days

• 60 mg prednisone for 14 days, then taper


11. Nolte KW, Unbehaun A, Sieker H, Kloss TM, Paulus W. Hashimoto encephalopathy: a brainstem vascu-litis? Neurology 2000;54:769–770.

12. Ozawa H, Saitou H, Mizutari K, Takata Y, Ogawa K. Hypothyroidism after radiotherapy for patients with head and neck cancer. Am J Otolaryngol 2007;28:46–49.

13. Pimentel L, Hansen KN. Thyroid disease in the emergency department: a clinical and laboratory review. J Emerg Med 2005;28:201–209.

14. Schreckenberger MF, Egle UT, Drecker S, et al. Positron emission tomography reveals correla-tions between brain metabolism and mood changes in hyperthyroidism. J Clin Endocrinol Metab 2006;91:4786–4791.

15. Sellal F, Berton C, Andriantseheno M, Clerc C. Hashimoto’s encephalopathy: exacerbations associated with menstrual cycle. Neurology 2002;59:1633–1635.

16. Serri O, Gagnon RM, Goulet Y, Somma M. Coma secondary to apathetic thyrotoxicosis. Can Med Assoc J 1978;119:605–607.

17. Shaw PJ, Walls TJ, Newman PK, Cleland PG, Cartlidge NE. Hashimoto’s encephalopathy: a steroid-responsive disorder associated with high anti-thyroid antibody titers--report of 5 cases. Neurology 1991;41:228–233.

607

A CONVERSATION

AN EXPLANATION

Neurologic examination is not always reliable in patients with sepsis, since they are usually on a mechanical ventilator and require vasopressors or episodic fluid resuscitation to main-tain blood pressure, multiple antibiotics, and sedative agents. In some patients, marked third spacing has occurred, resulting in ballooning of the face, conjunctiva, and extremi-ties, making neurologic examination almost impossible. Most patients lie flaccid with gen-eralized areflexia and remain motionless even after pain stimuli. Myoclonus, seizures, or other diagnostic neurologic signs are often absent. The term “septic encephalopathy” has

Comatose and sepsis/ / / 76 / / /


been introduced to explain a marked decline in responsiveness, even coma, but there are other clinical scenarios in sepsis that can lead to a global brain dysfunction.

The causes of coma in sepsis are shown in Table 76-1.3,8,11 Septic encephalopathy reflects a diffuse bihemispheric brain injury. Endocarditis with embolic infarcts or mul-tiple microabscesses (Chapter 77), acute renal and liver failure associated with multiple organ failure, diffuse intravascular coagulation, cortical ischemic injury from cardiovas-cular failure, and shock could all play a role. Therefore, how sepsis decreases conscious-ness and in some patients produces profound coma, is difficult to explain or to collate into a unifying hypothesis or chain of events. Neuropathological findings in patients who died from septic shock are generally nonspecific, although a recent study found notable abnormalities in brain areas susceptible to ischemia. These lesions were located in the Ammon’s horn, lenticular nuclei, frontal cortex, and watershed territories, and very few hemorrhages or microabscesses were found. These findings may support some theories concerning the pathogenesis of “septic encephalopathy.”1–3,7,10,13 The leading explana-tions are either bacterial invasion and an endotoxin affecting the central nervous system (CNS), or global ischemia from reduction of cerebral blood flow and increased cerebral oxygen consumption.3 Evidence of blood–brain barrier breakdown has been described in rabbits with endotoxemia, with increased pinocytosis in endothelia and swelling of astro-cytes.4 Other studies found severe perivascular edema in the cerebral cortex eight hours after induction of peritonitis in septic pigs, resulting in the impairment of movement of oxygen, nutrients, and other metabolites and finally astrocyte damage.11 It has been hypothesized that some of the circulating inflammatory mediators could enter the brain parenchyma through this impaired blood–brain barrier and impair neuronal function, possibly even triggering an apoptosis sequence. Microglia activation has been suggested (microglia are the putative macrophages of the CNS and participate in the immunore-sponse), with some neuropathology studies reporting inflammatory changes.5,8

Several case reports have been reported with MRI abnormalities, some reflecting cerebritis evolving into a brain abscess.6 Recently, one study found increased signal in the midbrain, cerebellum, and medial portion of both temporal lobes in patients with a clinical suspicion of septic encephalopathy. However, most MRI studies, including diffusion-weighted imaging (DWI) studies, have been normal or showed scattered white

TABLE 76-1 Causes of Coma in sepsis

• Anoxic-ischemic cortical injury• Infarctions in watershed territories• Acute renal failure requiring dialysis• Accumulation of opioids and benzodiazepines

Comatose and sepsis / / 609

matter abnormalities.14 No specific abnormalities were found on somatosensory-evoked potentials (SSEP) studies.12 This all leaves clinicians with a pathophysiologically poorly defined encephalopathy caused by multiple systemic triggers.


It is uncertain whether aggressive and successful management of sepsis or septic shock reverses septic encephalopathy. It is more likely that the brain is part of multiorgan involve-ment and damage may remain. In the absence of confounders (e.g., opioids and benzo-diazepines), outcome is poor in comatose patients. Markers of neuronal injury (S-100, neuron-specific enolase [NSE]) are increased in septic patients and predict early mor-tality in septic encephalopathy (Fig. 76-1).9 This suggests that there may be a structural

NSE

leve

ls a

t 24

h a

fter

ICU

adm

issi

on (

mg/

L)

60P<.005

P<.005

*

*

50

40

30

20

10

0

Patients with severe sepsis and septic shock

Early death Late death Survivors

S-10

0 le

vels

at

24 h

aft

erIC

U a

dmis

sion

(m

g/L)

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0.0

P<.005P<.005

*

**

**********

**

Patients with severe sepsis and septic shock

Early death Late death Survivors

FIGURE 76-1 NSE and S-100 levels are predictive of early outcome in septic encephalopathy.

Data from Nguyen et al.9


neuronal injury in septic encephalopathy rather than a reversible neuronal dysfunction during severe bacteriemia.12

A CONCLUDING NOTE

Failure to awaken after sepsis with multiorgan failure requiring vasopressors is most likely a diffuse ischemic encephalopathy. Multiple triggers are present; however, the patho-physiological pathways are uncertain. Direct bacterial invasion may set off a cascade of responses, some with inflammatory mediators.

REFERENCES

1. Adam N, Kandelman S, Mantz J, Chretien F, Sharshar T. Sepsis-induced brain dysfunction. Expert Rev Anti Infect Ther 2013;11:211–221.

2. Basler T, Meier-Hellmann A, Bredle D, Reinhart K. Amino acid imbalance early in septic encephalopa-thy. Intensive Care Med 2002;28:293–298.

3. Bowton DL, Bertels NH, Prough DS, Stump DA. Cerebral blood flow is reduced in patients with sepsis syndrome. Crit Care Med 1989;17:399–403.

4. Davies DC. Blood–brain barrier breakdown in septic encephalopathy and brain tumours. J Anat 2002;200:639–646.

5. Finelli PF, Uphoff DF. Magnetic resonance imaging abnormalities with septic encephalopathy. J Neurol Neurosurg Psychiatry 2004;75:1189–1191.

6. Hollinger P, Zurcher R, Schroth G, Mattle HP. Diffusion magnetic resonance imaging findings in cereb-ritis and brain abscesses in a patient with septic encephalopathy. J Neurol 2000;247:232–234.

7. Jacob A, Brorson JR, Alexander JJ. Septic encephalopathy: inflammation in man and mouse. Neurochem Int 2011;58:472–476.

8. Lemstra AW, Groen in’t Woud JC, Hoozemans JJ, et al. Microglia activation in sepsis: a case-control study. J Neuroinflammation 2007;4:4.

9. Nguyen DN, Spapen H, Su F, et al. Elevated serum levels of S-100beta protein and neuron-specific enolase are associated with brain injury in patients with severe sepsis and septic shock. Crit Care Med 2006;34:1967–1974.

10. Papadopoulos MC, Davies DC, Moss RF, Tighe D, Bennett ED. Pathophysiology of septic encephalopa-thy: a review. Crit Care Med 2000;28:3019–3024.

11. Papadopoulos MC, Lamb FJ, Moss RF, et al. Faecal peritonitis causes oedema and neuronal injury in pig cerebral cortex. Clin Sci (Lond) 1999;96:461–466.

12. Sharshar T, Carlier R, Bernard F, et al. Brain lesions in septic shock: a magnetic resonance imaging study. Intensive Care Med 2007;33:798–806.

13. Voigt K, Kontush A, Stuerenburg HJ, et al. Decreased plasma and cerebrospinal fluid ascorbate levels in patients with septic encephalopathy. Free Radic Res 2002;36:735–739.

14. Zauner C, Gendo A, Kramer L, et al. Metabolic encephalopathy in critically ill patients suffering from septic or nonseptic multiple organ failure. Crit Care Med 2000;28:1310–1315.

611

A CONVERSATION

AN EXPLANATION

Even with early antibiotic use, central nervous system (CNS) complications are com-mon among patients with infective endocarditis. Staphylococcus aureus endocarditis has a particularly poor outcome due to embolic cerebral infarcts.6 There is a high mortality associated with these complications, and only 50% of patients survive the first year.1 In addition, septic emboli lodge in the adventitia and weaken the arterial wall, resulting in

Comatose and endocarditis/ / / 77 / / /


a fusiform dilatation or infectious aneurysm. Infectious (mycotic) aneurysms are often friable and prone to rupture. However, the natural history of infectious aneurysm is ill defined, and some aneurysms shrink or disappear with continuation of antibiotic therapy.

The causes of coma in endocarditis are shown in Table 77-1. CNS complications occur commonly during the early phase (<1 week) of an established infectious endocarditis. In fact, in up to 40% of patients, an ischemic stroke can be the presenting manifestation of infective endocarditis. The evidence suggests that in infective endocarditis, the number of embolic complications peaks before diagnosis and in the first week after initiation of antibiotics7 but thereafter declines rapidly. After the first week, embolization of the brain (and other organs or limbs) occurs less frequently, and the recurrence rate decreases to less than 1% after antibiotic drugs have been administered.2 Both ischemic and hemor-rhagic strokes can occur. Anoxic-ischemic brain injury is a possible mechanism for coma in patients with valve failure and cardiogenic shock.

MRI and CT scan are able to demonstrate small embolic strokes, but emboli may also be found at other locations (e.g., spleen) (Fig. 77-1). Infectious aneurysms may rapidly form and rupture. Blood may be in a single sulcus (peripheral location) or more dramatic within the ventricles.

TABLE 77-1 Causes of Coma in infective endocarditis

• Multiple cerebral infarcts• Multiple lobar hematoma due to septic emboli• Anoxic-ischemic encephalopathy due to cardiogenic shock• Ruptured mycotic aneurysm with intraventricular hemorrhage

FIGURE 77-1 (A) Diffusion-weighted MRI shows acute scattered infarcts in bilateral cerebral

hemispheres associated with infective endocarditis. (B) CT of the abdomen shows a liquefactive

necrosis of the spleen.

Comatose and endocarditis / / 613


Use of anticoagulation is of concern in patients with infective endocarditis. An increased risk of intracranial hemorrhage during the septic phase of infective endocarditis (two to three days after diagnosis) has been found.12 Therefore, during this phase, temporary discontinuation of anticoagulants could be considered. Anticoagulation probably has a role only in select populations such as in patients with mechanical valves, and then there is concern about discontinuing anticoagulants for fear of valve thrombosis. A cerebral angiogram is needed to exclude one or more infectious aneurysms before anticoagula-tion. However, small distal infective aneurysms may not be visualized on a cerebral angio-gram and are even beyond the resolution of digital subtraction cerebral angiography. More likely, a panvasculitis without aneurysm formation may be present. This must be borne in mind before initiating anticoagulation.10

Treatment of infective endocarditis consists of aggressive antibiotic therapy, which does not cure most infectious aneurysms. (Approximately 30% disappear with antibiotic therapy.) The mortality after rupture of such an aneurysm is high (80%).4,5 Aneurysms that persist or even enlarge after a course of antibiotics can be treated surgically or with endovascular occlusion (Fig. 77-2). Indications for surgery are ongoing cerebral emboli and intracerebral hemorrhage, but only if recovery can be achieved and the neurologic devastation is not too great.9

A CONCLUDING NOTE

Endocarditis may damage the brain early (multiple septic emboli) or after a short delay (multiple hemorrhages associated with panvasculitis). The size of infective aneurysms is

(A) (B)

FIGURE 77-2 Cerebral angiogram showing mycotic aneurysm (A) with successful coil occlusion

of the infected artery (B).


monitored during antibiotic treatment; they may be microsurgically resected or endovas-cularly occluded.

REFERENCES

1. Anderson DJ, Goldstein LB, Wilkinson WE, et al. Stroke location, characterization, severity, and out-come in mitral vs aortic valve endocarditis. Neurology 2003;61:1341–1346.

2. Davenport J, Hart RG. Prosthetic valve endocarditis 1976-1987. Antibiotics, anticoagulation, and stroke. Stroke 1990;21:993–999.

3. Heiro M, Nikoskelainen J, Engblom E, et al. Neurologic manifestations of infective endocarditis: a 17-year experience in a teaching hospital in Finland. Arch Intern Med 2000;160:2781–2787.

4. Mansur AJ, Grinberg M, da Luz PL, Bellotti G. The complications of infective endocarditis. A reappraisal in the 1980s. Arch Intern Med 1992;152:2428–2432.

5. Phuong LK, Link M, Wijdicks E. Management of intracranial infectious aneurysms: a series of 16 cases. Neurosurgery 2002;51:1145–1151; discussion 1151–1142.

6. Pruitt AA. Neurologic complications of infective endocarditis. Curr Treat Options Neurol 2013;15:465–476.

7. Remadi JP, Habib G, Nadji G, et al. Predictors of death and impact of surgery in Staphylococcus aureus infective endocarditis. Ann Thorac Surg 2007;83:1295-1302.

8. Roder BL, Wandall DA, Espersen F, et al. Neurologic manifestations in Staphylococcus aureus endocar-ditis: a review of 260 bacteremic cases in nondrug addicts. Am J Med 1997;102:379–386.

9. Rossi M, Gallo A, De Silva RJ, Sayeed R. What is the optimal timing for surgery in infective endocarditis with cerebrovascular complications? Interact Cardiovasc Thorac Surg 2012;14:72–80.

10. Salgado AV, Furlan AJ, Keys TF, Nichols TR, Beck GJ. Neurologic complications of endocarditis: a 12-year experience. Neurology 1989;39:173–178.

11. Thuny F, Avierinos JF, Tribouilloy C, et al. Impact of cerebrovascular complications on mortality and neurologic outcome during infective endocarditis: a prospective multicentre study. Eur Heart J 2007;28:1155–1161.

12. Tornos P, Almirante B, Mirabet S, et al. Infective endocarditis due to Staphylococcus aureus: deleterious effect of anticoagulant therapy. Arch Intern Med 1999;159:473–475.

615

A CONVERSATION

AN EXPLANATION

Syncope and stroke are seen in about 5% to 15% of patients with a proximal aortic dis-section (Stanford classification type A). The diagnosis of aortic dissection can be dif-ficult if the patient is aphasic and unable to signal the typical excruciating knife-like chest pain. Moreover, painless aortic dissection has been described in 6% in a recent Mayo Clinic series.5,10 Slow dissection that may reduce wall stretching and underlying diabetes

Comatose After Aortic Dissection

/ / / 78 / / /


mellitus causing possible denervation of periaortic pain receptors are explanations for pain-free presentations.5

Acute coma from bilateral infarction is unusual after an aortic dissection (Fig. 78-1). However, this case again demonstrates the intricate relationship between a neurologic and cardiologic examination. Using only a few cues, an aortic regurgitation murmur in a patient with acute hypertensive crisis should point toward a dissection.3 Acute aortic regurgitation is a high-pitched decrescendo early diastolic murmur at the left sternal border and is noted after the second sound. A considerable variation of blood pressure between the arms may be a helpful sign. Increased left ventricular isovolumetric contrac-tion (d Plat) may explain hypertension. A mediastinal widening on the chest x-ray is com-monly seen, but the transesophageal echocardiogram (TEE) more likely will show the dissection (Fig. 78-2).

FIGURE 78-1 MRI shows multiterritorial infarcts. On DWI, restricted diffusion in parasagittal

bifrontal regions right insular and left temporal areas is present.

FIGURE 78-2 TEE showing dissection.

Comatose After Aortic Dissection / / 617

The causes of coma in aortic dissection are shown in Table 78-1. Aortic dissection may occlude both carotid arteries, impede flow, or cause a barrage of emboli into both hemispheres and cortical areas. Acute middle cerebral and anterior cerebral arteries may become occluded acutely from common carotid occlusion, with brain swelling occur-ring rapidly (<24 hours).7 Acute hypertension may cause hypertensive encephalopathy with protracted resolution of symptoms (Chapter 72). Aortic dissection may be asso-ciated with cardiac arrest and could leave patients in a coma due to anoxic-ischemic encephalopathy.


Outcome of aortic dissection is determined by the severity of cardiac failure, control of hypertension, and early surgical repair.4,10,11 Maintaining systolic blood pressure at 120 mm Hg using labetalol, sodium nitroprusside, or nicardipine may halt progression of the dissection.2 Endovascular repair of type A dissections—mainly the ascending aorta—may become a preferred method.9 Following vascular repair, successful outcome has been reported in patients presenting in a coma.1,6 The prognosis is poor in patients with bilateral hemispheric infarcts. In-hospital mortality may reach 20% and is higher in patients with cardiac tamponade.8

A CONCLUDING NOTE

One of the unusual heart–brain associations in acute coma is an acute aortic dissection. Key findings are sudden loss of consciousness, acute hypertension, and a new-onset car-diac diastolic murmur.

REFERENCES

1. Estrera AL, Garami Z, Miller CC, et al. Acute type A aortic dissection complicated by stroke: can imme-diate repair be performed safely? J Thorac Cardiovasc Surg 2006;132:1404–1408.

2. Lee SJ, Kim JH, Na CY, et al. Eleven years of experience with the neurologic complications in Korean patients with acute aortic dissection: a retrospective study. BMC Neurol 2013;13:46.

TABLE 78-1 Causes of Coma after Aortic Dissection

• Bilateral frontal infarcts• Massive hemispheric infarct with swelling• Diffuse anoxic-ischemic injury (after CPR)• Hypertensive encephalopathy


3. Nienaber CA, Eagle KA. Aortic dissection: new frontiers in diagnosis and management: Part I: from etiology to diagnostic strategies. Circulation 2003;108:628–635.

4. Nienaber CA, Rehders TC, Ince H. Interventional strategies for treatment of aortic dissection. J Cardiovasc Surg (Torino) 2006;47:487–496.

5. Park SW, Hutchison S, Mehta RH, et al. Association of painless acute aortic dissection with increased mortality. Mayo Clin Proc 2004;79:1252–1257.

6. Pocar M, Passolunghi D, Moneta A, Mattioli R, Donatelli F. Coma might not preclude emergency opera-tion in acute aortic dissection. Ann Thorac Surg 2006;81:1348–1351.

7. Shimazaki Y, Minowa T, Watanabe T, et al. Acute aortic dissection with new massive cerebral infarc-tion—a successful repair with ligature of the right common carotid artery. Ann Thorac Cardiovasc Surg 2004;10:64–66.

8. Song JK, Kang SJ, Song JM, et al. Factors associated with in-hospital mortality in patients with acute aortic syndrome involving the ascending aorta. Int J Cardiol 2007;115:14–18.

9. Sorokin VA, Chong CF, Lee CN, et al. Combined open and endovascular repair of acute type A aortic dissection. Ann Thorac Surg 2007;83:666–668.

10. Veyssier-Belot C, Cohen A, Rougemont D, et al. Cerebral infarction due to painless thoracic aortic and common carotid artery dissections. Stroke 1993;24:2111–2113.

11. von Kodolitsch Y, Schwartz AG, Nienaber CA. Clinical prediction of acute aortic dissection. Arch Intern Med 2000;160:2977–2982.

619

A CONVERSATION

AN EXPLANATION

Repeated episodes of hypoglycemia in diabetes mellitus can lead to reduced hypogly-cemic awareness and even hypoglycemia with no symptoms. Hypoglycemia results in confusion and impaired judgment, sensation of warmth, weakness, fatigue and tremulous-ness, palpitations, anxiety, and sweating. Paresthesias are less commonly noted and could be due to involvement of the autonomic system in patients with longstanding diabetes.8,11 Hypoglycemic coma is mostly seen in patients with prior diabetes. Hypoglycemia may

Comatose and hypoglycemia/ / / 79 / / /


also be caused by other drug interactions. It is important to consider a factitious disorder. Hypoglycemia rarely is a presenting symptom of an insulinoma.

The pathophysiology of hypoglycemia is likely due to reduced neuronal activity from insufficient glucose supply.13 Many pathways are involved, and the mechanism of brain injury in hypoglycemia is shown in Figure 79-1. The neuropathology findings in hypo-glycemia are different from those in anoxic-ischemic brain injury. The Purkinje cells are not affected by hypoglycemia and no abnormalities in the brainstem nuclei are expected. Cortical damage in hypoglycemia involves the superficial layers and is evenly distributed. This distinguishes it from anoxic-ischemic changes that involve the third, fifth, and sixth layers of the neocortical ribbon, and there is a predilection of anoxic-ischemic injury for the posterior third of each hemisphere.5 In hypoglycemia, the CA1 and CA4 sectors of the hippocampi and basal ganglia including the thalami are damaged.

The causes of coma in hypoglycemia are shown in Table 79-1. Hypoglycemia can be part of a suicide attempt combining insulin with illicit drugs. Patients with severe hypoglycemia cannot protect the upper airway and may vomit; thus, severe hypoxia or hypotension may be a cofactor. MRI is often surprisingly normal but could detect the consequences of severe hypoglycemia. Symmetric involvement of the internal cap-sule, corona radiata, and splenium of the corpus callosum may appear early.1,3,6 These

Hypoglycemia

GlutamateAspartate

GABACalcium

Mitochondrialdamage Neuronal

necrosis

FIGURE 79-1 Hypoglycemia and the brain.

TABLE 79-1 Causes of Coma in hypoglycemia

• Depleted neuronal glucose reserves• Diffuse neocortical damage• Insulin overdose combined with illicit drugs• Anoxic-ischemic encephalopathy (asphyxia)

Comatose and hypoglycemia / / 621

abnormalities are potentially reversible.12 Others have found hyperintense lesions in the internal capsule, corona radiata, and frontoparietal cortex or diffuse white matter injury on MRI.9,10 MRI is not very helpful in prognostication after hypoglycemic coma.14


A 50 ml IV bolus of 50% glucose should be administered urgently in any patient with known diabetes; if there is no immediate result, it should be repeated. One should antici-pate that hypoglycemia in patients with diabetes can be particularly severe and repeated injection of glucose might be necessary. If available, 1 mg subcutaneous glucagon should be administered. Nonetheless, severe brain damage can occur and mortality can be high (>10%).7 In one study of 102 diabetic patients with drug-induced hypoglycemia, 40 patients responded to treatment within the first 12 hours and 62 had protracted recovery from hypoglycemia that lasted for 3 days.2 Severe periods of hypoglycemia (defined as <20 mg/dL) occur in the minority of the cases, but awakening is much less common.4 It remains unclear how long hypoglycemia has to be present for it to produce a long-lasting effect including persistent coma. Prolonged hypoglycemia of 12 hours has been arbi-trarily chosen; after this time window, a greater likelihood of persistent brain damage exists. There are very few systematic studies on outcome of patients in a prolonged coma due to hypoglycemia. Furthermore, it is unlikely that the rules of prognostication in hypoxic-ischemic injury can be extrapolated to hypoglycemic coma, particularly because the pathology and regions of the brain that are involved are different.

A CONCLUDING NOTE

Hypoglycemia that lasts more than 12 hours is poorly tolerated by the brain and may result in persistent unconsciousness. Immediate administration of glucose and glucagon is necessary. Accurate prognostication of patients in prolonged coma due to hypoglyce-mia remains difficult but one series reported 50% mortality.14

REFERENCES

1. Aoki T, Sato T, Hasegawa K, Ishizaki R, Saiki M. Reversible hyperintensity lesion on diffusion-weighted MRI in hypoglycemic coma. Neurology 2004;63:392–393.

2. Ben-Ami H, Nagachandran P, Mendelson A, Edoute Y. Drug-induced hypoglycemic coma in 102 dia-betic patients. Arch Intern Med 1999;159:281–284.

3. Chan R, Erbay S, Oljeski S, Thaler D, Bhadelia R. Case report: hypoglycemia and diffusion-weighted imaging. J Comput Assist Tomogr 2003;27:420–423.


4. Cryer PE. Symptoms of hypoglycemia, thresholds for their occurrence, and hypoglycemia unawareness. Endocrinol Metab Clin North Am 1999;28:495–500, v–vi.

5. Dolinak D, Smith C, Graham DI. Hypoglycaemia is a cause of axonal injury. Neuropathol Appl Neurobiol 2000;26:448–453.

6. Finelli PF. Diffusion-weighted MR in hypoglycemic coma. Neurology 2001;57:933.7. Fischer KF, Lees JA, Newman JH. Hypoglycemia in hospitalized patients. Causes and outcomes. N Engl

J Med 1986;315:1245–1250.8. Homma M, Shimizu S, Ogata M, et al. Hypoglycemic coma masquerading thyrotoxic storm. Intern Med

1999;38:871–874.9. Kim JH, Koh SB. Extensive white matter injury in hypoglycemic coma. Neurology 2007;68:1074.

10. Lo L, Tan AC, Umapathi T, Lim CC. Diffusion-weighted MR imaging in early diagnosis and prognosis of hypoglycemia. AJNR Am J Neuroradiol 2006;27:1222–1224.

11. Malouf R, Brust JC. Hypoglycemia: causes, neurological manifestations, and outcome. Ann Neurol 1985;17:421–430.

12. Maruya J, Endoh H, Watanabe H, Motoyama H, Abe H. Rapid improvement of diffusion-weighted imaging abnormalities after glucose infusion in hypoglycaemic coma. J Neurol Neurosurg Psychiatry 2007;78:102–103.

13. Scheen AJ. Central nervous system: a conductor orchestrating metabolic regulations harmed by both hyperglycaemia and hypoglycaemia. Diabetes Metab 2010;36 Suppl 3:S31–38.

14. Witsch J, Neugebauer H, Flechsenhar J et al. Hypoglycemic encephalopathy: a case series and literature review on outcome determination. J Neurol 2012:259:2172–2181.

623

A CONVERSATION

AN EXPLANATION

Type 1 diabetes predisposes to ketoacidosis. Nonketotic hyperglycemia is far more com-mon in type 2 diabetes. Hyperglycemic ketoacidosis is a common reason for admission to medical intensive care units. Most patients are stuporous and awaken quickly after plasma glucose and osmolality have reached normal levels. A few patients remain coma-tose, however.

Comatose and hyperglycemia/ / / 80 / / /


The causes of coma and hyperglycemia are shown in Table 80-1. The pathways involving diabetic ketoacidosis (DKA) or hyperosmotic hyperglycemic state (HHS) are still unclear, and it is unknown how hyperglycemia would produce diffuse neuronal dysfunction. A common explanation has been increasing tissue acidosis and increased lactate accumulation, but it is not triggering an ischemic cascade. It is conceivable that hyperglycemia regulates neurotransmitter efflux. Typically, there are major precipitat-ing factors. Because infection is a common trigger, CNS infection is considered first. In other patients, ischemic stroke may lead to severe worsening of diabetes—DKA or HHS. Inadequate water intake, development of renal failure, and recent introduction of drugs such as corticosteroids, beta-blockers, calcium-channel blockers, and interferon are all factors. Most problematic are patients who discontinued insulin or other antidiabetic medication themselves.5,8,11,17

A recent new insight is that a neuroleptic malignant syndrome and a hyperosmo-lar hyperglycemic state may coexist.1,2,7 It may well be that the hypermetabolic state of neuroleptic malignant syndrome may activate the sympathetic system, in turn resulting in hyperglycemia.16,18 Outcome can be poor if rhabdomyolysis and acute renal failure are not recognized. In other situations, lithium affects glucose intolerance and causes a nephrogenic diabetes insipidus, resulting in marked dehydration.9,15 Clinically patients are markedly stuporous without any focal findings, but there are exceptions. Usually non-ketotic hyperglycemic coma occurs with a 10-fold increase in serum glucose. There have been several reports of early presentation with focal neurologic signs such as aphasia, hemiparesis, and visual field defects. Transient bilateral Babinski’s signs and resolving hemiparesis with improving glucose levels, muscle twitching, and forced eye deviation may also occur. Focal seizures may dominate the clinical picture. None of these focal signs is easily explained, and neuroimaging may be normal or show prior strokes.

Persistent coma could be due to treatment rather than diabetic coma. Aggressive fluid resuscitation in patients with diabetic coma could lead to marked osmolality shifts. Patients with a decrease in serum osmolality of more than 3 mOsm per hour may be at higher risk not only of cerebral edema but also central pontine myelinolysis.

TABLE 80-1 Causes of Coma in hyperglycemia

• Cerebral edema• Seizures (e.g., hyponatremia)• Acute structural brain injury causing hyperglycemia• Central nervous system infection• Coexisting ischemic stroke

Comatose and hyperglycemia / / 625

Diagnostic criteria to distinguish DKA from HHS have been proposed and are listed in Table 80-2. Usually, patients in a nonketotic hyperosmolar state have a severe fluid deficit. There is also a total body sodium deficit despite normal or high serum sodium values. Therefore, a rapid change of serum sodium (>1 mmol/h) may actually indicate a much faster rise. Other possibilities are the presence of a major phosphate deficit associ-ated with ketonuria and osmotic diuresis. Very low phosphorus levels (<0.5 mg/dL) can lead to seizures and also to rhabdomyolysis and acute renal failure. Finally, hyperglycemia can be due to prior drug use, most notably methadone.17

Diabetic coma rarely, at least in adults, causes cerebral edema; if it does, it is often demonstrated on CT scan or MRI and leads to rapid fatal brain tissue shift (Fig. 80-1).

TABLE 80-2 Diagnostic Criteria of DKA and hhs

Mild DKA Moderate DKA Severe DKA HHS

Arterial pH 7.25–7.30 7.00–7.24 <7.00 >7.30Serum bicarbonate (mEq/L) 15–18 10–15 <10 >15Urine ketones Positive Positive Positive SmallSerum ketones Positive Positive Positive SmallEffective serum osmolality

(mOsm/kg)

Variable Variable Variable >320

Anion gap >10 >12 >12 VariableConsciousness Alert Drowsy Coma Coma


FIGURE 80-1 Diffuse severe brain edema associated with ketotic hyperglycemia in a young

patient. Note obliteration of cisterns and slit ventricles.


If the CT scan fails to document cerebral edema, MR is often entirely normal in patients with DKA.

TREATMENT PLAN AND PROGNOSIS

Hyperglycemic hyperosmolar nonketotic syndrome is a potentially life-threatening dis-order in patients who have diagnosed or undiagnosed type 2 diabetes. Mortality is high because of marked dehydration and often concomitant infection that precipitated the development of hyperglycemia. The major complications, at least in one study,6 are due to myocardial infarction and pulmonary emboli, and mortality may reach 20%.

How fast hyperglycemia can be corrected is unknown, but we and others have seen the development of central pontine myelinolysis.4,13 There are concerns of fluid balance in patients with diabetic hyperosmolarity.19 Fluid therapy to expand the vascular vol-ume is essential, and this is usually started with a bolus of 20 mL/kg isotonic saline and additional fluid boluses. In patients with hyperglycemia, approximately 50% of the body weight is decreased and, therefore, improvement can be expected if the fluid deficit is corrected; it should be corrected over 24 to 48 hours with half-normal saline. The puta-tive mechanisms are shown in Figure 80.2. Underestimation of dehydration is common, and therefore at least replacement of urinary losses is recommended. Fluid with higher sodium content should be used if there is continuous hypotension. Electrolytes should be carefully monitored and replaced, and this includes calcium, magnesium, and phos-phate. Intravenous insulin is rarely used, and only in patients who have an associated acidosis.

Mixed forms of HHS and DKA are known, and therefore treatment might be iden-tical. When a malignant hyperthermia-like syndrome is developing, these patients will have to be treated with dantrolene. The prognosis, in general, is good if adequate hydra-tion can be maintained.

The recommended dose of insulin for DKA is approximately 0.1 units/kg bolus plus a 0.1 unit/kg/h drip, which is far less than the recommended dose of insulin for hyperosmolar nonketonic coma (Table 80-3).8,14 Large doses of insulin may a cause a significant fall in the glucose level and therefore also a fall in serum osmolality. This serum osmolality decrease is relative to the hyperosmolar cerebrospinal fluid and therefore may draw fluid into the brain, causing cerebral edema. Brain edema remains difficult to treat; mannitol, fluid restriction, and corticosteroids are not successful. A mandatory proto-col to treat hyperglycemia has reduced hospital stay.3 The prognosis for recovery in most patients, however, is very good.

Comatose and hyperglycemia / / 627

A CONCLUDING NOTE

A new structural brain lesion may have exacerbated hyperglycemia. Recovery from coma after hyperglycemia can be protracted, but most patients recover quickly. Brain edema is a rare complication in adults but may occur in children and adolescents with DKA.

ECV ICV

H2O

Osmoticdiuresis

Osmoticdiuresis

H2O

Insulin

GlucoseandH2O

(A)

(B)

(C)

(D)

FIGURE 80-2 Schematic representation of fluid compartment collapse with insulin and no ade-

quate hydration. (A) Normal glycemia and hydration. (B) Extracellular fluid (ECV) is hyperos-

molar, causing water to shift from the intracellular to the extracellular fluid component. (C)

Continuous osmotic diuresis causes dehydration, volume loss, and hyperosmolarity in both the

extracellular and the intracellular (ICV) compartments. (D) Insulin therapy without adequate fluid

replacement will shift glucose and water from the extracellular into the intracellular fluid, caus-

ing vascular collapse, shock, and death. Data from Morales and Rosenbloom.12

TABLE 80-3 initial management of hyperglycemic Coma

• Infuse 2–4 L normal saline in first hour.• Replete potassium; start insulin until potassium is 3.2 mmol/L.• Blood glucose >300 mg/dL, give 10 units regular insulin, then 6 units/h.• Blood glucose <300 mg/dL, give 5 units regular insulin, then 3 units/h.

Data from Bull et al.3


REFERENCES

1. Baluch AR, Oommen SP. Malignant hyperthermia associated with diabetic hyperosmolar hyperglyce-mic nonketotic state in a young man. J Clin Anesth 2007;19:470–472.

2. Balzan M, Cacciottolo JM. Neuroleptic malignant syndrome presenting as hyperosmolar non-ketotic diabetic coma. Br J Psychiatry 1992;161:257–258.

3. Bull SV, Douglas IS, Foster M, Albert RK. Mandatory protocol for treating adult patients with diabetic ketoacidosis decreases intensive care unit and hospital lengths of stay: results of a nonrandomized trial. Crit Care Med 2007;35:41–46.

4. Burns JD, Kosa SC, Wijdicks EF. Central pontine myelinolysis in a patient with hyperosmolar hypergly-cemia and consistently normal serum sodium. Neurocrit Care 2009;11:251–254.

5. Capes SE, Hunt D, Malmberg K, Pathak P, Gerstein HC. Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke 2001;32:2426–2432.

6. Fadini GP, de Kreutzenberg SV, Rigato M, et al. Characteristics and outcomes of the hyperglycemic hyperosmolar non-ketotic syndrome in a cohort of 51 consecutive cases at a single center. Diabetes Res Clin Pract 2011;94:172–179.

7. Hollander AS, Olney RC, Blackett PR, Marshall BA. Fatal malignant hyperthermia-like syndrome with rhabdomyolysis complicating the presentation of diabetes mellitus in adolescent males. Pediatrics 2003;111:1447–1452.

8. Inzucchi SE. Clinical practice. Management of hyperglycemia in the hospital setting. N Engl J Med 2006;355:1903–1911.

9. Kamboj MK, Zhou P, Molofsky WJ, et al. Hemorrhagic pituitary apoplexy in an 18 year-old male pre-senting as non-ketotic hyperglycemic coma (NKHC). J Pediatr Endocrinol Metab 2005;18:611–615.

10. Kitabchi AE, Umpierrez GE, Murphy MB, et al. Hyperglycemic crises in patients with diabetes mellitus. Diabetes Care 2003;26 Suppl 1:S109–117.

11. Krinsley JS, Jones RL. Cost analysis of intensive glycemic control in critically ill adult patients. Chest 2006;129:644–650.

12. Morales AE, Rosenbloom AL. Death caused by hyperglycemic hyperosmolar state at the onset of type 2 diabetes. J Pediatr 2004;144:270–273.

13. O’Malley G, Moran C, Draman MS, et al. Central pontine myelinolysis complicating treatment of the hyperglycaemic hyperosmolar state. Ann Clin Biochem 2008;45:440–443.

14. Riddle MC. Glycemic management of type 2 diabetes: an emerging strategy with oral agents, insulins, and combinations. Endocrinol Metab Clin North Am 2005;34:77–98.

15. Rock W, Elias M, Lev A, Saliba WR. Haloperidol-induced neuroleptic malignant syndrome complicated by hyperosmolar hyperglycemic state. Am J Emerg Med 2009;27:1018 e1011–1013.

16. Stunkard ME, Pikul VT, Foley K. Hyperosmolar hyperglycemic syndrome with rhabdomyolysis. Clin Lab Sci 2011;24:8–13.

17. Tiras S, Haas V, Chevret L, et al. Nonketotic hyperglycemic coma in toddlers after unintentional metha-done ingestion. Ann Emerg Med 2006;48:448–451.

18. Yang CW, Lu C, Wu CC, Wen SC. Coexistence of neuroleptic malignant syndrome and a hyperosmolar hyperglycemic state. Am J Emerg Med 2012;30:833 e831–832.

19. Zeitler P, Haqq A, Rosenbloom A, Glaser N. Hyperglycemic hyperosmolar syndrome in children: patho-physiological considerations and suggested guidelines for treatment. J Pediatr 2011;158:9-14, 14 e11–12.

629

A CONVERSATION

AN EXPLANATION

The relationship between hyponatremia and acute brain injury is reciprocal. Acute brain injury due to trauma, stroke, meningitis, or encephalitis and after pituitary surgery can cause hyponatremia.15 Cerebral salt-wasting syndrome is a volume-depleted state, and this condition commonly contributes to the development of hyponatremia after acute brain injury. Cerebral salt wasting remains poorly understood and may be partly due to catecholamine-induced pressure diuresis and increased natriuretic peptides. However,

Comatose and hyponatremia/ / / 81 / / /


under those circumstances, hyponatremia is seldom severe, with serum sodium values between 120 and 130 mmol/L.

Hyponatremia can also cause significant brain injury. Normally the brain is able to extrude inorganic solubles within hours of hyponatremia. This is followed by water loss, reducing the risk of cellular swelling. However, this compensatory system may be over-whelmed, leading to brain edema.3

The causes of coma in hyponatremia are shown in Table 81-1. Hyponatremia typi-cally manifests with restlessness and confusion, followed by generalized tonic-clonic seizures. Both the rapidity of decline and the ultimate level of serum sodium deter-mine symptomatology (Fig. 81-1). Correction of hyponatremia (usually rapid) may result in osmotic myelinolysis (Chapter 47).4 There is considerable controversy about what determines a hyponatremic encephalopathy. Some investigators have noted that hypoxemia with a Po2 of less than 50 mm Hg significantly increases the chance of brain injury, but this observation has not been replicated in animal studies, and even in the presence of severe hyponatremia and hypoxemia, neuropathological abnormal-ities were not found.11

TABLE 81-1 Causes of Coma in hyponatremia

• Cerebral edema• Seizure-associated postictal state• Status epilepticus (convulsive-nonconvulsive)• Osmotic demyelination (after correction)

140

120

11012 24 36

Hours

StuporSodi

um (

mm

ol)

DrowsyComa

NA+

FIGURE 81-1 Relationship between serum sodium level, rapidity of decline, and decline in

consciousness.

Comatose and hyponatremia / / 631


The causes of hyponatremia are summarized in Table 81-2. Evaluation of hyponatremia involves measurement of serum osmolality. In most cases, hyponatremia is associated with low serum osmolality, but a normal serum osmolality can be found in cases of severe hypertriglyceridemia or hyperglobulinemia. (Iron-specific electrodes measure true serum sodium concentration, thus reducing these laboratory errors of pseudo-hyponatremia.) Urine osmolality should document a reduction in urine osmolality (<100 mOsm/kg). A urine osmolality greater than 200 mOsm/kg is inappropriately high and reflects an abnormality of water excretion.

The next step is to assess volume status. Correction of hyponatremia and prevention of further seizures in patients with hyponatremia and prevention of additional possible sys-temic factors such as hypoxemia or hypovolemia are warranted.1,5,8,9,12,13 A useful approach to the correction of hyponatremia is shown in Table 81-3.2,14 Vasopressin antagonists have been suggested and oral tolvaptan rapidly increases serum sodium and urine output. It is used in chronic forms of hyponatremia and is not for acute symptomatic hyponatremia due to its potential to cause a rapid rise within 24 hours after administration.7

In most patients, outcome is excellent with gradual correction of hyponatremia. Nonetheless, in clinical practice hyponatremia is a severe electrolyte abnormality. More recently, it has been documented that a further decrease in serum sodium during

TABLE 81-2 Causes of hyponatremia

Hypovolemia Cerebral salt wasting

Diuretics

Acute corticosteroid withdrawal

Gastrointestinal losses

Skin losses

Ketonuria

IatrogenicNormovolemia SIADH

Hypothyroidism

Adrenal insufficiency

Hypotonic solutions, sufficient volumeHypervolemia SAIDH

Congestive heart failure

Acute renal failure

Cirrhosis

Hypotonic solutions but excessive volumeSIADH = syndrome of inappropriate antidiuretic hormone.


hospitalization of patients with hyponatremia is associated with a further increase in mortality.6,10 Mortality in hyponatremic patients with an admission serum sodium of 125 mmol/L or less is approximately 30% and increases further with more severe degrees (≤115 mmol/L).6 It is anticipated that outcome is more likely related to the cause of hyponatremia rather than being directly correlated with hyponatremia or its treatment.

A CONCLUDING NOTE

Hyponatremia may cause brain injury or be caused by brain injury. Correction of plasma sodium is seldom complicated by further brain injury; when it occurs, it may be charac-terized by brain edema or diffuse demyelination.

TABLE 81-3 Formulas for Use in managing hyponatremia and Characteristics of infusate

Formula* Clinical Use

Change in serum Na+ =

(Infusate Na Infusate K serum NaTotalbody water

+ + ++ −+)

1

Estimate the effect of 1 L of any infusate on

serum Na+


Infusate Na serum NaTotalbody water

+ +

+−

1

Estimate the effect of 1 L of any infusate

containing Na+ and K+ on serum Na+

Infusate Infusate Na+ (mmol/L) Extracellular-fluid distribution (%)5% Sodium chloride in water 855 100†

3% Sodium chloride in water 513 100†

0.9% Sodium chloride in water 154 100Ringer’s lactate solution 130 970.45% Sodium chloride in water 77 730.2% Sodium chloride in 5%

dextrose in water

34 55

5% Dextrose in water 0 40

* The numerator in formula 1 is a simplification of the expression (infusate Na+ − serum Na+) ×

1 L, with the value yielded by the equation in millimoles per liter. The estimated total body

water (in liters) is calculated as a fraction of body weight. The fraction is 0.6 in children; 0.6 and

0.5 in nonelderly men and women, respectively; and 0.5 and 0.45 in elderly men and women,

respectively. Normally, extracellular and intracellular fluids account for 40% and 60% of total

body water, respectively.

†In addition to its complete distribution in the extracellular compartment, this infusate induces

osmotic removal of water from the intracellular compartment.

From Adrogue and Madias with permission of New England Journal of Medicine.2

Comatose and hyponatremia / / 633

REFERENCES

1. Adrogue HJ, Madias NE. Aiding fluid prescription for the dysnatremias. Intensive Care Med 1997;23:309–316.

2. Adrogue HJ, Madias NE. Hyponatremia. N Engl J Med 2000;342:1581–1589.3. Arieff AI, Llach F, Massry SG. Neurological manifestations and morbidity of hyponatremia: correlation

with brain water and electrolytes. Medicine (Baltimore) 1976;55:121–129.4. Berl T. Treating hyponatremia: damned if we do and damned if we don’t. Kidney Int 1990;37:1006–1018.5. Fraser CL, Arieff AI. Epidemiology, pathophysiology, and management of hyponatremic encephalopa-

thy. Am J Med 1997;102:67–77.6. Gill G, Huda B, Boyd A, et al. Characteristics and mortality of severe hyponatraemia—a hospital-based

study. Clin Endocrinol (Oxf) 2006;65:246–249.7. Hays RM. Vasopressin antagonists—progress and promise. N Engl J Med 2006;355:2146–2148.8. Lauriat SM, Berl T. The hyponatremic patient: practical focus on therapy. J Am Soc Nephrol

1997;8:1599–1607.9. Oh M, Carroll H. Regulation of intracellular and extracellular volume. In: Arieff AI, DeFronzo RA, eds.

Fluid, Electrolyte, and Acid-Base Disorders. 2nd ed. New York: Churchill Livingstone; 1995:1–28.10. Schrier RW, Sharma S, Shchekochikhin D. Hyponatraemia: more than just a marker of disease severity?

Nat Rev Nephrol 2013;9:37–50.11. Soupart A, Penninckx R, Stenuit A, Decaux G. Lack of major hypoxia and significant brain damage in

rats despite dramatic hyponatremic encephalopathy. J Lab Clin Med 1997;130:226–231.12. Sterns RH. Severe symptomatic hyponatremia: treatment and outcome. A study of 64 cases. Ann Intern

Med 1987;107:656–664.13. Sterns RH. The treatment of hyponatremia: first, do no harm. Am J Med 1990;88:557–560.14. Verbalis JG, Goldsmith SR, Greenberg A, Schrier RW, Sterns RH. Hyponatremia treatment guidelines

2007: expert panel recommendations. Am J Med 2007;120:S1–21.15. Zada G, Liu CY, Fishback D, Singer PA, Weiss MH. Recognition and management of delayed hyponatre-

mia following transsphenoidal pituitary surgery. J Neurosurg 2007;106:66–71.

634

A CONVERSATION

AN EXPLANATION

Hypernatremia in hospitalized patients is more common than hyponatremia and is due to either water loss or gain of hypertonic sodium.4,7,10 In elderly patients, it is a very common cause of impaired consciousness and is recognized not only by signs of dehydration such as position-related hypotension and dry skin, but also repetitive myoclonic twitching in most muscles. Decline in consciousness relates to the speed of serum sodium increase. Osmolality in serum may correlate better than the serum sodium level but is not always measured (Fig. 82-1). Absence of thirst due to failure of hypothalamic osmoreceptors

Comatose and hypernatremia/ / / 82 / / /

Comatose and hypernatremia / / 635

may occur due to tumors in that region, but in clinical practice there usually has been an inability to correct water intake. In the ICU, failure to provide hypotonic fluids may cause hypernatremia.8

The causes of coma in hypernatremia are shown in Table 82-1. Marked hypoten-sion and volume depletion is common and patients become drowsy or stuporous. Consciousness further declines after a period of delirium; this is due to hypertonic dehy-dration of the brain. Adaptation of the brain to a hypernatremic state involves influx of sodium, reduction in volume loss, and (a much slower process) formation of organic osmolytes. Therefore, when fluids are infused quickly, brain edema will occur due to the failure of the brain to eliminate these water-attracting osmolytes rapidly. In young chil-dren, the dehydrated brain may pull at the bridging veins, causing subdural hematomas, intravascular venous sludging, and occlusion, but in adults, this complication is unusual. Masses located in the hypothalamic and thalamic areas may cause marked hypernatremia due to the inability of the patient to sense thirst and thus to rehydrate. Hypernatremia is associated with rhabdomyolysis and may cause acute renal failure and acute uremia.5 Hypernatremia may be one of the first laboratory signs that a catastrophic brain injury has damaged the pituitary stalk, resulting in diabetes insipidus.

180

Stupor

160So

dium

(m

mol

/L)

14012 24 36

Hours

NA+

DrowsyComa

FIGURE 82-1 Relationship between serum sodium level, rapidity of increase, and decline in

consciousness.

TABLE 82-1 Causes of Coma in hypernatremia

• Hypertonic dehydration of the brain• Seizures• Bilateral subdural hematomas• Coexisting acute brain injury with damage to pituitary stalk• Brain edema



The common causes of hypernatremia are shown in Table 82-2. Pure water loss requires an infusion of 5% dextrose. Rapid correction may cause cerebral edema, but this has rarely been reported. A formula for correcting hypernatremia is shown in Table 82-3.1 The speed of correction is less than 0.5 mmol/h, or not more than 10% per day. Central diabetes insipidus is treated with desmopressin and nephrogenic diabetes insipidus with

TABLE 82-2 Causes of hypernatremia

Hypovolemia Gastrointestinal lossesExcessive insensible lossesDiabetes insipidusExcessive diuresis

Normovolemia Diabetes insipidus(sufficient fluid replacement)

Hypervolemia IatrogenicCorticosteroid excess

TABLE 82-3 Formulas for Use in managing hypernatremia and Characteristics of infusates

Formula* Clinical Use


Infusate Na serum NaTotalbody water

+ −+

+

1

Estimate the effect of 1 L of any infusate on

serum Na+


(Infusate Na Infusate K serum NaTotalbody water

+ + ++ −+)

1

Estimate the effect of 1 L of any infusate

containing Na+ and K+ on serum Na+

Infusate Infusate Na+ (mmol/L) Extracellular-fluid distribution (%)5% Dextrose in water 0 400.2% Sodium chloride in 5% 34 55dextrose in water0.45% Sodium chloride in water 77 73Ringer’s lactate 130 970.9% Sodium chloride in water 154 100

* The numerator in formula 1 is a simplification of the expression (infusate Na+ – serum Na+) ×

1 L, with the value yielded by the equation in millimoles per liter. The estimated total body

water (in liters) is calculated as a fraction of body weight. The fraction is 0.6 in children; 0.6 and

0.5 in nonelderly men and women, respectively; and 0.5 and 0.45 in elderly men and women,

respectively. Normally, extracellular and intracellular fluids account for 40% and 60% of total

body water, respectively.

From Adrogue and Madias with permission of New England Journal of Medicine.1

Comatose and hypernatremia / / 637

thiazide diuretics or nonsteroidal anti-inflammatory drugs.11 In medical ICUs, hypona-tremia of more than 150 mmol/L was associated with approximately 40% mortality.6 In the neurologic ICU, only serum sodium values of more than 160 mmol/L were associ-ated with fatal outcome.2,9 However, survival with a serum sodium level of 180 mmol/L has been described after treatment with desmopressin and 5% dextrose.3

A CONCLUDING NOTE

Elderly patients with altered sense of thirst or gastrointestinal losses are at risk of hyperna-tremia. Hypernatremia is common, although thirst protects against the development of a steep increase. Overzealous infusion of fluids may potentially cause brain edema, but this is rare.

REFERENCES

1. Adrogue HJ, Madias NE. Hypernatremia. N Engl J Med 2000;342:1493–1499.2. Aiyagari V, Deibert E, Diringer MN. Hypernatremia in the neurologic intensive care unit: how high is too

high? J Crit Care 2006;21:163–172.3. Gomez-Daspet J, Elko L, Grebenev D, Vesely DL. Survival with serum sodium level of 180 mEq/L: per-

manent disorientation to place and time. Am J Med Sci 2002;324:321–325.4. Howanitz JH, Howanitz PJ. Evaluation of serum and whole blood sodium critical values. Am J Clin

Pathol 2007;127:56–59.5. Lima EQ, Aguiar FC, Barbosa DM, Burdmann EA. Severe hypernatraemia (221 mEq/l), rhabdomyoly-

sis and acute renal failure after cerebral aneurysm surgery. Nephrol Dial Transplant 2004;19:2126–2129.6. Lindner G, Funk GC, Schwarz C, et al. Hypernatremia in the critically ill is an independent risk factor for

mortality. Am J Kidney Dis 2007;50:952–957.7. Pfennig CL, Slovis CM. Sodium disorders in the emergency department: a review of hyponatremia and

hypernatremia. Emerg Med Pract 2012;14:1–26.8. Polderman KH, Schreuder WO, Strack van Schijndel RJ, Thijs LG. Hypernatremia in the intensive care

unit: an indicator of quality of care? Crit Care Med 1999;27:1105–1108.9. Qureshi AI, Suri MF, Sung GY, et al. Prognostic significance of hypernatremia and hyponatremia among

patients with aneurysmal subarachnoid hemorrhage. Neurosurgery 2002;50:749–755.10. Sam R, Feizi I. Understanding hypernatremia. Am J Nephrol 2012;36:97–104.11. Workeneh B, Balakumaran A, Bichet DG, Mitch WE. The dilemma of diagnosing the cause of hyperna-

traemia: drinking habits vs diabetes insipidus. Nephrol Dial Transplant 2004;19:3165–3167.

638

A CONVERSATION

AN EXPLANATION

Acute hypercalcemia (>10 mg/dL) occurs in approximately 20% of patients with advanced cancer, typically due to bone metastases.4,7 In children, hypercalcemia is often associated with solid neoplasms, lymphomas, or leukemia.5,6 The clinical signs are ini-tially difficult to recognize. It can be preceded not only by gastrointestinal symptoms of anorexia and constipation but also by fatigue and lethargy. Hypercalcemia may not be recognized if cancer has not been previously diagnosed or in patients who present with an acute leukemia that focuses all attention.6 If not treated, rapid deterioration can occur,

Comatose and hypercalcemic Crisis

/ / / 83 / / /

Comatose and hypercalcemic Crisis / / 639

resulting in renal failure and even cardiac arrest. ST elevation is a recognizable electrocar-diographic sign of hypercalcemia.9 Extreme hypercalcemia (>13 mg/dL) may be associ-ated with severe hypokalemia, hyperkalemia, and cardiac arrhythmias.

The causes of coma in acute hypercalcemic crisis are shown in Table 83-1. In the vast majority of cases, coma can indeed be explained as a result of a severe decline in calcium. How hypercalcemia and its associated dehydration impair consciousness is unknown, but there are electroencephalographic alterations showing monomorphic delta rhythms. Hypernatremia and hypercalcemia are so closely linked with each other that hypernatre-mia may be causing most of the symptoms. Moreover, rapid increase in serum calcium may cause seizures—perhaps through cerebral vasoconstriction—resulting in a postic-tal stupor that may confound assessment.3 Conversely, it is important to recognize that hypercalcemia could be associated with brain and bone metastases, and correction of hypercalcemia may not result in improvement of consciousness.


The causes of acute hypercalcemia are shown in Table 83-2. Interventions are shown in Figure 83-1.1,2,8,10-13 Rehydration with 0.9% saline is mandatory with intravenous furose-mide (20 to 40 mg) after the patient becomes clinically normovolemic. Saline rehydration

TABLE 83-1 Causes of Coma in Acute hypercalcemic Crisis

• Reduced neuronal excitability• Hypernatremia• Postictal stupor• Multiple brain and bone metastases

TABLE 83-2 Causes of Acute hypercalcemia

Malignant diseasesSecretion of humoral factors by tumorsBony metastasesLymphoid neoplasms

Granulomatous diseasesSarcoidosisMycobacterial infectionThyrotoxicosisHyperparathyroidismDrug reactions

Adapted from Foss et al.5


reverses the increased proximal tubular calcium reabsorption, and calcitonin inhibits the distal tubular calcium reabsorption. After patients are rehydrated, improvement of serum calcium coincides with improving level of consciousness. Intravenous zoledronic acid (4 mg) and subcutaneous calcitonin will correct serum calcium rapidly. In patients with primary hyperthyroidism, removal of the parathyroid gland is necessary.8

A CONCLUDING NOTE

Patients with a metastatic cancer and coma may have severe hypercalcemia that is a treatable condition. Correction can result in marked improvement in consciousness. Hypercalcemia can occur in patients who may have other explanations for an impaired consciousness such as metastases to the brain, and they will not improve after normaliza-tion of serum calcium.

REFERENCES

1. Body JJ, Bouillon R. Emergencies of calcium homeostasis. Rev Endocr Metab Disord 2003;4:167–175.2. Calvo-Romero JM, Bonilla-Gracia MC. Severe symptomatic hypercalcaemia. Postgrad Med J

2000;76:662; 668.3. Chen TH, Huang CC, Chang YY, et al. Vasoconstriction as the etiology of hypercalcemia-induced sei-

zures. Epilepsia 2004;45:551–554.4. Flombaum CD. Metabolic emergencies in the cancer patient. Semin Oncol 2000;27:322–334.5. Foss FM, Aquino SL, Ferry JA. Case records of the Massachusetts General Hospital. Weekly clinico-

pathological exercises. Case 10-2003. A 72-year-old man with rapidly progressive leukemia, rash, and multiorgan failure. N Engl J Med 2003;348:1267–1275.

6. Kounami S, Yoshiyama M, Nakayama K, et al. Severe hypercalcemia in a child with acute nonlympho-cytic leukemia: the role of parathyroid hormone-related protein and proinflammatory cytokines. Acta Haematol 2004;112:160–163.

FIGURE 83-1 Strategies to treat hypercalcemia.

Comatose and hypercalcemic Crisis / / 641

7. Lamy O, Jenzer-Closuit A, Burckhardt P. Hypercalcaemia of malignancy: an undiagnosed and under-treated disease. J Intern Med 2001;250:73–79.

8. Lew JI, Solorzano CC, Irvin GL, 3rd. Long-term results of parathyroidectomy for hypercalcemic crisis. Arch Surg 2006;141:696–699; discussion 700.

9. Littmann L, Taylor L, 3rd, Brearley WD, Jr. ST-segment elevation: a common finding in severe hypercal-cemia. J Electrocardiol 2007;40:60–62.

10. Pecherstorfer M, Brenner K, Zojer N. Current management strategies for hypercalcemia. Treat Endocrinol 2003;2:273–292.

11. Rosner MH, Dalkin AC. Onco-nephrology: the pathophysiology and treatment of malignancy associ-ated hypercalcemia. Clin J Am Soc Nephrol 2012:7:1722–1729.

12. Shanks D, Linke R, Saxon B. Bones, groans and blasts. J Paediatr Child Health 2001;37:504–506.13. Ziegler R. Hypercalcemic crisis. J Am Soc Nephrol 2001;12 Suppl 17:S3–9.

642

A CONVERSATION

AN EXPLANATION

In a steady state, hypercapnia is due to alveolar hypoventilation. Hypercapnia can also be due to increased CO2 production with fever, sepsis, and increased work of breath-ing in respiratory distress. To prevent an increase in PaCO2 patients compensate, but this may not be possible if ventilatory reserve is absent or if the mechanics fail.7 Thus, patients cannot maintain the degree of minute ventilation to compensate for an increase in Paco2. Some patients with chronic obstructive pulmonary disease (COPD) use oxygen per nasal prongs and may self-manipulate and increase oxygen flow when an intercurrent

Comatose and hypercapnia/ / / 84 / / /

Comatose and hypercapnia / / 643

infection causes shortness of breath. Respiratory acidosis is associated with hypercarbia and tachycardia and causes arterial vasodilation and hypotension. The renal compensa-tory system, acting through a mechanism that retains bicarbonate, is slow (takes hours) and is not effective in acute hypercarbia.

Common early signs of hypercapnia are irritability, anxiety, and delirium.11 Neurologic examination may show fine twitches in the face, but gross myoclonic limb movements or asterixis may occur. Profound flaccidity is characteristic in deeper levels of CO2 narco-sis.10 The correlation between consciousness level and Paco2 is poor (Fig. 84-1), and this great variation in laboratory values has been explained by individual susceptibility. The narcotic effect of CO2 may better correlate with cerebrospinal fluid pH and less with arte-rial pH.2 Coma may persist after correction of hypercapnia and seems to correlate with the time the patient has remained hypercapnic. Thus, patients may tolerate brief periods of hypercapnia (less than one hour) and awaken rapidly.

The causes of coma in hypercapnia are shown in Table 84-1. Oxygen administration is the main cause of hypercapnia in a hypoventilating patient.6 Other major categories causing hypercapnic respiratory failure are impaired central drive (brainstem lesions),5,9 neuromuscular disorders (amyotrophic lateral sclerosis), and mechanical failure from chest wall deformities or pneumothorax.8 Hypercapnia produces narcosis. (In the past, inhaled 30% carbon dioxide was used as an anesthetic agent for animal experiments.) Its

7.6

7.4

7.2pHPa

CO

2 (m

m H

g)

7.0

6.8200

180

160

140

120

100

80

60

40Comatose Stupor Confused

drowsyAlert

FIGURE 84-1 Relationship of level of consciousness to arterial blood pH and Paco2 in patients

with substantial carbon dioxide retention and chronic pulmonary disease. Note poor correlation

between improvements in Paco2 and improvement of consciousness (reprinted from Westlake

et al.11 with permission).


inert gas effect—such as is the case with nitrous oxide—is probably low. Most likely, CO2 reduces intracellular pH, and acidosis is injurious to neuronal cells and may affect their excitability.12 It is unclear whether maximal vasodilation and luxury perfusion resulting in increased intracranial pressure is a plausible mechanism. Coma will occur when PaCO2 is between 90 and 120 mm Hg (except in patients with reset respiratory centers, also known as “CO2 retainers”). Hypoventilation may occur with drug or alcohol ingestion; these toxins depress consciousness. Shock may be marked and may cause permanent anoxic-ischemic brain damage.


Noninvasive mechanical ventilation can be useful to decrease respiratory muscle load.1 It provides oxygen treatment and does not worsen hypercapnia.3 A brief period of mechani-cal ventilation may be successful in patients with severe hypercapnia that is refractory to treatment.4 Improvement of consciousness is rapid and without neurologic sequelae in most patients. Hypercapnia is better tolerated by the patient than hypoxemia.6

A CONCLUDING NOTE

Hypercapnia is associated with oxygen administration in patients with COPD. Myoclonus and asterixis due to hypercapnia may herald a rapid decline in conscious-ness. Mechanical ventilation or noninvasive ventilation will normalize both hypoxemia and hypercarbia.

REFERENCES

1. Brochard L. Noninvasive ventilation for acute respiratory failure. Jama 2002;288:932–935.2. Eisele JH, Eger EI, 2nd, Muallem M. Narcotic properties of carbon dioxide in the dog. Anesthesiology

1967;28:856–865.3. Gomersall CD, Joynt GM, Freebairn RC, Lai CK, Oh TE. Oxygen therapy for hypercapnic patients

with chronic obstructive pulmonary disease and acute respiratory failure: a randomized, controlled pilot study. Crit Care Med 2002;30:113–116.

4. Hemmila MR, Napolitano LM. Severe respiratory failure: advanced treatment options. Crit Care Med 2006;34:S278–290.

TABLE 84-1 Causes of Coma in hypercapnia

• CO2-induced neuronal suppression• Anoxic-ischemic encephalopathy from shock• Illicit drug use or alcohol intoxication with hypoventilation

Comatose and hypercapnia / / 645

5. Hui SH, Wing YK, Poon W, Chan YL, Buckley TA. Alveolar hypoventilation syndrome in brainstem glioma with improvement after surgical resection. Chest 2000;118:266–268.

6. Lumb AB. Nunn’s Applied Respiratory Physiology, 5th ed. Oxford: Butterworth-Heinemann, 2000.7. Maloney JP. Acute ventilatory failure. Current Diagnosis and Treatment in Pulmonary Medicine.

New York: McGraw-Hill, 2003:251–267.8. Otten M, Schwarte LA, Oosterhuis JW, Loer SA, Schober P. Hypercapnic coma due to spontaneous

pneumothorax: case report and review of the literature. J Emerg Med 2012;42:e1–6.9. Rao GS, Ramesh VJ, Lalla RK. Ventilatory management and weaning in a patient with central hypoven-

tilation caused by a brainstem cavernoma. Acta Anaesthesiol Scand 2005;49:1214–1217.10. Sieker HO, Hickam JB. Carbon dioxide intoxication: the clinical syndrome, its etiology and management

with particular reference to the use of mechanical respirators. Medicine (Baltimore) 1956;35:389–423.11. Westlake EK, Simpson T, Kaye M. Carbon dioxide narcosis in emphysema. Q J Med 1955;24:155–173.12. Yang L, Su J, Zhang X, Jiang C. Hypercapnia modulates synaptic interaction of cultured brainstem neu-

rons. Respir Physiol Neurobio 2008;160:147–159.

646

A CONVERSATION

AN EXPLANATION

Pituitary apoplexy occurs in pituitary adenoma, a tumor abundantly supplied by hypo-physial arteries and prone to bleeding.8 Another mechanism is vascular stasis and clotting in a tumor mass outgrowing its blood supply; this may lead to necrosis and hemorrhagic infarction. Precipitating factors for pituitary apoplexy are surgical procedures, adminis-tration of bromocriptine, diabetic ketoacidosis, radiation, and acute hypertensive crisis.5 Pituitary edema associated with use of the cardiopulmonary pump has been proposed as

Comatose and Pituitary Apoplexy

/ / / 85 / / /

Comatose and Pituitary Apoplexy / / 647

an explanation for the association of pituitary apoplexy with cardiac surgery.7,11,12,14 True subarachnoid hemorrhage may occur in pituitary apoplexy, and the CT appearance in some cases may suggest a ruptured giant aneurysm rather than a hemorrhagic pituitary tumor.17

Pituitary apoplexy may be the first presentation of the tumor, with clinical signs that range from trivial ones to signs that are immediately life-threatening from glucocorticoid deficiency. Common is a thunderclap headache (80%) that is indistinguishable (although often located retro-orbitally) from aneurysmal subarachnoid hemorrhage and is followed by visual field deficits or oculomotor abnormalities (45%) (Fig. 85-1).2,3,13,16 Impaired consciousness is not common.

The causes of coma in pituitary apoplexy are shown in Table 85-1. Hypotension and hyponatremia result from a glucocorticoid deficiency; these clinical signs are easily over-looked and may result in a fatal outcome.13,15 Compression of the thalamus due to sudden hematoma expansion is another mechanism.4 Hypopituitarism occurs in a large propor-tion of patients, and shock in itself may contribute to a decrease in consciousness. CT of the brain will visualize the tumor, but its density may be similar to that of brain tissue

TABLE 85-1 Causes of Coma in Pituitary Apoplexy

• Compression of the diencephalon• Hyponatremia• Hypotension• Hypothyroidism

84

13

61

43 43

5

%

100

80

60

40

20

0H LOC VA VF CN LT

FIGURE 85-1 Clinical features in 62 patients with pituitary apoplexy. H = headache; LOC = dimin-

ished level of consciousness; VA = diminished visual acuity; VF = visual field defect; CN = cranial

nerve deficits; LT = long-tract signs. Adapted from Semple et al.13 with permission.


and thus difficult to detect. MRI of the brain shows not only the hemorrhage (Fig. 85-2) but also compression of diencephalon, optic chiasm, or even hemorrhage into the optic tract.9 Endocrine investigations are essential and dysfunction of many endocrine systems may occur.13


Following corticosteroid administration, responsiveness of the patient rapidly improves. glucocorticoid and thyroid hormone replacement may suffice in some patients with-out visual deficits who show improved levels of consciousness. Surgical decompres-sion, however, is urgently needed in many cases.1 Permanent visual deficits may occur if tumors compress the chiasm, particularly when surgery is delayed for more than a week after presentation of pituitary apoplexy. The management of pituitary hormone replace-ment is shown in Table 85-2.6,10

A CONCLUDING NOTE

Pituitary apoplexy is a cause of sudden and unexplained hypotension. It is difficult to recognize clinically and is often apparent only on neuroimaging studies. MRI is the required diagnostic test. Neurosurgical and endocrine management is urgently needed.

FIGURE 85-2 MRI of pituitary apoplexy (hyperintensity in pituitary tumor).

Comatose and Pituitary Apoplexy / / 649

REFERENCES

1. Ayuk J, McGregor EJ, Mitchell RD, Gittoes NJ. Acute management of pituitary apoplexy—surgery or conservative management? Clin Endocrinol (Oxf) 2004;61:747–752.

2. Bills DC, Meyer FB, Laws ER, Jr., et al. A retrospective analysis of pituitary apoplexy. Neurosurgery 1993;33:602–608; discussion 608–609.

3. Bonicki W, Kasperlik-Zaluska A, Koszewski W, Zgliczynski W, Wislawski J. Pituitary apoplexy: endo-crine, surgical and oncological emergency. Incidence, clinical course and treatment with reference to 799 cases of pituitary adenomas. Acta Neurochir (Wien) 1993;120:118–122.

4. Cardoso ER, Peterson EW. Pituitary apoplexy: a review. Neurosurgery 1984;14:363–373.5. Carija R, Vucina D. Frequency of pituitary tumor apoplexy during treatment of prolactinomas with

dopamine agonists: a systematic review. CNS Neurol Disord Drug Targets 2012;11:1012–1014.6. Chanson P, Lepeintre JF, Ducreux D. Management of pituitary apoplexy. Expert Opin Pharmacother

2004;5:1287–1298.7. Cooper DM, Bazaral MG, Furlan AJ, et al. Pituitary apoplexy: a complication of cardiac surgery. Ann

Thorac Surg 1986;41:547–550.8. Fanous AA, Quigley EP, Chin SS, Couldwell WT. Giant necrotic pituitary apoplexy. J Clin Neurosci

2013;20(10):1462–1464.9. Kim HJ, Cho WH. Optic tract hemorrhage after pituitary apoplexy. AJNR Am J Neuroradiol

2007;28:141–142.10. Levy A. Pituitary disease: presentation, diagnosis, and management. J Neurol Neurosurg Psychiatry

2004;75 Suppl 3:iii47–52.11. Pliam MB, Cohen M, Cheng L, et al. Pituitary adenomas complicating cardiac surgery: summary and

review of 11 cases. J Card Surg 1995;10:125–132.12. Savage EB, Gugino L, Starr PA, et al. Pituitary apoplexy following cardiopulmonary bypass: consider-

ations for a staged cardiac and neurosurgical procedure. Eur J Cardiothorac Surg 1994;8:333–336.13. Semple PL, Webb MK, de Villiers JC, Laws ER, Jr. Pituitary apoplexy. Neurosurgery 2005;56:65–72.

TABLE 85-2 Pituitary hormone Replacement

GlucocorticoidHydrocortisone 15 mg twice daily (to mimic normal diurnal variation)

Thyroid HormoneL-thyroxine 100-125 µg daily as a single dose

Sex HormoneWomenCyclical estrogens and progestogens

MenTestosterone is replaced as a mixture of testosterone esters (Sustanon intramuscularly) or testosterone

enanthate (250 mg every 3 weeks).Growth HormoneGH by daily subcutaneous injection, titrated over 3 months to bring IGF-1 concentrations into the middle of

the normal range and continued for 6 monthsVasopressinDDAVP nasal spray if diabetes insipidus remains (usually transient after surgery)

Data from Levy10 and Chanson et al.6


14. Tang-Wai DF, Wijdicks EF. Pituitary apoplexy presenting as postoperative stupor. Neurology 2002;58:500–501.

15. Warwar RE, Bhullar SS, Pelstring RJ, Fadell RJ. Sudden death from pituitary apoplexy in a patient pre-senting with an isolated sixth cranial nerve palsy. J Neuroophthalmol 2006;26:95–97.

16. Wiesmann M, Gliemroth J, Kehler U, Missler U. Pituitary apoplexy after cardiac surgery presenting as deep coma with dilated pupils. Acta Anaesthesiol Scand 1999;43:236–238.

17. Wohaibi MA, Russell NA, Ferayan AA, et al. Pituitary apoplexy presenting as massive subarachnoid hemorrhage. J Neurol Neurosurg Psychiatry 2000;69:700–701.

651

A CONVERSATION

AN EXPLANATION

The clinical spectrum of central nervous system (CNS) involvement in active systemic lupus erythematosus (SLE) is diverse, and for practical purposes a detailed nomenclature has been developed. The American College of Rheumatology lists a wide array of neu-ropsychiatric syndromes associated with SLE. These include aseptic meningitis, stroke, demyelinating syndromes, myelopathy, seizures, and psychiatric manifestations.5

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/ / / 86 / / /

652 / / ThE ComaToSE PaTiEnT

Neuropsychiatric symptoms include altered mood and acute psychotic derange-ments, and it might be difficult to attribute them to an SLE exacerbation. A more severe or even fulminant involvement of the CNS termed cerebral lupus has been described, and it could lead to coma. A more problematic explanation for CNS involvement is the term cerebritis; undoubtedly the term was more popular before neuroimaging studies showed abnormalities, such as this index case. The pathological mechanisms of CNS involvement in lupus are speculative. A current theory is that there is initially direct blood–brain bar-rier damage from microthrombi that, in turn, leads to an immune-mediated attack fol-lowed by further blood–brain barrier breakdown.4

The causes of coma in SLE are shown in Table 86-1. In the more severe and fulmi-nant forms of SLE, CNS involvement may lead to marked impairment of conscious-ness, and several causes can be considered. Multiple cerebral infarctions or a pontine infarct can impair consciousness. These infarcts can be due to thrombi; indeed, when patients are studied with transcranial Doppler ultrasound, embolic signals have been found.2 There is early accelerated atherosclerosis in SLE with large cerebral vessel occlu-sive disease, but emboli can be cardiac in origin.11 Both ischemic heart disease and endo-carditis are potential sources, but mitral valvulitis has been described in approximately half of SLE patients at autopsy.3 Vasculitis, causing large or small vessel disease, is rare. More common pathology in patients with cerebral lupus is the presence of destructive and proliferative changes in both arteries and capillaries but no inflammation. However, CNS infections such as aspergillosis, cytomegalovirus, or herpes zoster infection could cause vasculitis in unusual cases.6 Cryptococcal meningitis has been reported in SLE.6 In SLE, generalized tonic-clonic seizures may be observed that could evolve into refrac-tory status epilepticus.

Laboratory investigations in SLE associated with coma include immunologic tests. These autoantibodies are listed in Table 86-2. Higher levels of IgG and IgM and anti-cardiolipin (ACL) antibodies were measured in patients with neuropsychiatric lupus syndromes compared with patients without neuropsychiatric symptoms. ACL antibody has more significance than lupus anticoagulant (LAC) antibodies.1,9 A recent study found that a microtubule associated protein-2 (MAP-2), a protein associated with the

TABLE 86-1 Causes of Coma in Systemic Lupus Erythematosus

• Multiple hemispheric infarction (antiphospholipid antibody syndrome)• Pontine demyelination• Status epilepticus• Opportunistic central nervous system infections

Comatose and Systemic Lupus Erythematosus / / 653

cytoskeleton, is elevated in approximately two thirds of the patients with neuropsychiat-ric symptoms and SLE.1,12

MRI can remain normal in active SLE. However, white matter changes have been described in SLE resembling relapsing multiple sclerosis. White matter necrosis with myelin vacuolization has been reported in the brainstem. In addition, clinical enti-ties almost identical to acute disseminated encephalomyelitis have been described (Chapter 45). In SLE, scattered T2-weighted images are present in the frontoparietal subcortical white matter, but cerebral infarcts and hemorrhages have also been found. Restricted diffusion on diffusion-weighted images may be an indicator of active disease or infarction. A more recent study identified that FLAIR imaging in SLE had the highest sensitivity for abnormalities, although the overall yield of abnormalities remains small. Most of the abnormalities are small focal white matter lesions,13 some localized periven-tricular, and in others the images show a recent infarction, acute leukoencephalopathy, or brainstem involvement (Fig. 86-1). After immunosuppression is provided, MRI abnor-malities can be entirely reversible. The value of single photon emission computed tomog-raphy is unclear. Most studies show diffusely decreased cerebral blood flow, but blood flow improves with clinical improvement.13 These changes in cerebral blood flow remain unexplained.


Treatment of cerebral lupus includes high-dose pulse intravenous corticosteroids (1 g methylprednisolone daily for three days). Cyclophosphamide is often added in patients

TABLE 86-2 major antibodies in Systemic Lupus Erythematosus

Autoantibody Major Autoantigen(s) Tentative Neurologic Associations

Antineuronal Unidentified Cognitive impairmentBrain cross-reactive

lymphocytotoxic

31–32, 50–52, 54–56, and

97–98 kDa

Visuospatial cognitive impairment

Antiribosomal P 60S eukaryotic ribosomal

subunit proteins P0, P1, P2

Lupus psychosis and severe depression

Antiphospholipid (aPL)

(cofactor β2-glycoprotein 1)Cardiolipin, prothrombin,

protein C, and protein S

Stroke, seizures, transverse myelitis, transient

ischemic attacksAntiganglioside Acid glycolipid on neuronal

and myelin membranes

Migraine, stroke, depression, seizures, and

psychosisAntiendothelial (AECA) Unidentified Cognitive impairment, depression, epilepsy



with cerebral lupus. The regimen includes monthly intravenous bolus of cyclophospha-mide in a dose of 1 g/m2 body surface area.8 Five days of immunoglobulin therapy has been successful in treating neuropsychiatric lupus.10 Plasma exchange could be used in more severe cases, but neither the number of treatments nor the effectiveness is exactly known. Catastrophic antiphospholipid antibody syndrome associated with SLE requires strict anticoagulation, with international normalized ratio (INR) ranging from 3.0 to 3.5. Recognition of seizures in SLE is important, particularly because one recent large study found evidence of single or multiple seizures in 42% of patients with cerebral lupus.7 When appropriate to the case, video-EEG monitoring is set up. The most important clini-cal considerations are shown in Figure 86-2.

FIGURE 86-1 MRI (FLAIR) showing hyperintensity in pons during an SLE exacerbation resulting

in transient coma.

Comatose and Systemic Lupus Erythematosus / / 655

A CONCLUDING NOTE

SLE may cause coma due to multiple infarcts or due to severe demyelination and could involve the pons. The clinical signs and MR abnormalities are potentially reversible after treatment with high-dose pulse corticosteroids, cyclophosphamide, and plasma exchange.

REFERENCES

1. Abbott NJ, Mendonca LL, Dolman DE. The blood-brain barrier in systemic lupus erythematosus. Lupus 2003;12:908–915.

2. Dahl A, Omdal R, Waterloo K, et al. Detection of cerebral embolic signals in patients with systemic lupus erythematosus. J Neurol Neurosurg Psychiatry 2006;77:774–779.

3. Devinsky O, Petito CK, Alonso DR. Clinical and neuropathological findings in systemic lupus erythe-matosus: the role of vasculitis, heart emboli, and thrombotic thrombocytopenic purpura. Ann Neurol 1988;23:380–384.

4. Frieri M. Mechanisms of disease for the clinician: systemic lupus erythematosus. Ann Allergy Asthma Immunol 2013;110:228–232.

5. Greenberg BM. The neurologic manifestations of systemic lupus erythematosus. Neurologist 2009;15:115–121.

6. Hung JJ, Ou LS, Lee WI, Huang JL. Central nervous system infections in patients with systemic lupus erythematosus. J Rheumatol 2005;32:40–43.

7. Joseph FG, Lammie GA, Scolding NJ. CNS lupus: a study of 41 patients. Neurology 2007;69:644–654.8. Kobayashi H, Watanabe H, Seino T, Suzuki S, Sato Y. Quantitative imaging of cerebral blood flow using

SPECT with 123I-iodoamphetamine in neuropsychiatric systemic lupus erythematosus. J Rheumatol 2003;30:2075–2076.

9. Parikh T, Shifteh K, Lipton ML, Bello JA, Brook AL. Deep brain reversible encephalopathy: association with secondary antiphospholipid antibody syndrome. AJNR Am J Neuroradiol 2007;28:76–78.

10. Petri M, Jones RJ, Brodsky RA. High-dose cyclophosphamide without stem cell transplantation in sys-temic lupus erythematosus. Arthritis Rheum 2003;48:166–173.

11. Roman MJ, Shanker BA, Davis A, et al. Prevalence and correlates of accelerated atherosclerosis in sys-temic lupus erythematosus. N Engl J Med 2003;349:2399–2406.

12. Williams RC, Jr., Sugiura K, Tan EM. Antibodies to microtubule-associated protein 2 in patients with neuropsychiatric systemic lupus erythematosus. Arthritis Rheum 2004;50:1239–1247.

13. Zhang L, Harrison M, Heier LA, et al. Diffusion changes in patients with systemic lupus erythematosus. Magn Reson Imaging 2007;25:399–405.

SLE coma

Immuno-suppression

Lymph-oma

CNSinfection

CVT StrokeFlare

up SLE Stroke

Antiphospholipidantibody syndrome Seizures

FIGURE 86-2 Diagnostic considerations in SLE and coma. CVT = Cerebral venous thrombosis,

CNS = Central nervous system, SLE = Systemic lupus erythematosus.

656

A CONVERSATION

AN EXPLANATION

Vasculitis of the central nervous system (CNS) is a rare disorder, with an annual inci-dence rate of 2.4 cases per 10,000 person-years.14 Clinical criteria for CNS vasculitis have been proposed and include (1) acquired neurologic deficit with no other explana-tion after a complete evaluation; (2) a diagnostic cerebral angiogram that includes parts with symmetric arterial narrowing, with other parts showing dilatation or occlusion; and (3) no evidence of systemic vasculitis or any other condition that could mimic the

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cerebral angiogram findings.2,5–7,11 A biopsy could provide a histopathological diagnosis if the following criteria are present: transmural inflammation of small or medium-sized blood vessels of the meninges or cortex of the brain and the presence of an inflammatory infiltrate predominantly consisting of plasma cells, histiocytes, neutrophils, eosinophils, granulomas, or multinucleated giant cells. Fibrinoid necrosis of the vessel walls should be present for the diagnosis. Although alternative explanations are uncommonly found after brain biopsy, biopsy remains mandatory in most patients. A diagnosis such as cere-bral autosomal dominant arteriopathy (CADASIL) and multiple emboli associated with marantic endocarditis have been surprising findings on biopsies or at autopsy in patients suspected of having CNS vasculitis.13 Moreover, a recent study of 14 patients found that in those with typical angiographic findings of vasculitis (defined as irregularities of the contour of arteries and focal arterial narrowing), angiitis was not confirmed at biopsy.1 This emphasizes the need for brain and meningeal biopsy.

The causes of coma in CNS vasculitis are shown in Table 87-1. Coma can be explained by the rapid development of ischemic infarctions in both hemispheres. Several causes of vasculitis that can affect the CNS have been reported (Table 87-2).4,8–10,13,17 When the vessel wall is inflamed and necrotic, it is likely that not only vasoconstriction occurs but also that the endothelial cell wall could produce a procoagulant effect.15 Vasculitis, therefore, can present with recurrent ischemic strokes, and the location of the infarc-tion determines the clinical presentation. Bifrontal infarcts will result in marked abulia or akinetic mutism. A fulminant form of CNS vasculitis exists that is resistant to pred-nisone and cyclophosphamide and relentlessly causes infarction in multiple areas of the brain. Patients may present with subarachnoid hemorrhage, but most patients—at least initially—present in a good grade because mostly the peripheral sulcal arteries are involved.12 Renal involvement is common in systematic arteritis and may cause a severe uremic encephalopathy.

MRI will demonstrate posterior lesions mimicking posterior encephalopathy syn-drome (Chapter 72), but often lesions at other locations appear on repeat MR studies.16 When multifocal or bilateral parenchymal lesions appear on MRI, it indicates a fulminant form of vasculitis, and these patients should be aggressively treated (Figs. 87-1 and 87-2).

TABLE 87-1 Causes of Coma in CnS Vasculitis

• Multiple hemispheric infarcts• Ischemic strokes in frontal lobes (akinetic mutism)• Ischemic stroke in brainstem• Uremic encephalopathy



Treatment of a CNS vasculitis includes standard regimens such as prednisone (2 mg/kg) and cyclophosphamide (1 g/m2). After six months, and depending on clinical improve-ment, prednisone is gradually tapered.3 Patients also should receive prophylaxis

TABLE 87-2 Classification of Vasculitis That Could involve the nervous System

Granulomatous angiitis of the nervous systemSystemic necrotizing arteritisPolyarteritis nodosaChurg-Strauss syndromeMicroscopic polyangiitis

Hypersensitivity vasculitisHenoch-Schönlein purpuraHypocomplementemic vasculitisCryoglobulinemia

Systemic granulomatous vasculitisGranulomatosis with polyangiitisLymphomatoid granulomatosis

Giant cell arteritisTemporal arteritisTakayasu arteritis

Connective tissue disorders associated with vasculitisSystemic lupus erythematosusSclerodermaRheumatoid arthritisSjögren syndromeMixed connective tissue diseaseBehçet disease

Vasculitis associated with infectionVaricella zoster virusSpirochetes

Treponema pallidumBorrelia burgdorferi

FungiRickettsiaBacterial meningitisMycobacterium tuberculosisHuman immunodeficiency virus

Vasculitis associated with amphetamine abuseParaneoplastic vasculitis

Data adapted from reference 17.


(sulfamethoxazole/trimethoprim) for Pneumocystis jiroveci pneumonia. Prognosis depends on the severity and size of cerebral infarctions.

A CONCLUDING NOTE

CNS vasculitis is a rare cause of multiple cerebral infarcts and a brain biopsy is mandatory for diagnosis. Clinical and radiological criteria are not specific, and a brain biopsy should confirm the presence of vessel wall inflammation and necrosis. Minimally conscious state, akinetic mutism, and persistent vegetative state are all possible outcomes when a fulminant form of CNS vasculitis is not controlled early.

FIGURE 87-1 Cerebral angiogram showing typical beading and occlusive disease in small arter-

ies consistent with CNS vasculitis (proven with biopsy).


REFERENCES

1. Alrawi A, Trobe JD, Blaivas M, Musch DC. Brain biopsy in primary angiitis of the central nervous sys-tem. Neurology 1999;53:858–860.

2. Aviv RI, Benseler SM, DeVeber G, et al. Angiography of primary central nervous system angiitis of child-hood: conventional angiography versus magnetic resonance angiography at presentation. AJNR Am J Neuroradiol 2007;28:9–15.

3. Barron TF, Ostrov BE, Zimmerman RA, Packer RJ. Isolated angiitis of CNS: treatment with pulse cyclo-phosphamide. Pediatr Neurol 1993;9:73–75.

4. Benseler SM, Silverman E, Aviv RI, et al. Primary central nervous system vasculitis in children. Arthritis Rheum 2006;54:1291–1297.

5. Calabrese LH, Duna GF, Lie JT. Vasculitis in the central nervous system. Arthritis Rheum 1997;40:1189–1201.

6. Calabrese LH, Furlan AJ, Gragg LA, Ropos TJ. Primary angiitis of the central nervous system: diagnos-tic criteria and clinical approach. Cleve Clin J Med 1992;59:293–306.

FIGURE 87-2 MRI shows multiple infarcts and gray and white matter involvement.


7. Calabrese LH, Mallek JA. Primary angiitis of the central nervous system. Report of 8 new cases, review of the literature, and proposal for diagnostic criteria. Medicine (Baltimore) 1988;67:20–39.

8. Clarke P, Glick S, Reilly BM. Clinical problem-solving. On the threshold—a diagnosis of exclusion. N Engl J Med 2005;352:919–924.

9. Gotkine M, Vaknin-Dembinsky A. Central nervous system vasculitis. Curr Treat Options Neurol 2013;15:367–374.

10. Gowdie P, Twilt M, Benseler SM. Primary and secondary central nervous system vasculitis. J Child Neurol 2012;27:1448–1459.

11. Kadkhodayan Y, Alreshaid A, Moran CJ, et al. Primary angiitis of the central nervous system at conven-tional angiography. Radiology 2004;233:878–882.

12. Kumar R, Wijdicks EF, Brown RD, Jr., Parisi JE, Hammond CA. Isolated angiitis of the CNS presenting as subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 1997;62:649–651.

13. MacLaren K, Gillespie J, Shrestha S, Neary D, Ballardie FW. Primary angiitis of the central nervous sys-tem: emerging variants. QJM 2005;98:643–654.

14. Salvarani C, Brown RD, Jr., Calamia KT, et al. Primary central nervous system vasculitis: analysis of 101 patients. Ann Neurol 2007;62:442–451.

15. Stern DM, Bank I, Nawroth PP, et al. Self-regulation of procoagulant events on the endothelial cell sur-face. J Exp Med 1985;162:1223–1235.

16. Wijdicks EF, Manno EM, Fulgham JR, Giannini C. Cerebral angiitis mimicking posterior leukoencepha-lopathy. J Neurol 2003;250:444–448.

17. Younger DS. Vasculitis of the nervous system. Curr Opin Neurol 2004;17:317–336.

662

A CONVERSATION

AN EXPLANATION

Coma and acute thrombocytopenia is an unusual combination, with only a few causes known. Thrombocytopenia is common in hospitalized patients, but severe (platelet counts <75,000) could indicate a thrombotic thrombocytopenic purpura (TTP) or heparin-induced thrombocytopenia (HIT) syndrome.11 Drug-induced thrombocyto-penia (antiepileptic agents, diuretics, sulfonamides or nonsteroidal anti-inflammatory drugs [NSAIDs], and vancomycin)14 is rarely associated with neurologic complications.

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HIT is due to antibodies linked to the heparin-platelet factor 4 complex, activates platelet function, and enhances the coagulation cascade.7–10,15 These antibodies also activate endothelium and monocytes, further promoting coagulation. These HIT anti-bodies may be found up to 4 months after the presenting symptoms. HIT may occur five to 12 days after starting heparin or low-molecular-weight heparin and is associated with various routes of administration, including subcutaneous injections or intravenous flushes. The most common major manifestations are deep venous thrombosis, pulmo-nary embolus, and skin necrosis. Ischemic stroke may occur in up to 3% of cases, is more common in females, and has a higher proclivity of fatal outcome. The outcome is better in patients treated with argatroban.10

Another disorder to consider is TTP, which is increasing in frequency. The diagnosis of TTP is established when the following abnormalities are found: platelet level less than 20,000 µL, hemolytic anemia, fragmented erythrocytes (helmet cells), acute renal failure, increased lactate dehydrogenase levels, and if available, megakaryocytes on bone marrow biopsy. Vascular occlusions resulting in infarctions can be widespread throughout both hemispheres (Fig. 88-1), and this is certainly a possible explanation and mechanism for unconsciousness because infarction in other organs has been found at autopsy.

The causes of coma in acute thrombocytopenia are shown in Table 88-1. Theoretically, thrombocytopenia can be associated with both hemorrhagic and ischemic strokes.13 Ischemic strokes are likely multiple and bihemispheric. Thrombocytopenia may be asso-ciated with diffuse intravascular coagulation and septic shock; in those instances, the mechanism of coma is diffuse ischemic cortical laminar injury in watershed territories. A lobar cerebral hemorrhage may occur as a presenting manifestation of severe acute thrombocytopenia. Any patient with a thrombocytopenia may develop a traumatic sub-arachnoid hemorrhage, contusions, or a subdural hematoma that may require evacuation. However, it has been recently appreciated that seizures or nonconvulsive status epilepti-cus may occur in 40% to 50% of patients with TTP, and this may be one reason for failure to improve after plasma exchange.3


The prognosis is determined by the extent of the infarction. The treatment of HIT is obvi-ously discontinuation of heparin, but it is a common misunderstanding that warfarin may be helpful; in fact, it may, in high loading doses, exacerbate procoagulation. It should not be administered because of the risk of precipitating limb gangrene or increasing the risk of skin necrosis. When platelet counts are normal warfarin can be introduced at 5 mg


daily. Fondaparinux (7.5 mg subcutaneously daily) is indicated in any symptomatic—or asymptomatic—patient.9 Argatroban is another option as is bivalirudin or danaparoid.10

Plasma exchange is the preferred treatment in TTP and usually will rapidly reverse neurologic findings and awaken the patient. Rituximab is used when TTP relapses or does not respond to plasma exchange.1,2,4,12 Mortality has markedly decreased due to early use

FIGURE 88-1 MRI showing bilateral infarcts due to HIT.

TABLE 88-1 Causes of Coma in acute Thrombocytopenia

• Lobar hematoma with mass effect• Acute subdural hematoma with mass effect• Multiple hemispheric strokes• Anoxic-ischemic encephalopathy• Nonconvulsive status epilepticus

Comatose and acute Thrombocytopenia / / 665

of plasma exchange, and survival is now likely in 90% of patients.2,5 Patients with a severe thrombocytopenia and intracranial hematoma should receive urgent platelet infusions.

A CONCLUDING NOTE

Both hemorrhagic and ischemic strokes can occur, depending on the cause of throm-bocytopenia. Comatose patients with thrombocytopenia represent a unique subset of patients who need specific treatment. HIT may cause multiple ischemic strokes and responds well to argatroban.

REFERENCES

1. Ahmad A, Aggarwal A, Sharma D, et al. Rituximab for treatment of refractory/relapsing thrombotic thrombocytopenic purpura (TTP). Am J Hematol 2004;77:171–176.

2. Arnold DM, Dentali F, Crowther MA, et al. Systematic review: efficacy and safety of rituximab for adults with idiopathic thrombocytopenic purpura. Ann Intern Med 2007;146:25–33.

3. Beydoun A, Vanderzant C, Kutluay E, Drury I. Full neurologic recovery after fulminant thrombotic thrombocytopenic purpura with status epilepticus. Seizure 2004;13:549–552.

4. Boctor FN, Smith JA. Timing of plasma exchange and rituximab for the treatment of thrombotic throm-bocytopenic purpura. Am J Clin Pathol 2006;126:965; author reply 965–966.

5. Franchini M. Thrombotic microangiopathies: an update. Hematology 2006;11:139–146.6. Gajra A, Vajpayee N, Smith A, Poiesz BJ, Narsipur S. Lepirudin for anticoagulation in patients with

heparin-induced thrombocytopenia treated with continuous renal replacement therapy. Am J Hematol 2007;82:391–393.

7. Girolami B, Girolami A. Heparin-induced thrombocytopenia: a review. Semin Thromb Hemost 2006;32:803–809.

8. Hassell K. The management of patients with heparin-induced thrombocytopenia who require antico-agulant therapy. Chest 2005;127:1S–8S.

9. Kelton JG, Arnold DM, Bates SM. Non heparin anticoagulants for heparin-induced thrombocytopenia. N Engl J Med. 2013:368:737–744.

10. LaMonte MP, Brown PM, Hursting MJ. Stroke in patients with heparin-induced thrombocytopenia and the effect of argatroban therapy. Crit Care Med 2004;32:976–980.

11. Levy JH, Hursting MJ. Heparin-induced thrombocytopenia, a prothrombotic disease. Hematol Oncol Clin North Am 2007;21:65–88.

12. Ozdogu H, Boga C, Kizilkilic E, et al. A dramatic response to rituximab in a patient with resistant thrombotic thrombocytopenic purpura (TTP) who developed acute stroke. J Thromb Thrombolysis 2007;23:147–150.

13. Seckin H, Kazanci A, Yigitkanli K, Simsek S, Kars HZ. Chronic subdural hematoma in patients with idiopathic thrombocytopenic purpura: A case report and review of the literature. Surg Neurol 2006;66:411–414.

14. Von Drygalski A, Curtis BR, Bougie DW, et al. Vancomycin-induced immune thrombocytopenia. N Engl J Med 2007;356:904–910.

15. Warkentin TE, Sheppard JA. Testing for heparin-induced thrombocytopenia antibodies. Transfus Med Rev 2006;20:259–272.

666

A CONVERSATION

AN EXPLANATION

Acute myelogenous leukemia (AML) may present with multiple localizations in the cen-tral nervous system (CNS).2,4,7 Cytology of the cerebrospinal fluid (CSF) often confirms the clinical diagnosis, with mature monocytes and promonocytes being present.

The causes of coma in acute leukemia are shown in Table 89-1. Rapid declining consciousness in AML or acute lymphoblastic leukemia (ALL) can be caused by CNS localization due to leukemic infiltration or subarachnoid hemorrhage.8 However, more

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Comatose and acute Leukemia / / 667

often patients are at risk of worsening neurologically during induction chemotherapy. Chemotherapy includes intrathecal methotrexate, idarubicin, and ara-C. Ara-C, or cyta-rabine, is a pyrimidine analog and is administered intravenously to treat leptomeningeal infiltration. Intrathecal methotrexate may cause not only acute chemical meningitis with headache but also transient focal neurologic deficits, seizures, and a more profound acute leukoencephalopathy. The incidence is up to 10% in patients treated with high-dose methotrexate. This acute toxic leukoencephalopathy mostly occurs with high-dose intra-venous infusions (3 g/m2 or more every 12 hours). MRI scan is nonspecific, and the presence of diffuse white matter involvement is as expected in an acute leukoencephalop-athy. Seizures may occur and the patient may progress to a profound encephalopathy and coma, but the symptoms can completely resolve after discontinuation of the infusion.

Infiltration into the liver may cause hepatomegaly and hepatic encephalopathy. An idiopathic hyperammonemia has been described in patients with induction high-dose cytoreductive therapy; it may occur several months after allogeneic bone marrow trans-plantation.1,5 The use of opioids also may cause deterioration in consciousness. In a series of 140 patients with cancer, drugs were a contributing factor in 64% of patients with encephalopathy, more than organ dysfunction (54%) or infection (46%).9

CT scan in AML may show a hyperintensity that can be confirmed on MRI (Fig. 89-1). Enhancement may occur but is not diagnostic for leukemic infiltration. Repeated CSF examination is often necessary to find the abnormal blasts, with nuclei that are typically irregular, lobulated, or cloverleaf.


Intrathecal therapies with methotrexate and cytarabine are preferred and some institu-tions use cranial irradiation therapy, but unfortunately there is very little evidence in adults that cranial radiation can control CNS leukemia.6 After complete remission has been achieved, an abnormal cytogenic evaluation determines the need for bone marrow transplantation or further use of high-dose cytarabine. Cytogenic analysis is important in classifying subgroups of AML and has implications for prognosis (Table 89-2). Outcome

TABLE 89-1 Causes of Coma in acute myelogenous Leukemia

• Leukemic meningoencephalitis• High-dose methotrexate leukoencephalopathy• Acute hyperammonemia• Seizures• High doses of opioids


(A) (B)

FIGURE 89-1 (A) CT scan showing hyperintensity in the sulci, which could indicate subarachnoid

hemorrhage or CNS localization of leukemia. (B) MRI showing abnormal FLAIR images compat-

ible with the CT scan and higher intensity in the clivus, compatible with AML localization.

Comatose and acute Leukemia / / 669

is uncertain, but a major factor is whether remission is achieved after induction chemo-therapy or bone marrow transplantation (estimated in 60% to 70% of patients).3

A CONCLUDING NOTE

Progressive encephalopathy may be a presenting symptom of AML. Induction chemo-therapy (methotrexate) may cause a toxic leukoencephalopathy with diffuse white matter edema but is not a common occurrence. Leukemic infiltration or subarachnoid hemor-rhage may also explain impaired consciousness.

REFERENCES

1. Davies SM, Szabo E, Wagner JE, Ramsay NK, Weisdorf DJ. Idiopathic hyperammonemia: a frequently lethal complication of bone marrow transplantation. Bone Marrow Transplant 1996;17:1119–1125.

2. Deschler B, Lubbert M. Acute myeloid leukemia: epidemiology and etiology. Cancer 2006;107: 2099–2107.

3. Litzow MR. Progress and strategies for patients with relapsed and refractory acute myeloid leukemia. Curr Opin Hematol 2007;14:130–137.

4. Lowenberg B, Downing JR, Burnett A. Acute myeloid leukemia. N Engl J Med 1999;341:1051–1062.5. Mitchell RB, Wagner JE, Karp JE, et al. Syndrome of idiopathic hyperammonemia after high-dose chemo-

therapy: review of nine cases. Am J Med 1988;85:662–667.6. Sanders KE, Ha CS, Cortes-Franco JE, et al. The role of craniospinal irradiation in adults with a central

nervous system recurrence of leukemia. Cancer 2004;100:2176–2180.7. Sham RL, Phatak PD, Kouides PA, Janas JA, Marder VJ. Hematologic neoplasia and the central nervous

system. Am J Hematol 1999;62:234–238.8. Spataro R, La Bella V. Neurological picture. Petechial brain hemorrhages in acute lymphoblastic leuke-

mia. J Neurol Neurosurg Psychiatry 2013;84:908.9. Tuma R, DeAngelis LM. Altered mental status in patients with cancer. Arch Neurol 2000;57:1727–1731.

TABLE 89-2 Classification of acute myelogenous Leukemia

Type of AML Prognosis

With t(8;21)(q22;q22) GoodWith t(15;17)(q22;q12) GoodWith inv (16)(p13;q22) GoodWith 11q23 abnormalities PoorWith multilineage dysplasia Poor


670

A CONVERSATION

AN EXPLANATION

Acute intermittent porphyria (AIP) is an autosomal dominant disorder caused by a partial deficiency of porphobilinogen (PBG) deaminase, the third enzyme in the heme synthesis pathway. The condition is quiescent until stress, menstruation, fasting, preg-nancy, surgery, or medications precipitate an acute attack.13,14 The acute episodes are accompanied by a plethora of signs such as abdominal pain, nausea, vomiting, consti-pation, myalgias, seizures, and psychiatric manifestations that are all nonspecific and

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Comatose and acute Porphyria / / 671

do not point toward the diagnosis.16 Generalized myalgia is explained by the underpro-duction of myoglobin. Myoglobin contains one heme group and performs an analo-gous function. It stores and facilitates oxygen diffusion into rapidly contracting muscle. A porphyric crisis induces a switch to anaerobic metabolism and lactic acidosis with consequent myalgia. During an acute attack, heme precursors such as aminolevulinic acid (ALA) and PBG are excreted in large quantities in the urine. Clinical features include dark-colored (tea-like) urine.

In acute porphyria, the MRI lesions are large, diffuse, and reversible and show a striking contrast enhancement, but they lack changes on diffusion-weighted sequences. MR spectroscopy (MRS) shows normal spectroscopic peaks that exclude acute demy-elination or tissue necrosis. After treatment, most lesions regress on subsequent studies. This implies there is only vasogenic edema with temporary breakdown of the blood–brain barrier, possibly induced by abnormal porphyrin metabolites (Fig. 90-1).

The causes of coma in acute porphyria are shown in Table 90-1. MRI abnormalities associated with AIP resemble a posterior reversible encephalopathy syndrome.5,8–10,17 These lesions involve the occipital or frontoparietal cortices (anterior lesions are seen in 90% of imaged cases).6 Although the lesions are readily reversible, impaired microcircu-lation and tissue ischemia with protracted or recurrent episodes can lead to infarction.6 Other abnormalities include central pontine myelinolysis due to AIP-associated hypo-natremia15 and occipital infarctions.11 White matter lesions can resemble the plaques of multiple sclerosis.3,4 There are no comprehensive data on imaging accompaniments of porphyric encephalopathy, although it is likely that most episodes are accompanied by transient or permanent changes on MRI. The cause of seizures in porphyric encepha-lopathy is unclear. Among the suggested mechanisms is a direct neurotoxic effect of ALA (which is structurally similar to gamma-aminobutyric acid [GABA] and interacts with GABA receptors). ALA also crosses the blood–brain barrier easily, accumulates in neuro-nal tissue, and alters tryptophan metabolism.13


How to best treat acute porphyria is not exactly known.1,7 However, treatment of declin-ing consciousness in AIP should involve immediate administration of Hematin. This hydroxylated form of heme is administered intravenously 2 to 5 mg/kg daily for 14 days or until improvement is noted. Seizures are probably treated only if recurrent. The reason is that they are uncommon among patients with symptomatic AIP (<5%) and AIP can also be exacerbated by conventional antiepileptic drugs such as phenytoin, barbiturates,


(A)

(B)

(C)

(D)

(E)

FIGURE 90-1 MRI shows multiple large subcortical white matter hyperintensities on T2-weighted

images in the frontal and temporal lobes. The lesions are hypointensive on T1-weighted images.

Diffusion-weighted images and MR spectroscopy are normal. Composite shows from Row A–E;

A = axial T1-weighted images; B = axial T1 contrast images; C = coronal T1 contrast images;

D = coronal FLAIR images; and E = MR spectroscopy peaks at TR 1500 and TEs of 35, 144, and

288. From Maramattom et al.12 with permission.

Comatose and acute Porphyria / / 673

and valproate.2,4 Control of seizures thus requires the use of alternative agents such as gabapentin and clonazepam.

A CONCLUDING NOTE

AIP is a rare cause of coma and is difficult to diagnose. The diagnosis could be considered in a patient with prior abdominal symptoms, hypertension, seizures, and tea-colored urine.

REFERENCES

1. Balwani M, Desnick RJ. The porphyrias: advances in diagnosis and treatment. Hematology Am Soc Hematol Educ Program 2012;2012:19–27.

2. Bonkowsky HL, Sinclair PR, Emery S, Sinclair JF. Seizure management in acute hepatic porphyria: risks of valproate and clonazepam. Neurology 1980;30:588–592.

3. Bylesjo I, Brekke OL, Prytz J, Skjeflo T, Salvesen R. Brain magnetic resonance imaging white-matter lesions and cerebrospinal fluid findings in patients with acute intermittent porphyria. Eur Neurol 2004;51:1–5.

4. Bylesjo I, Forsgren L, Lithner F, Boman K. Epidemiology and clinical characteristics of seizures in patients with acute intermittent porphyria. Epilepsia 1996;37:230–235.

5. Celik M, Forta H, Dalkilic T, Babacan G. MRI reveals reversible lesions resembling posterior reversible encephalopathy in porphyria. Neuroradiology 2002;44:839–841.

6. Covarrubias DJ, Luetmer PH, Campeau NG. Posterior reversible encephalopathy syndrome: prognostic utility of quantitative diffusion-weighted MR images. AJNR Am J Neuroradiol 2002;23:1038–1048.

7. Deybach JC, Badminton M, Puy H, et al. European porphyria initiative (EPI): a platform to develop a common approach to the management of porphyrias and to promote research in the field. Physiol Res 2006;55 Suppl 2:S67–73.

8. Garg RK. Acute intermittent porphyria: a cause of posterior leukoencephalopathy syndrome. J Assoc Physicians India 2000;48:658.

9. King PH, Bragdon AC. MRI reveals multiple reversible cerebral lesions in an attack of acute intermittent porphyria. Neurology 1991;41:1300–1302.

10. Kupferschmidt H, Bont A, Schnorf H, et al. Transient cortical blindness and bioccipital brain lesions in two patients with acute intermittent porphyria. Ann Intern Med 1995;123:598–600.

11. Lai CW, Hung TP, Lin WS. Blindness of cerebral origin in acute intermittent porphyria. Report of a case and postmortem examination. Arch Neurol 1977;34:310–312.

12. Maramattom BV, Zaldivar RA, Glynn SM, Eggers SD, Wijdicks EF. Acute intermittent porphyria pre-senting as a diffuse encephalopathy. Ann Neurol 2005;57:581–584.

TABLE 90-1 Causes of Coma in acute Porphyria

• Acute leukoencephalopathy• Acute hypertensive encephalopathy• Central pontine myelinolysis• Seizures


13. Meyer UA, Schuurmans MM, Lindberg RL. Acute porphyrias: pathogenesis of neurological manifesta-tions. Semin Liver Dis 1998;18:43–52.

14. Pischik E, Kauppinen R. Can pregnancy stop cyclical attacks of porphyria? Am J Med 2006;119:88–90.15. Susa S, Daimon M, Morita Y, et al. Acute intermittent porphyria with central pontine myelinolysis and

cortical laminar necrosis. Neuroradiology 1999;41:835–839.16. Trier H, Krishnasamy VP, Kasi PM. Clinical manifestations and diagnostic challenges in acute porphyr-

ias. Case Rep Hematol 2013:628602.17. Utz N, Kinkel B, Hedde JP, Bewermeyer H. MR imaging of acute intermittent porphyria mimicking

reversible posterior leukoencephalopathy syndrome. Neuroradiology 2001;43:1059–1062.

675

A CONVERSATION

AN EXPLANATION

Ornithine transcarbamylase (OTC) deficiency is an X-linked chromosomal defect and results in a urea cycle disorder. Hyperammonemia in adults is most often associated with laboratory evidence of acute or chronic liver failure; it is rare to find it as an isolated labo-ratory abnormality. Hyperammonemia may present in the neonatal period or early child-hood and as late as in the fifth decade.

Comatose and Urea Cycle Disorder

/ / / 91 / / /


Hyperammonemia can be provoked by valproic acid, which further inhibits the urea cycle; it is elicited by gastrointestinal bleeding or brought about by recent introduction of parenteral nutrition. However, any recent infection or bariatric surgery can represent a stressor.1,2,5–7,9–11,13–15

The urea cycle defect is shown in Figure 91-1.16,19 OTC is a mitochondrial enzyme that converts ornithine and carbamyl phosphatase to citrulline, and this deficiency will lead to hyperammonemia. Ammonia is cytotoxic and depletes intermediates of cell energy metabolism, and it most likely acts as an osmolyte, causing astrocyte swelling. An opened blood–brain barrier can lead to accumulation of glutamine that eventually leads to cerebral edema if untreated.19,20

The causes of coma in acute hyperammonemic encephalopathy are shown in Table 91-1. Hyperammonemia causes brain swelling and could lead to brain death. Hypoglycemia is concurrently seen; it may be severe and thus can be a major component in the clinical picture. Seizures with a prolonged postictal period of stupor should be con-sidered, and they occur with sudden elevations of ammonia. CT scan may show cerebral

N-acetyl glutamic acid Ammonium

Orotic acid

Citrulline

Aspartate

ArgininosuccinateArginine

Fumarate

Ornithine

Carbamylphosphate

Urea

FIGURE 91-1 Urea cycle with ornithine transcarbamylase deficiency resulting in hyperammonemia.

TABLE 91-1 Causes of Coma in Urea Cycle Disorder

• Neuronal cytotoxicity from hyperammonemia• Brain edema• Seizures and postictal unconsciousness• Hypoglycemia

Comatose and Urea Cycle Disorder / / 677

edema similar to that in fulminant hepatic failure, but very few case examples are known. Plasma and urinary amino acid and urinary orotic acid levels are the necessary diagnostic tests. In addition, increased plasma levels of citrulline or arginosuccinic acid should be sought. Allopurinol loading (300 mg orally) leads to increased urinary excretion of oroti-dine and is an important diagnostic test.3,4,17


The treatment of hyperammonemia due to OTC deficiency is highly specialized and war-rants a medical genetic consult. Emergency treatment of hyperammonemia is not only continuous hemofiltration but also the intravenous administration of sodium phenylac-etate, sodium benzoate, and supplemental arginine, citrulline, and carnitine. Other drugs such as dextromethorphan or other competitive inhibitors such as kynurenic acid are therapeutic options. Morbidity in children is substantial, with mental retardation and later seizures. Time in hyperammonemic coma is linked to cognitive deficits, in particu-lar when it lasts longer than 3 days.12 Liver transplantation may be the ultimate option in some patients, but the prognosis in patients who develop cerebral edema is poor, similar to that in fulminant hepatic failure. There have been successful outcomes after liver trans-plantation, including axillary partial orthotopic liver transplantation.8,18

A CONCLUDING NOTE

Progressive impaired consciousness in females with normal liver function may be due to hyperammonemia and from an undiagnosed OTC deficiency. Valproate use is a common trigger, but any nonspecific infection, illness, or surgery can overwhelm the deficient urea cycle.

REFERENCES

1. Cuturic M, Abramson RK. Acute hyperammonemic coma with chronic valproic acid therapy. Ann Pharmacother 2005;39:2119–2123.

2. Felig DM, Brusilow SW, Boyer JL. Hyperammonemic coma due to parenteral nutrition in a woman with heterozygous ornithine transcarbamylase deficiency. Gastroenterology 1995;109:282–284.

3. Felipo V, Butterworth RF. Neurobiology of ammonia. Prog Neurobiol 2002;67:259–279.4. Gaspari R, Arcangeli A, Mensi S, et al. Late-onset presentation of ornithine transcarbamylase deficiency

in a young woman with hyperammonemic coma. Ann Emerg Med 2003;41:104–109.5. Gordon N. Ornithine transcarbamylase deficiency: a urea cycle defect. Eur J Paediatr Neurol

2003;7:115–121.6. Hawkes ND, Thomas GA, Jurewicz A, et al. Non-hepatic hyperammonaemia: an important, potentially

reversible cause of encephalopathy. Postgrad Med J 2001;77:717–722.


7. Hu WT, Kantarci OH, Merritt JL, 2nd, et al. Ornithine transcarbamylase deficiency presenting as encephalopathy during adulthood following bariatric surgery. Arch Neurol 2007;64:126–128.

8. Iyer H, Sen M, Prasad C, et al. Coma, hyperammonemia, metabolic acidosis, and mutation: lessons learned in the acute management of late onset urea cycle disorders. Hemodial Int 2012:16:95–100.

9. Kurihara A, Takanashi J, Tomita M, et al. Magnetic resonance imaging in late-onset ornithine transcarba-mylase deficiency. Brain Dev 2003;25:40–44.

10. Legras A, Labarthe F, Maillot F, et al. Late diagnosis of ornithine transcarbamylase defect in three related female patients: polymorphic presentations. Crit Care Med 2002;30:241–244.

11. Mathias RS, Kostiner D, Packman S. Hyperammonemia in urea cycle disorders: role of the nephrologist. Am J Kidney Dis 2001;37:1069–1080.

12. Msall M, Batshaw ML, Suss R, Brusilow SW, Mellits ED. Neurologic outcome in children with inborn errors of urea synthesis. Outcome of urea-cycle enzymopathies. N Engl J Med 1984;310:1500–1505.

13. Nagasaka H, Yorifuji T, Egawa H, et al. Successful living-donor liver transplantation from an asymptom-atic carrier mother in ornithine transcarbamylase deficiency. J Pediatr 2001;138:432–434.

14. Nicolaides P, Liebsch D, Dale N, Leonard J, Surtees R. Neurological outcome of patients with ornithine carbamoyltransferase deficiency. Arch Dis Child 2002;86:54–56.

15. Peterson DE. Acute postpartum mental status change and coma caused by previously undiagnosed orni-thine transcarbamylase deficiency. Obstet Gynecol 2003;102:1212–1215.

16. Rimbaux S, Hommet C, Perrier D, et al. Adult onset ornithine transcarbamylase deficiency: an unusual cause of semantic disorders. J Neurol Neurosurg Psychiatry 2004;75:1073–1075.

17. Scaglia F, Zheng Q, O’Brien WE, et al. An integrated approach to the diagnosis and prospective manage-ment of partial ornithine transcarbamylase deficiency. Pediatrics 2002;109:150–152.

18. Schmidt J, Kroeber S, Irouschek A, et al. Anesthetic management of patients with ornithine transcarba-mylase deficiency. Paediatr Anaesth 2006;16:333–337.

19. Shaw PJ, Dale G, Bates D. Familial lysinuric protein intolerance presenting as coma in two adult siblings. J Neurol Neurosurg Psychiatry 1989;52:648–651.

20. Walker V. Severe hyperammonaemia in adults not explained by liver disease. Ann Clin Biochem. 2012:49:214–228.

21. Yamanouchi H, Yokoo H, Yuhara Y, et al. An autopsy case of ornithine transcarbamylase deficiency. Brain Dev 2002;24:91–94.

679

A CONVERSATION

AN EXPLANATION

For years, Wernicke-Korsakoff syndrome has been described in patients with chronic alcoholism.7,17,18,21 Thiamine deficiency has been recognized as a complication of malnu-trition or malabsorption, prolonged parenteral nutrition, gastrojejunostomy, and hyper-emesis gravidarum.1,3,6,14 Wernicke-Korsakoff syndrome after bariatric surgery is a more recent association. It may not be well appreciated because the misunderstanding is that morbidly obese patients are well fed, but in fact their eating habits include consumption

Comatose and Wernicke-Korsakoff Syndrome

/ / / 92 / / /


of foodstuffs with poor nutritional value.4,5 Vomiting can occur due to a stricture of the gastrojejunal anastomosis, and this can further lead to thiamine deficiency. Depletion of thiamine stores can occur within three weeks in patients who have a thiamine-free diet. Glucose infusion activates glucolysis, which consumes vitamin B1 and depletes thia-mine stores if any are present.10 In Wernicke-Korsakoff syndrome, there is characteristic involvement in the mammillary bodies, aqueductal region, medial thalami, third ven-tricle, pons, medulla, and basal ganglia and occasionally the cortex. Lesions in the ante-rior thalamic nuclei predict future memory loss but are not associated with hippocampal structural damage.

The causes of coma in Wernicke-Korsakoff syndrome are shown in Table 92-1. Thiamine deficiency is the major trigger of neurologic abnormalities, but the cause of neuronal loss in specific areas is more complex and could be mediated through hista-mine or downregulation of glutamate transporters.11 Coma is often preceded by ataxia and development of oculomotor disturbances. Bithalamic injury is a common finding. Alcohol intoxication and other nutritional deficiencies should be considered but are rare. The association with niacin deficiency (pellagra) is known and has manifested without the characteristic dermatitis.8 Alcohol withdrawal seizures should be considered.16

The initial CT scan is unremarkable, but a later one could demonstrate thalamic lesions and a hypodense area around the aqueduct and third ventricle.13 More recently, acute necrosis of the fornices was documented on neuroimaging studies that mimicked a lesion in the vicinity of the third ventricle.15 More often, MRI shows bilateral hyperden-sity not only in mammillary bodies, medial thalami, and periductal gray but also in the pons, medulla oblongata, and frontoparietal cortex9,12,19,20,22,23 (Fig. 92-1).


Management of Wernicke-Korsakoff syndrome should include not only the immediate administration of thiamine (100 mg IV) but also magnesium administration and addi-tional multivitamin supplements. Improvement of consciousness can be expected in some patients, but it is protracted or minimal when there are profound MRI abnormalities.

TABLE 92-1 Causes of Coma in Wernicke-Korsakoff Syndrome

• Thalamic lesions• Pontine lesions• Alcohol withdrawal seizures• Niacin deficiency (rare)

Comatose and Wernicke-Korsakoff Syndrome / / 681

Persistent, longstanding cognitive abnormalities and difficulty with ambulating due to severe ataxia are expected.2

A CONCLUDING NOTE

Coma of uncertain etiology in a poorly fed patient with prior ophthalmoplegia should point toward a Wernicke-Korsakoff syndrome. Moreover, any patient with total paren-teral nutrition or glucose infusions without any vitamin supplementation or patients after bariatric surgery are at additional risk. MR abnormalities may predict long-term neuro-logic deficits.

FIGURE 92-1 MRI shows involvement of the periductal gray and thalami, all predilection sites for

Wernicke-Korsakoff syndrome.


REFERENCES

1. Carrodeguas L, Kaidar-Person O, Szomstein S, Antozzi P, Rosenthal R. Preoperative thiamine deficiency in obese population undergoing laparoscopic bariatric surgery. Surg Obes Relat Dis 2005;1:517–522.

2. Caulo M, Van Hecke J, Toma L, et al. Functional MRI study of diencephalic amnesia in Wernicke-Korsakoff syndrome. Brain 2005;128:1584–1594.

3. D'Aprile P, Tarantino A, Santoro N, Carella A. Wernicke's encephalopathy induced by total parenteral nutrition in patient with acute leukaemia: unusual involvement of caudate nuclei and cerebral cortex on MRI. Neuroradiology 2000;42:781–783.

4. Dallal RM. Wernicke encephalopathy after bariatric surgery: losing more than just weight. Neurology 2006;66:1786.

5. Foster D, Falah M, Kadom N, Mandler R. Wernicke encephalopathy after bariatric surgery: losing more than just weight. Neurology 2005;65:1987; discussion 1847.

6. Francini-Pesenti F, Brocadello F, Famengo S, Nardi M, Caregaro L. Wernicke's encephalopathy during parenteral nutrition. JPEN J Parenter Enteral Nutr 2007;31:69–71.

7. Isenberg-Grzeda E, Kutner HE, Nicolson SE. Wernicke-Korsakoff-syndrome: under-recognized and under-treated. Psychosomatics 2012;53:507–516.

8. Ishii N, Nishihara Y. Pellagra among chronic alcoholics: clinical and pathological study of 20 necropsy cases. J Neurol Neurosurg Psychiatry 1981;44:209–215.

9. Kaineg B, Hudgins PA. Images in clinical medicine. Wernicke's encephalopathy. N Engl J Med 2005;352:e18.

10. Koguchi K, Nakatsuji Y, Abe K, Sakoda S. Wernicke's encephalopathy after glucose infusion. Neurology 2004;62:512.

11. Langlais PJ, McRee RC, Nalwalk JA, Hough LB. Depletion of brain histamine produces regionally selec-tive protection against thiamine deficiency-induced lesions in the rat. Metab Brain Dis 2002;17:199–210.

12. Mascalchi M, Simonelli P, Tessa C, et al. Do acute lesions of Wernicke's encephalopathy show contrast enhancement? Report of three cases and review of the literature. Neuroradiology 1999;41:249–254.

13. Mensing JW, Hoogland PH, Slooff JL. Computed tomography in the diagnosis of Wernicke's encepha-lopathy: a radiological-neuropathological correlation. Ann Neurol 1984;16:363–365.

14. Selitsky T, Chandra P, Schiavello HJ. Wernicke's encephalopathy with hyperemesis and ketoacidosis. Obstet Gynecol 2006;107:486–490.

15. Swenson AJ, St Louis EK. Computed tomography findings in thiamine deficiency-induced coma. Neurocrit Care 2006;5:45–48.

16. Thomson AD. Mechanisms of vitamin deficiency in chronic alcohol misusers and the development of the Wernicke-Korsakoff syndrome. Alcohol Alcohol Suppl 2000;35:2–7.

17. Victor M, Adams RD, Collins GH. The Wernicke-Korsakoff Syndrome and Related Neurologic Disorders Due to Alcoholism and Malnutrition. Philadelphia: F. A. Davis Co., 1989.

18. Wernicke C. Die akute, haemorrhagische polioencephalitis superior. Lehrbuch der Gehirnkrankheiten fur Aerzte und Studierende 1881;2:229.

19. White ML, Zhang Y, Andrew LG, Hadley WL. MR imaging with diffusion-weighted imaging in acute and chronic Wernicke encephalopathy. AJNR Am J Neuroradiol 2005;26:2306–2310.

20. Yokote K, Miyagi K, Kuzuhara S, Yamanouchi H, Yamada H. Wernicke encephalopathy: follow-up study by CT and MR. J Comput Assist Tomogr 1991;15:835–838.

21. Zahr NM, Kaufman KL, Harper CG. Clinical and pathological features of alcohol-related brain damage. Nat Rev Neurol 2011;7:284–294.

22. Zhong C, Jin L, Fei G. MR Imaging of nonalcoholic Wernicke encephalopathy: a follow-up study. AJNR Am J Neuroradiol 2005;26:2301–2305.

23. Zuccoli G, Gallucci M, Capellades J, et al. Wernicke encephalopathy: MR findings at clinical presenta-tion in twenty-six alcoholic and nonalcoholic patients. AJNR Am J Neuroradiol 2007;28:1328–1331.

683

A CONVERSATION

AN EXPLANATION

MELAS is an acronym for a distinctive clinical syndrome that eventually presents with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke. The diagnosis can be considered when certain telltale signs are present. Seizures, stroke-like episodes, short stature, and mental retardation are common features; muscle weakness, headaches, and easy fatigability are nonspecific presenting symptoms. Clinical signs that have received little attention but are equally common and indicate a systemic disorder include hearing

Comatose and mELaS/ / / 93 / / /


loss, myoclonus, cerebellar signs, optic atrophy, and cardiomyopathy.9,13,14,16 The first abnormalities are usually noted between the ages of 5 and 15 years and the clinical mani-festations are progressive. Some antecedent stressor (including infections) may cause worsening of symptoms, similar to that in ornithine transcarbamylase (OTC) deficiency (Chapter 91). Valproic acid has been implicated as a trigger.7 Coma has been reported in up to 85% of patients, but usually in end-stage MELAS.16 It certainly should be considered in any young individual who is readmitted with an ischemic stroke and seizures.

In MELAS, there is a deficiency in the mitochondrial respiratory chain complex.1,6 The diagnosis of MELAS is made after mitochondrial DNA analyses of peripheral blood showing A→G point mutation at position 3243. A muscle biopsy could demonstrate so-called “ragged red muscle fibers,” a signature of all mitochondrial diseases. Patients with MELAS have an increased serum lactic acid level, but only an increased lactate value in cerebrospinal fluid correlates with outcome.4 Brain biopsy is usually not revealing and may show the nonspecific findings of an ischemic infarct.

The causes of coma in MELAS are shown in Table 93-1. MELAS has a predilec-tion for the posterior cortices, and thus impairment of consciousness is not expected. MELAS, however, may become more extensive, involving temporal cortex and other areas. Moreover, MRI may not image all abnormal regions. In other patients, hypercapnia may be a cause. Ventilatory depression causes hypercapnia but may also be caused by lactic acidosis or may be due to accumulation of adenosine.2,12 Status epilepticus is not an unusual presentation and is often accompanied by the appearance of new cortical lesions. MELAS may present with severe depression, so a suicide attempt with medication may be a reason for emergency department admission.

Cortical involvement is prominent on MRI (Fig. 93-1), and in some cases there is sparing of the deep white matter. This has been explained by a higher metabolic turn-over in the cortex and therefore also makes it more vulnerable to injury. The neuropa-thology of MELAS is extensive neuronal loss, neuronal eosinophilia, vacuolization, and astrogliosis. The abnormalities also extend beyond the typical vascular territories. Most interesting is that basal ganglia are involved with globus pallidus and caudate nucleus abnormalities in about half of the patients with calcification on CT. In some individuals,

TABLE 93-1 Causes of Coma in mELaS

• Bilateral parietal and frontal ischemic strokes• Hypercapnia• Status epilepticus (complex partial and convulsive)• Suicide attempt (antidepressants)

Comatose and mELaS / / 685

cerebral atrophy eventually emerges, including the cerebellum and brainstem. Apparent diffusion coefficient (ADC) mapping can be normal, although in many cases restricted diffusion can be found.5,8,11,17 MRS has shown elevated levels of lactate and reduced levels of N-acetylaspartate (NAA), glutamate, and myoinositol.10


Coenzyme Q10 may restore the defect in oxidative phosphorylation due to the trans-fer of electrons from complex 1 and 2 to 3 (Fig. 93-2). Patients with MELAS usually are treated with coenzyme Q10 (2 mg/kg/d) for six months.3,15 More recently, the use of L-arginine has been proposed, but apart from improvement in endothelial function, its effect on outcome remains uncertain. L-arginine is a precursor of nitric oxide and therefore could reduce ischemic strokes. This treatment is based on the observation

FIGURE 93-1 Serial MRI showing typical MELAS features with cortical involvement more than

white matter involvement. There is marked progression between the two MRI scans.

Matrix

Intermembranespace

Subunits Complex I Complex II Complex III Complex IV Complex V

Innermitrochondrial

membrane

Fumarate Succinate

TCA cycle

H+ H+

O2 H2OADP ATP

e−e−

e−e−

H+ H+

e−

ND1 ND2 ND3

CoQ

COXI A8

A6

COXIICOXIII

Cyt c

CytbND4

ND4LND5ND6

FIGURE 93-2 Electron transport chain in mitochondria.


that MELAS is associated with a decreased vasodilatation capacity in small arteries, and therefore L-arginine would provide endothelium-dependent vasodilatation.

A CONCLUDING NOTE

Strokes in young individuals with cognitive decline, short stature, and even more multiple cerebral infarctions should point toward MELAS. Recurrent seizures and complex partial status epilepticus may be a major mechanism of impaired consciousness. In many other patients, impaired level of consciousness is due to the development of multiple cerebral infarctions at once or in a rapid sequence.

REFERENCES

1. Betts J, Jaros E, Perry RH, et al. Molecular neuropathology of MELAS: level of heteroplasmy in individual neurones and evidence of extensive vascular involvement. Neuropathol Appl Neurobiol 2006;32:359–373.

2. Carroll JE, Zwillich C, Weil JV, Brooke MH. Depressed ventilatory response in oculocraniosomatic neu-romuscular disease. Neurology 1976;26:140–146.

3. Kaufman KR, Zuber N, Rueda-Lara MA, Tobia A. MELAS with recurrent complex partial seizures, non-convulsive status epilepticus, psychosis, and behavioral disturbances: case analysis with literature review. Epilepsy Behav 2010;18:494–497.

4. Kaufmann P, Shungu DC, Sano MC, et al. Cerebral lactic acidosis correlates with neurological impair-ment in MELAS. Neurology 2004;62:1297–1302.

5. Kisanuki YY, Gruis KL, Smith TL, Brown DL. Late-onset mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes with bitemporal lesions. Arch Neurol 2006;63:1200–1201.

6. Lertrit P, Noer AS, Jean-Francois MJ, et al. A new disease-related mutation for mitochondrial encepha-lopathy lactic acidosis and strokelike episodes (MELAS) syndrome affects the ND4 subunit of the respi-ratory complex I. Am J Hum Genet 1992;51:457–468.

7. Lin CM, Thajeb P. Valproic acid aggravates epilepsy due to MELAS in a patient with an A3243G muta-tion of mitochondrial DNA. Metab Brain Dis 2007;22:105–109.

8. Majoie CB, Akkerman EM, Blank C, et al. Mitochondrial encephalomyopathy: comparison of con-ventional MR imaging with diffusion-weighted and diffusion tensor imaging: case report. AJNR Am J Neuroradiol 2002;23:813–816.

9. Mizrachi IB, Gomez-Hassan D, Blaivas M, Trobe JD. Pitfalls in the diagnosis of mitochondrial encepha-lopathy with lactic acidosis and stroke-like episodes. J Neuroophthalmol 2006;26:38–43.

10. Moller HE, Kurlemann G, Putzler M, et al. Magnetic resonance spectroscopy in patients with MELAS. J Neurol Sci 2005;229–230:131–139.

11. Ohshita T, Oka M, Imon Y, et al. Serial diffusion-weighted imaging in MELAS. Neuroradiology 2000;42:651–656.

12. Osanai S, Takahashi T, Enomoto H, et al. Hypoxic ventilatory depression in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes. Respirology 2001;6:163–166.

13. Pavlakis SG, Phillips PC, DiMauro S, De Vivo DC, Rowland LP. Mitochondrial myopathy, encephalopa-thy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome. Ann Neurol 1984;16:481–488.

14. Sato W, Hayasaka K, Shoji Y, et al. A mitochondrial tRNA(Leu)(UUR) mutation at 3,256 associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Biochem Mol Biol Int 1994;33:1055–1061.

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15. Scaglia F, Northrop JL. The mitochondrial myopathy encephalopathy, lactic acidosis with stroke-like episodes (MELAS) syndrome: a review of treatment options. CNS Drugs 2006;20:443–464.

16. Thambisetty M, Newman NJ, Glass JD, Frankel MR. A practical approach to the diagnosis and manage-ment of MELAS: case report and review. Neurologist 2002;8:302–312.

17. Wang XY, Noguchi K, Takashima S, et al. Serial diffusion-weighted imaging in a patient with MELAS and presumed cytotoxic oedema. Neuroradiology 2003;45:640–643.

688

A CONVERSATION

AN EXPLANATION

Coma in a preterm neonate or newborn is, in most instances, due to perinatal asphyxia leading to hypoxic-ischemic encephalopathy.1,2 The neurologic examination immediately shows abnormalities, although a careful assessment is difficult in preterm infants. Pupils are small and difficult to assess for light reflexes. Corneal reflexes are most of the time not reliably present as a result of incomplete maturation. Abnormal motor responses are slow, stereotyped and often repeatedly demonstrated.

Comatose and Preterm newborn/ / / 94 / / /

Comatose and Preterm newborn / / 689

Intraventricular hemorrhage (IVH) is another major neurologic complication that may present with irritability and apneic episodes. In 50% of the cases focal or multifocal seizures occur. These hemorrhages arise from the choroid plexus, thalamus subependymal germinal matrix, with one in 10 instances from an unknown origin. Mostly, IVH is seen within the first 24 hours, but it can progress after 48 hours. Most of the hemorrhages are seen in the first postnatal week, and this is also when hydro-cephalus occurs.

A complete assessment would require neurophysiological tests such as EEG or MRI and ultrasound. Cranial ultrasound often can demonstrate different grades of IVH and is usually repeated to demonstrate ventriculomegaly that may require treatment.3 Posthemorrhagic hydrocephalus and periventricular leukomalacia are major conse-quences of IVH. IVH can be graded in infants of 32 weeks’ gestation or less.

These grades are:

• Grade 1: germinal matrix hemorrhage• Grade 2: intraventricular blood without distention of the ventricular system• Grade 3: blood filling and distending the ventricular system• Grade 4: parenchymal involvement of the hemorrhage—also labeled as

periventricular venous infarction

Seizures are most common in preterm infants at IVH grades 3 and 4, and mortality is much higher. In other instances, hypoxic-ischemic encephalopathy can be attributed to a prior intra-uterine event or infection or due to a complicated delivery.

Causes of coma in premature newborns are shown in Table 94-1. Figure 94-1 shows evidence of a germinal matrix hemorrhage.


Management of IVH in more severe cases requires mechanical ventilation and correction of associated blood pressure surges. These newborns may need fentanyl and sedation and measures to reduce the negative effects of manipulation on ICP.

TABLE 94-1 Causes of Coma in Premature newborn

• Anoxic-ischemic encephalopathy• Intraventricular matrix hemorrhage• Anencephaly• Major malformation


Phenobarbital has been used for sedation but did not result in improved outcome. The cerebral hemodynamics are best controlled with cautious control of blood pres-sure. Serial ultrasound may be needed to monitor for posthemorrhagic hydrocephalus and can be communicating. Hydrocephalus may be secondary to acute obstruction of the foramen of Monro and may require the use of intraventricular streptokinase or repeated lumbar or ventricular punctures (the treatment is often called “DRIFT”—drainage, irrigation, and fibrinolytic therapy). Some leading textbooks have suggested close observation for two weeks and serial lumbar punctures in preterm newborns with matrix IVH. Failure to control dilatation would lead to ventriculostomy and ventricu-loperitoneal shunt.5 No study has found improvement in outcome or prevention of developmental delay with any of these measures. Neurologic examination is usually supported by MRI, which can show abnormalities in the basal ganglia and deep gray white matter, and also into the thalamus. These abnormalities are often also associ-ated with abnormal SSEP or visual-evoked potentials. Presence of these abnormalities would indicate poor outcome.4

FIGURE 94-1 Cranial ultrasound showing echodensity indicating a left-sided hemorrhagic IVH

and ventriculomegaly.

Comatose and Preterm newborn / / 691

A CONCLUDING NOTE

Neonates and preterm infants may become comatose from anoxic-ischemic injury or IVH. Both conditions may have a poor prognosis.

REFERENCES

1. Albertine KH. Brain injury in chronically ventilated preterm neonates: collateral damage related to venti-lation strategy. Clin Perinatol 2012;39:727–740.

2. Bell JE, Becher JC, Wyatt B, Keeling JW, McIntosh N. Brain damage and axonal injury in a Scottish cohort of neonatal deaths. Brain 2005;128:1070–1081.

3. McCrea HJ, Ment LR. The diagnosis, management, and postnatal prevention of intraventricular hemor-rhage in the preterm neonate. Clin Perinatol 2008;35:777–792.

4. van Laerhoven H, de Haan TR, Offringa M, Post B, van der Lee JH. Prognostic tests in term neonates with hypoxic-ischemic encephalopathy: a systematic review. Pediatrics 2013;131:88–98.

5. Volpe JJ. Neurology of the Newborn, 5th ed. Philadelphia: Saunders Elsevier, 2008.

692

A CONVERSATION

AN EXPLANATION

Cerebral vasoconstriction syndrome usually starts with a thunderclap headache. It typically involves young persons. If imaged correctly, segmental arterial vasoconstriction is seen. Imaging of cerebral arteries remains normal in a large proportion of patients. Often in the acute setting, the cerebral angiogram is initially normal, with abnormal follow-up studies five to seven days later. Reversible cerebral vasoconstriction syndrome RCVS is gener-ally considered a relatively benign and reversible syndrome.2,6 It has been recognized and

Comatose and Fulminant Cerebral Vasoconstriction

/ / / 95 / / /

Comatose and Fulminant Cerebral Vasoconstriction / / 693

described in more detail in recent years and is mostly considered reversible. Drugs such as phenylpropanolamine, pseudoephedrine, and ergotamine tartrate, as well as selective sero-tonin reuptake inhibitors (SSRIs), have been implicated in the past (Table 95.1). It is likely that published series of patients with prior benign forms of CNS vasculitis or “less severe forms” of vasculitis did include some of these cases. In Mayo Clinic’s experience about one-third of the patients with RCVS deteriorated and developed ischemic strokes.5

The range of neurologic disorders causing severe vasoconstriction of the cerebral arteries is small and includes malignant hypertension (and its close connection with posterior reversible encephalopathy syndrome [PRES]), postoperative vasospasm after neurosurgical procedures (often pituitary surgery), vasospasm after aneurysmal subarach-noid hemorrhage, or traumatic subarachnoid hemorrhage and cerebral angiogram-related vasospasm. Historically, extreme cerebral vasospasm has been known in extreme cases of pheochromocytoma.

There are more severe fulminant and fatal presentations of RCVS.1,3,4,6,7,8 These patients have a progressive vasoconstriction, resulting in multiterritorial strokes and brain edema (Fig. 95.1). Most of the time there is no identifiable precipitating factor.

Postpartum cerebral vasoconstriction syndrome is an entity that is not well defined; in particular, it is unclear whether this represents part of the spectrum of RCVS and a more severe manifestation or a separate entity.

In our NICU, four patients were seen who developed cortical ischemia, global edema, and lobar hemorrhage. All had a rapid deterioration within a number of days, often after a cerebral angiogram was performed, tentatively suggesting that the cerebral angiogram might have further triggered vasoconstriction. Autopsy has not shown any clear evidence

TABLE 95-1 Factors associated With the Reversible Cerebral Vasoconstriction Syndrome

IdiopathicPrior headache disorder (migraine, primary thunderclap headache, benign exertional headache, benign sexual

headache, and primary cough headache)Pregnancy and puerperiumEarly puerperium, late pregnancy, preeclampsia, eclampsia, delayed postpartum eclampsiaDrugs and blood productsPhenylpropanolamine, pseudoephedrine, ergotamine tartrate, methylergonovine, bromocriptine, lisuride,

selective serotonin reuptake inhibitors, sumatriptan, tacrolimus, cyclophosphamide, erythropoietin,

intravenous immune globulin, and red-cell transfusions

Cocaine, Ecstasy, amphetamine derivatives, marijuana, lysergic acid diethylamideMiscellaneous associationsHypercalcemia, porphyria, pheochromocytoma, bronchial carcinoid tumor, head trauma, spinal subdural

hematoma, post-carotid endarterectomy, postdural puncture, open neurosurgical procedures



of abnormalities in the cerebral vasculature that could suggest a primary vascular anomaly. In preeclampsia, there are several circulating factors that are elevated compared to healthy pregnant females. However, such a study has not been performed. Cerebral vasoconstric-tion syndrome with a fulminant course could be related to post-pregnancy eclampsia, but seizures are very uncommon in this condition.

The causes of coma in fulminant RCVS are listed in Table 95-2.

FIGURE 95-1 MRI showing cerebral hemorrhagic infarction with severe brain edema and extreme

vasospasm on cerebral angiogram.

TABLE 95-2 Causes of Coma and Fulminant Cerebral Vasoconstriction

• Multiple cerebral infarcts• Diffuse cerebral edema• Cerebral hemorrhage• Seizures

Comatose and Fulminant Cerebral Vasoconstriction / / 695


Treatment with calcium channel antagonists, corticosteroids, and blood pressure- modulating agents may not be successful. Other therapies have included intravenous magnesium and blood pressure augmentation, and that remains the most logical option. None of these interventions has been proven to improve outcome. Whether endovascu-lar opening of the arteries may expose the brain to risk of reperfusion injuries is unclear.

A CONCLUDING NOTE

Thunderclap headache and new neurologic signs, but completely normal blood pressure, could be the first sign of fulminant cerebral vasoconstriction syndrome.

REFERENCES

1. Buckle RM, Duboulay G, Smith B. Death due to cerebral vasospasm. J Neurol Neurosurg Psychiatry 1964;27:440–444.

2. Ducros A, Boukobza M, Porcher R, et al. The clinical and radiological spectrum of reversible cerebral vasoconstriction syndrome. A prospective series of 67 patients. Brain 2007;130:3091–3101.

3. Fugate JE, Wijdicks EFM, Parisi JE, et al. Fulminant postpartum cerebral vasoconstriction syndrome. Arch Neurol 2012;69:111–117.

4. Geraghty JJ, Hoch DB, Robert ME, Vinters HV. Fatal puerperal cerebral vasospasm and stroke in a young woman. Neurology 1991;41:1145–1147.

5. Katz BS, Fugate JE, Ameriso SF et al. Clinical worsening in reversible cerebral vasoconstriction syn-drome. JAMA Neurol 2014;71:68–73.

6. Singhal AB. Postpartum angiopathy with reversible posterior leukoencephalopathy. Arch Neurol 2004;61:411–416.

7. Singhal AB, Kimberly WT, Schaefer PW, Hedley-Whyte ET. Case records of the Massachusetts General Hospital. Case 8-2009. A 36-year-old woman with headache, hypertension, and seizure 2 weeks post par-tum. N Engl J Med 2009;360:1126–1137.

8. Williams TL, Lukovits TG, Harris BT, Harker Rhodes C. A fatal case of postpartum cerebral angiopathy with literature review. Arch Gynecol Obstet 2007;275:67–77.

696

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AN EXPLANATION

The physiologic changes that occur during pregnancy are well tolerated, and serious neu-rologic complications are unusual. Therefore, both subarachnoid hemorrhage and intra-cerebral hematoma are very uncommon in pregnancy, with an estimated incidence of less than 0.05%.16 Pregnancy—despite blood volume increase—does not predispose to rupture of an arteriovenous malformation (AVM), nor is there documented evidence of growth of the vascular malformation, if present.2,12 Nonetheless, some studies suggest an

Comatose and Puerperium/ / / 96 / / /

Comatose and Puerperium / / 697

80% to 90% risk of rupture during pregnancy and a 27% risk of rebleeding when hemor-rhage occurs during pregnancy.14 Devastating injury at onset can occur in 75% of patients with an AVM rupture. Maternal and fetal mortality is uncommon, and patients may sig-nificantly improve after surgical evacuation (Fig. 96-1).1 Subarachnoid hemorrhage from a ruptured intracranial aneurysm is not likely more common in pregnancy, but its rupture is much more concentrated around the final trimester.

A dramatic complication in the puerperium is cerebral venous thrombosis. However, arterial occlusive disease remains more common in pregnancy,7 and the postpartum period presents a more likely risk for recurrence of arterial stroke.8,9 One study found 11.6 cases of cerebral venous thrombosis per 100,000 deliveries in

FIGURE 96-1 Serial CT scans of patient with recent uncomplicated delivery. Upper row: Ganglionic

hematoma from ruptured AVM with mass effect. Lower row: After removal of hematoma and

occlusion of the branch of the left middle cerebral artery that fed the AVM.


the United States.11 The risk of peripartum-associated cerebral venous thrombosis increased with increasing maternal age, cesarean delivery, hypertension, infections, and excessive vomiting during pregnancy.10 The cause remains unknown in many cases, but there is a 13-fold increased risk with oral contraceptives, a 30% risk with oral contraceptives and thrombophilia, and 10% to 15% risk with factor V Leiden, prothrombin gene mutation, and protein C or S deficiency.10 As alluded in Chapter 95 postpartum cerebral vasculopathy may present with an intracerebral hematoma. The majority of patients have been diagnosed several days to weeks after uncomplicated delivery.15,18 Cerebral angiography reveals findings of beading quite similar to that in isolated CNS vasculitis, with irregularities in cortical and leptomeningeal arteries. Heroin use and ergometrine are additional risk factors.4

The causes of coma during pregnancy and in the puerperium are shown in Table 96-1. Coma after delivery is expectedly serious and often a neurologic catastro-phy.7 Eclampsia may occur and is recognized by a rapid decline in consciousness and seizures. Its clinical presentation and MRI findings (but not its treatment) are identi-cal to those of any acute hypertensive encephalopathy leading to posterior reversible encephalopathy syndrome (PRES). Neurologic complications with devastating injury to the brain leading to coma can be seen in the early stages of pregnancy (first trimes-ter) or primarily in the postpartum period (Table 96-2). Ischemic stroke is more likely in patients with induced pregnancies and in mothers with fetal growth retardation, preterm delivery, and prior spontaneous abortions (particularly antiphospholipid antibody syndrome).10,11,13,17 Epileptic seizures in pregnant women with a seizure dis-order are predominantly observed during labor or within 24 hours of delivery.

Cerebral venous thrombosis is an uncommon complication of pregnancy, but marked decline in consciousness occurs exclusively in patients with deep cerebral venous thrombosis causing hemorrhagic thalamic infarcts, or extensive sagittal throm-bosis may lead to bihemispheric infarcts. An extremely rare but usually devastating complication includes an amniotic fluid embolization syndrome that may result in anoxic-ischemic encephalopathy.

TABLE 96-1 Causes of Coma in Pregnancy

• Mass effect from cerebral hematoma (AVM or aneurysm)• Multiple venous cerebral infarcts (thrombophilia)• White matter edema (eclampsia)• Anoxic-ischemic encephalopathy (air or amniotic fluid emboli)

Comatose and Puerperium / / 699


Depending on the disorder, treatment is medical or surgical. In our patient, immediate evacuation of the hematoma and AVM is warranted. Outcome is determined by the clini-cal neurologic examination before evacuation.5 Eclampsia is an obstetric emergency and requires immediate control of hypertension with magnesium sulfate (loading dose of 4 g followed by an intravenous infusion of 2 g/h). Clinical improvement is measured by onset of diuresis due to improved renal function and decreased vasospasm.3 Ischemic stroke in pregnancy precludes the use of thrombolytics except when it occurs in the last trimester and puerperium.6

A CONCLUDING NOTE

There are different causes of neurologic injury in each of the pregnancy trimesters and after delivery. Most of the complications are very uncommon. Albeit rare, intrace-rebral hematoma is a common cause of material mortality and neurologic morbidity. Eclampsia usually presents late in pregnancy and can be successfully treated with mag-nesium sulfate.

REFERENCES

1. Dias MS, Sekhar LN. Intracranial hemorrhage from aneurysms and arteriovenous malformations during pregnancy and the puerperium. Neurosurgery 1990;27:855–865.

2. Finnerty JJ, Chisholm CA, Chapple H, Login IS, Pinkerton JV. Cerebral arteriovenous malformation in pregnancy: presentation and neurologic, obstetric, and ethical significance. Am J Obstet Gynecol 1999;181:296–303.

TABLE 96-2 major neurologic complications of pregnancy.

Delivery/labor

Cesarian section

Puerperium

Uterine curettageInfective endocarditis and strokeair embolism

Air embolism

Cerebral venousthrombosisInfective endocarditisand strokeAmniotic fluid embolismPostpartum cerebral vasculopathySheehan syndrome

First trimesterOvarian hyperstimulationsyndrome and strokeWernicke-Korsakoff

Second trimesterAVMPituitary apoplexy

Third trimesterAVM, SAH

AVM, SAHEclampsia


3. Fontenot MT, Lewis DF, Frederick JB, et al. A prospective randomized trial of magnesium sulfate in severe preeclampsia: use of diuresis as a clinical parameter to determine the duration of postpartum therapy. Am J Obstet Gynecol 2005;192:1788–1793.

4. Geocadin RG, Razumovsky AY, Wityk RJ, Bhardwaj A, Ulatowski JA. Intracerebral hemorrhage and postpartum cerebral vasculopathy. J Neurol Sci 2002;205:29–34.

5. Hartmann A, Mast H, Choi JH, Stapf C, Mohr JP. Treatment of arteriovenous malformations of the brain. Curr Neurol Neurosci Rep 2007;7:28–34.

6. Hender J, Harris D, Richard B, Dawson A, Khanna P. A case of stroke in pregnancy: the optimum man-agement of such patients remains a challenge. J Obstet Gynaecol 2006;26:570–571.

7. Jaigobin C, Silver FL. Stroke and pregnancy. Stroke 2000;31:2948–2951.8. Kaplan PW. Coma in the pregnant patient. Neurol Clin 2011;29:973–994.9. Lamy C, Hamon JB, Coste J, Mas JL. Ischemic stroke in young women: risk of recurrence during subse-

quent pregnancies. French Study Group on Stroke in Pregnancy. Neurology 2000;55:269–274.10. Lanska DJ, Kryscio RJ. Risk factors for peripartum and postpartum stroke and intracranial venous

thrombosis. Stroke 2000;31:1274–1282.11. Lanska DJ, Kryscio RJ. Stroke and intracranial venous thrombosis during pregnancy and puerperium.

Neurology 1998;51:1622–1628.12. Lanzino G, Jensen ME, Cappelletto B, Kassell NF. Arteriovenous malformations that rupture during

pregnancy: a management dilemma. Acta Neurochir (Wien) 1994;126:102–106.13. Pell JP, Smith GC, Walsh D. Pregnancy complications and subsequent maternal cerebrovascular events: a

retrospective cohort study of 119,668 births. Am J Epidemiol 2004;159:336–342.14. Robinson JL, Hall CS, Sedzimir CB. Arteriovenous malformations, aneurysms, and pregnancy.

J Neurosurg 1974;41:63–70.15. Roh JK, Park KS. Postpartum cerebral angiopathy with intracerebral hemorrhage in a patient receiving

lisuride. Neurology 1998;50:1152–1154.16. Wiebers DO. Ischemic cerebrovascular complications of pregnancy. Arch Neurol 1985;42:1106–1113.17. Worrell GA, Wijdicks EF, Eggers SD, et al. Ovarian hyperstimulation syndrome with ischemic stroke

due to an intracardiac thrombus. Neurology 2001;57:1342–1344.18. Yasuda Y, Matsuda I, Kang Y, Saiga T, Kameyama M. Isolated angiitis of the central nervous system first

presenting as intracranial hemorrhage during cesarean section. Intern Med 1993;32:745–748.

701

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AN EXPLANATION

Most patients who undergo chemotherapy tolerate it well neurologically. Apart from “chemo brain” (which is still a poorly defined entity and indicates cognitive difficulties), some of the more aggressive chemotherapeutic agents can cause an acute leukoencepha-lopathy (Table 97-1).1,3

Mostly, patients may develop symptoms a day after intravenous infusion, but this entity may also progress within a matter of several days. Usually, patients become less

Comatose and Chemotherapy Toxicity

/ / / 97 / / /


attentive and may become mute. Occasionally a seizure or focal findings may appear, and some more severe cases can progress to akinetic mutism or minimally conscious state with sparse speech. CT scan may not be very informative, but an MRI is fairly typical, show-ing diffuse leukoencephalopathy (Fig. 97-1). These findings are largely a result of vaso-genic cerebral edema and are fully reversible. However, most of the chemotherapies that are currently used can cause hypertension or a reversible posterior leukoencephalopathy syndrome (PRES) that has lesions in the gray–white matter junction of posterior regions but can be located elsewhere. Some of these patients will have a thunderclap headache when this occurs, and this would certainly point toward this entity.5,8 The cause of PRES is unknown; it is likely toxic and has been seen with a variety of drugs (see Table 97-1). Most noticeable is that the hypertension is not a major feature, but patients may have fever, electrolyte abnormalities, acute renal failure, or tumor lysis syndrome that may contribute to leakage of cerebral arteries.6 Cerebral infarction has been noted with 5-FU cisplatinum and bevacizumab. Intra-arterial embolization may also cause hyperglycemia, and that may be a contributing factor.2,3 (The association between bevacizumab and cere-bral hemorrhage is well established and rare, but 50% fatal.7)

TABLE 97-1 antineoplastic agents associated With Reversible Posterior Leukoencephalopathy Syndrome (in alphabetical order)

ActinomycinBevacizumabCarboplatinCHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)CisplatinCyclosporin ACytarabine (intravenous or intrathecal)ErlotinibFOLFIRI (irinotecan, fluorouracil, leucovorin)GemcitabineInterferon alphaL-asparaginaseMethotrexate (intravenous or intrathecal)MitozantroneOxaliplatinPaclitaxelRAF kinase inhibitor BAY 43-9006 (sorafenib)RituximabSunitinib

From reference 4.

Comatose and Chemotherapy Toxicity / / 703

The mechanisms involved with most of these drugs thus remain unexplained. Some have suggested that they are due to folate deficiency and homocysteine elevation, which might have resulted in vasculopathy or might have indirect excitotoxic effects.4 However, several antiangiogenic drugs, such as bevacizumab and sorafenib, can cause significant hypertension and, therefore a hypertensive crisis in this situation can be implicated.4 Causes of coma after chemotherapy are shown in Table 97-2.


Generally prognosis is good, although the presentation can be initially dramatic, with pro-found MRI abnormalities. Supportive care is necessary. Corticosteroids do not improve outcome. Antihypertensive drugs should be used, but cautiously because aggressive use may lead to ischemic conversion of the edematous areas. In most instances, neuroimaging findings are completely reversible.

FIGURE 97-1 Methotrexate-induced MR abnormalities consistent with leukoencephalopathy.

TABLE 97-2 Causes of Coma after Chemotherapy

• Nonconvulsive status epilepticus• Posterior reversible encephalopathy syndrome (PRES)• Progressive multifocal leukoencephalopathy• Hyperglycemia (intra-arterial embolization)


A CONCLUDING NOTE

Chemotherapy agents can cause leukoencephalopathy resulting in coma in exceptional cases. MRI is diagnostic and the hyperintensities improve after discontinuation of infusion.

REFERENCES

1. Connolly RM, Doherty CP, Beddy P, O'Byrne K. Chemotherapy induced reversible posterior leukoen-cephalopathy syndrome. Lung Cancer 2007;56:459–463.

2. El Amrani M, Heinzlef O, Debroucker T, et al. Brain infarction following 5-fluorouracil and cisplatin ther-apy. Neurology 1998;51:899–901.

3. Glusker P, Recht L, Lane B. Reversible posterior leukoencephalopathy syndrome and bevacizumab. N Engl J Med 2006;354:980–982.

4. Han CH, Findlay MP. Chemotherapy-induced reversible posterior leucoencephalopathy syndrome. Intern Med J 2010;40:153–159.

5. Ito Y, Arahata Y, Goto Y, et al. Cisplatin neurotoxicity presenting as reversible posterior leukoencepha-lopathy syndrome. AJNR Am J Neuroradiol 1998;19:415–417.

6. Kaito E, Terae S, Kobayashi R, et al. The role of tumor lysis in reversible posterior leukoencephalopathy syndrome. Pediatr Radiol 2005;35:722–727.

7. Letarte N, Bressler LR, Villano JL. Bevacizumab and central nervous system (CNS) hemorrhage. Cancer Chemother Pharmacol 2013;71:1561–1565.

8. Tha KK, Terae S, Sugiura M, et al. Diffusion-weighted magnetic resonance imaging in early stage of 5-fluorouracil-induced leukoencephalopathy. Acta Neurol Scand 2002;106:379–386.

705

A CONVERSATION

AN EXPLANATION

Intrathecal baclofen and oral baclofen are common therapies to manage major spasticity in multiple sclerosis, spinal cord injury and cerebral palsy.3 Accidental oral baclofen intoxication has been described in children, but the major clinical problem is with intrathecal pumps that malfunction. Baclofen is also used as an illicit drug to get the so-called baclofen “kick.”9

Typically, the patient develops coma with muscle flaccidity, as expected, but it is also accompanied by sinus bradycardia and marked respiratory depression.7 The tendon

Comatose and Baclofen Toxicity/ / / 98 / / /


reflexes are depressed. Patients may have had seizures or may be in florid nonconvulsive status epilepticus. Seizures are expected, since baclofen activates postsynaptic GABA receptors and through this mechanism promotes epileptogenesis.5 Baclofen toxicity is primarily recognized by physical medicine and rehabilitation (PM&R) physicians and is less known by neurologists. Other causes should still be considered, depending on the underlying illness treated with baclofen. Because spasticity is common in multiple sclero-sis, acute exacerbation with brainstem demyelination causing coma should be excluded.

The causes of coma in baclofen overdose are listed in Table 98-1. Several cases of patients with malfunctioning baclofen pumps have been reported.5,6 The major clinical challenge is that baclofen intoxication and withdrawal can look very similar—impaired consciousness, agitation, and coma. In fact, an overdose of baclofen can evolve into a withdrawal syndrome.2 The difference between the two, apart from the tone, is the presence of areflexia in baclofen intoxication and hyperreflexia in baclofen withdrawal (Table 98-2). Patients with baclofen withdrawal may develop neuroleptic malignant syndrome and delirium. One should recog-nize the potential for hypothermia in some patients, though fever can also be seen.


The treatment is primarily supportive. Activated charcoal might be helpful in cases with oral ingestion, and forced diuresis may also improve recovery.3 Mechanical ventilation is

TABLE 98-1 Causes of Coma in Baclofen Toxicity

• Toxic cortical neuronal depression• Nonconvulsive status epilepticus• Hypothermia• Hypercarbia from respiratory depression

TABLE 98-2 Clinical Features of Baclofen intoxication and Withdrawal

Baclofen intoxication Baclofen withdrawalSomnolence, stupor, or coma Somnolence, stupor, or comaSeizures SeizuresFlaccid tetraparesis Rebound increase in spasticityAreflexia HyperreflexiaRespiratory failure Respiratory failureHypotension Hypotension or hypertensionFever Fever


Comatose and Baclofen Toxicity / / 707

often necessary. Baclofen has a fairly prolonged effect and thus in comatose patients, ven-tilatory support may be needed for several days until baclofen has been eliminated. The plasma half-life of baclofen is between two and six hours, with peak serum levels at one hour after ingestion. Baclofen may result in virtual loss of all brainstem reflexes and may closely, but not completely, mimic brain death.6 EEG may show burst suppression or may become markedly suppressed.8 In addition, if midazolam or fentanyl has been admin-istered, these drugs can be potentiated by baclofen, further complicating the clinical picture. Sinus bradycardia is treated with atropine. Physostigmine to reverse respiratory depression has been used in some cases but is not always successful. The best treatment for baclofen toxicity is hemodialysis, particularly if the patient has also developed renal failure.

A CONCLUDING NOTE

Both baclofen intoxication and baclofen withdrawal can cause coma. They are distin-guished by muscle tone.

REFERENCES

1. Berger B, Vienenkoetter B, Korporal M, et al. Accidental intoxication with 60 mg intrathecal baclofen: survived. Neurocrit Care 2012;16:428–432.

2. Darbari FP, Melvin JJ, Piatt JH, Jr., Adirim TA, Kothare SV. Intrathecal baclofen overdose followed by withdrawal: clinical and EEG features. Pediatr Neurol 2005;33:373–377.

3. Mathur SN, Chu SK, McCormick Z et al. Long term intrathecal baclofen: outcomes after more than 10 years of treatment. PM&R 2013:published ahead of print.

4. Ross JC, Cook AM, Stewart GL, Fahy BG. Acute intrathecal baclofen withdrawal: a brief review of treat-ment options. Neurocrit Care 2011;14:103–108.

5. Saltuari L, Marosi MJ, Kofler M, Bauer G. Status epilepticus complicating intrathecal baclofen overdose. Lancet 1992;339:373–374.

6. Sullivan R, Hodgman MJ, Kao L, Tormoehlen LM. Baclofen overdose mimicking brain death. Clin Toxicol (Phila) 2012;50:141–144.

7. Wall GC, Wasiak A, Hicklin GA. An initially unsuspected case of baclofen overdose. Am J Crit Care 2006;15:611–613.

8. Weissenborn K, Wilkens H, Hausmann E, Degen PH. Burst suppression EEG with baclofen overdose. Clin Neurol Neurosurg 1991;93:77–80.

9. Weisshaar GF, Hoemberg M, Bender K, et al. Baclofen intoxication: a “fun drug” causing deep coma and nonconvulsive status epilepticus—a case report and review of the literature. Eur J Pediatr 2012;171: 1541–1547.

708

A CONVERSATION

AN EXPLANATION

Neurotoxicity associated with antibiotics is well known but rarely considered. Penicillin toxicity has been known for years and is recognized by impaired consciousness, general-ized myoclonus, and even seizures. In some patients with meningoencephalitis, seizures and myoclonus were initially considered part of the primary illness and considerable clini-cal astuteness was required to recognize toxicity (renal failure was an important clue). This syndrome has not disappeared and is now also seen with newer-generation antibiotics.

Comatose and Cefepime Toxicity/ / / 99 / / /

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Cefepime, a fourth-generation cephalosporin, is a commonly used antibiotic, and because it is renally excreted any acute reduction in renal function changes its elimina-tion. Depending on the dose, cefepime toxicity may also occur in patients with normal renal function.2,6 Within a few days of cefepime administration, patients may develop hal-lucinations, confusion, and agitation that possibly can be attributed to the febrile illness for which the patient is being treated. However, these are not signs compatible with septic encephalopathy, although this is often put forward as an explanation. Moreover, many of these patients will have other causes for decreased level of consciousness, and this may include major electrolyte disturbances, hypoglycemia, uremia, shock, or major acid–base abnormalities—all gathered under the even more unsatisfactory moniker “multifacto-rial encephalopathy.” Neurologic symptoms usually begin approximately three days after cefepime initiation.3 They result in a decreased level of consciousness and diffuse appen-dicular myoclonus and may rarely be associated with nonconvulsive status epilepticus. In some patients, there is predominant myoclonus in facial muscles, but it quickly becomes generalized. The tone is normal, differentiating it from a serotonin syndrome.

EEGs are not distinctive and may show background slowing, triphasic waves, or mul-tifocal sharp waves, but nonconvulsive status that responds well to benzodiazepines has been described.5 Periodic epileptiform discharges are five times more frequent in patients receiving cefepime than patients receiving meropenem.4 The sudden emergence of myoc-lonus and renal impairment should point toward the diagnosis. Other causes of coma that should be considered in patients suspected of cefepime neurotoxicity are shown in Table 99-1. Most interesting is that neurotoxicity can also occur, despite concurrent hemo-dialysis. Unfortunately cefepime levels in blood and cerebrospinal fluid cannot typically be measured in clinical practice, and the diagnosis of toxicity is therefore based on clinical suspicion and is proven when symptoms disappear with discontinuation of the drug.7


Treatment is simple—discontinuing cefepime and replacing it with another antibiotic. Hemodialysis might improve the elimination of cefepime if the patient has marked renal

TABLE 99-1 Causes of Coma in Cefepime Toxicity

• Toxic cortical neuronal depression• Nonconvulsive status epilepticus• Uremic encephalopathy• Anoxic-ischemic encephalopathy after shock


failure.1 Recognition of nonconvulsive status epilepticus is important, but, in the reported cases, this is an unusual manifestation. Long-term antiepileptic drugs are not necessary. Nonetheless, the outcome remains poor in our experience, and up to two thirds of the patients succumb during hospitalization as a result of the major systemic illness that prompted aggressive antibiotic use in the first place.

A CONCLUDING NOTE

Patients treated with broad-spectrum antibiotics for a clinical illness such as a septic syndrome and multiorgan failure may develop cefepime toxicity. This is often under-appreciated but, when recognized and antibiotics are replaced or stopped, it may lead to unexpected improvement of the patient.

REFERENCES

1. Bresson J, Paugam-Burtz C, Josserand J, et al. Cefepime overdosage with neurotoxicity recovered by high-volume haemofiltration. J Antimicrob Chemother 2008;62:849–850.

2. Capparelli FJ, Diaz MF, Hlavnika A, et al. Cefepime- and cefixime-induced encephalopathy in a patient with normal renal function. Neurology 2005;65:1840.

3. Durand-Maugard C, Lemaire-Hurtel AS, Gras-Champel V, et al. Blood and CSF monitoring of cefepime-induced neurotoxicity: nine case reports. J Antimicrob Chemother 2012;67:1297–1299.

4. Fugate JE, Kalimullah EA, Hocker SE, Clark SL, Wijdicks EFM, Rabinstein AA. Cefepime neurotoxicity in the intensive care unit: a cause of severe, underappreciated encephalopathy. Crit Care 2013;17:R264.

5. Grill MF, Maganti R. Cephalosporin-induced neurotoxicity: clinical manifestations, potential pathogenic mechanisms, and the role of electroencephalographic monitoring. Ann Pharmacother 2008;42:1843–1850.

6. Maganti R, Jolin D, Rishi D, Biswas A. Nonconvulsive status epilepticus due to cefepime in a patient with normal renal function. Epilepsy Behav 2006;8:312–314.

7. Smith NL, Freebairn RC, Park MA, et al. Therapeutic drug monitoring when using cefepime in continu-ous renal replacement therapy: seizures associated with cefepime. Crit Care Resusc 2012;14:312–315.

711

A CONVERSATION

AN EXPLANATION

Acetaminophen overdose is an important cause of acute liver failure.11,13 A multicenter prospective study suggested that acetaminophen hepatotoxicity may be a leading cause of acute liver failure in the United States.12 Intentional versus unintentional overdoses are similar in frequency in the United States; however, in the United Kingdom, an over-whelming proportion of patients have attempted suicide.

Comatose and acetaminophen Toxicity

/ / / 100 / / /


Patients with acetaminophen overdose present with a markedly abnormal (several-fold increase) liver function test. The toxic liver damage leads to brain edema and, if not treated immediately, to brain death. Fortunately, many patients do have a worsening encephalopathy and a not-yet-irreversible coma which can be treated within 24 hours. Nomograms have been used that combine the plasma acetaminophen concentration with time of ingestion. This could place certain patients at high-risk (Fig. 100-1).

The causes of coma in acetaminophen overdose are shown in Table 100-1. Concurrent antidepressant overdose should be considered. Alcohol abuse and narcotic abuse in depressed patients with chronic pain are major risk factors that make these patients even more susceptible to acute liver failure with an acetaminophen overdose. Clinical neu-rologic examination of acute acetaminophen poisoning has been poorly detailed in the literature but probably corresponds with worsening grades of hepatic encephalopathy and is likely similar to that seen in fulminant hepatic failure (Chapter 73).

Lower limit for high-risk group5004000

3000

2000

13001000

500

100

50

Plas

ma

acet

amin

ophe

n co

ncen

trat

ion

30

mmol/L mg/mL 4 8 12

Hours after acetaminophen ingestion

16 20 24

400300

200150100

50

10

5

Lower limit for probable-risk groupTreatment nomogram line

FIGURE 100-1 Nomogram to assess the risk of hepatotoxicity after acetaminophen overdose;

includes a threshold line for when to start treatment.

TABLE 100-1 Causes of Coma in acetaminophen Toxicity

• Hyperammonemia• Fulminant brain edema• Coexisting alcohol intoxication• Coexisting amitriptyline overdose• Coexisting opioid overdose

Comatose and acetaminophen Toxicity / / 713


Administration of activated charcoal within one hour of acetaminophen poisoning may prevent systemic absorption. Gastric lavage does not provide any additional benefit.4 N-acetylcysteine is infused at a rate of 150 mg/kg over 24 to 48 hours until the liver func-tion tests improve or the patient proceeds with a liver transplant.8 Shorter courses have been suggested in low-risk patients.3 N-acetyl cysteine acts as a glutathione donor and causes few adverse reactions.1,9,10 Serial prothrombin times and serum lactate levels should be monitored; failure to normalize would indicate a poor prognosis.2,7 Hypotension is treated with vasopressors and aggressive fluid resuscitation.5,6,15 Hemofiltration may be required in patients who develop additional acute renal failure.14 Guidelines for contact-ing a liver transplant center for patients with acetaminophen overdose have been pub-lished (Table 100-2).

A CONCLUDING NOTE

Acetaminophen overdose is associated with rapid development of acute liver failure. Immediate administration of intravenous N-acetylcysteine may prevent liver transplanta-tion and can result in clearance of the ingested acetaminophen and clinical improvement.

REFERENCES

1. Acetaminophen toxicity in children. Pediatrics 2001;108:1020–1024.2. Bernal W, Donaldson N, Wyncoll D, Wendon J. Blood lactate as an early predictor of outcome in

paracetamol-induced acute liver failure: a cohort study. Lancet 2002;359:558–563.3. Betten DP, Cantrell FL, Thomas SC, Williams SR, Clark RF. A prospective evaluation of shortened

course oral N-acetylcysteine for the treatment of acute acetaminophen poisoning. Ann Emerg Med 2007;50:272–279.

4. Brok J, Buckley N, Gluud C. Interventions for paracetamol (acetaminophen) overdose. The Cochrane Database of Systematic Reviews 2006:CD003328.

TABLE 100-2 medical indicators increasing Probability of Liver Transplantation after acetaminophen Poisoning

Progressive coagulopathy (increasing International Normalized Ratio [INR])Renal failure (serum creatinine level two to three times increased)HypoglycemiaMetabolic acidosisHypotension despite fluid resuscitation

Data adapted from reference 2.


5. Dargan PI, Jones AL. Acetaminophen poisoning: an update for the intensivist. Crit Care 2002;6:108–110.6. Dargan PI, Jones AL. Management of paracetamol poisoning. Trends Pharmacol Sci 2003;24:154–157.7. Harrison PM, O’Grady JG, Keays RT, Alexander GJ, Williams R. Serial prothrombin time as prognostic

indicator in paracetamol induced fulminant hepatic failure. BMJ 1990;301:964–966.8. Hodgman MJ, Garrard AR. A review of acetaminophen poisoning. Crit Care Clin 2012;28:499–516.9. Mahadevan SB, McKiernan PJ, Davies P, Kelly DA. Paracetamol-induced hepatotoxicity. Arch Dis Child

2006;91:598–603.10. Miller RP, Roberts RJ, Fischer LJ. Acetaminophen elimination kinetics in neonates, children, and adults.

Clin Pharmacol Ther 1976;19:284–294.11. Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med 2006;354:731–739.12. Perkins JD. Acetaminophen sets records in the United States: number 1 analgesic and number 1 cause of

acute liver failure. Liver Transpl 2006;12:682–683.13. Rowden AK, Norvell J, Eldridge DL, Kirk MA. Acetaminophen poisoning. Clin Lab Med 2006;26:49–65.14. Sivilotti ML, Juurlink DN, Garland JS et al. Antidote removal during hemodialysis for massive acet-

aminophen overdose. Clin Toxicol. 2013;51:855–863.15. Vale JA, Proudfoot AT. Paracetamol (acetaminophen) poisoning. Lancet 1995;346:547–552.

715

A CONVERSATION

AN EXPLANATION

Tricyclic antidepressants (TCAs) are now used to treat many disorders, including obsessive- compulsive disorder, panic disorder, and eating disorder, and patients with migraine or longstanding neuropathic pain.4,5 They represent a common cause of poisoning in children and they have a higher fatality rate than poisonings with serotonin reuptake inhibitors.11

TCAs are rapidly absorbed, their metabolism is affected by function of the liver, and they usually have a half-life elimination of 24 to 48 hours.

Comatose and Tricyclic Antidepressant Toxicity

/ / / 101 / / /


The diagnosis of TCAs overdose or poisoning is confirmed using a quantitative mea-surement. Some drugs have a structural similarity and could confound the serum level (amphetamines, ranitidine, opiates, phencyclidine, ketamine, and carbamazepine).7 However, the distinction between tricyclic antidepressants and these other mimickers is made on the basis of their toxidromes (Chapter 7), and they can be further distinguished using gas chromatography with mass spectrometry. The anticholinergic effects of tricyclic antidepressants include dilated pupils and continuous myoclonic twitching. Seizures are much less common, occurring in less than 10% of cases.1 Some patients may develop clo-nus, increased tone, rigidity, or ophthalmoplegia that becomes apparent during resolution. The cardiovascular effects are substantial, particularly after ingestion of a dose sufficient to cause coma. Conversely, comatose patients with a normal EKG do not likely have a tricyclic antidepressant overdose. Inhibition of the sodium pump reduces depolarization of the action potential. The EKG changes are characteristic, with prolongation of the QRS complex, right axis deviation, and a prominent R-wave (Fig. 101-1).8

The causes of coma in TCAs are shown in Table 101-1. TCA’s create havoc due to the inhibition of norepinephrine reuptake at neuronal terminals, an alpha-adrenergic block, and anticholinergic action. This marked physiological brain dysfunction can be

FIGURE 101-1 EKG in a 40-year-old patient with amitriptyline overdose showing characteris-

tic widening of the QRS complex, prominent R-wave in lead aVR, and deviation of the axis to

the right.

TABLE 101-1 Causes of Coma and TCA Toxicity

• Toxic cortical neuronal depression• Anoxic-ischemic encephalopathy• Status epilepticus• Coexisting alcohol ingestion

Comatose and Tricyclic Antidepressant Toxicity / / 717

enhanced by associated anoxic-ischemic injury to the brain or ingestion of other drugs. Nonconvulsive status epilepticus is an unusual explanation for persistent coma overdose with tricyclic antidepressants, and suppression on the EEG is more common. Tricyclic antidepressant overdose can result in absence of all brainstem reflexes, including apnea, and can mimic brain death (Chapter 5).


As with many other poisonings, gastric lavage is probably not useful and will not change outcome.12,14 Activated charcoal can be provided if the patient is seen within one hour of ingestion; it is followed by sodium bicarbonate if the pH is less than 7.0.9 Prolongation of the QRS duration for more than 0.16 second also predicts seizures or ventricular arrhyth-mias.3,6 When arrhythmias occur, sodium bicarbonate should be provided together with magnesium sulfate to prevent refractory ventricular fibrillation.10,13 A new treatment is lipid emulsion therapy, which reverses cardiotoxicity.2 Phenytoin increases the rate of phase depolarization and has been successfully used to treat ventricular arrhythmias. (Phenytoin, although it acts through a similar mechanism, does not compete for the same binding site as tricyclic antidepressants.) Lidocaine binds to the sodium channel and dis-places slow-acting agents from the channel; therefore, it is a useful treatment in refractory cardiotoxicity. Other laboratory abnormalities include hyperkalemia and hyperglycemia, but these have to be corrected. Prognosis, even after prolonged cardiopulmonary resusci-tation, can be quite good. In a recent case, a 2-year-old with TCA poisoning fully recov-ered after prolonged resuscitation with alternating pulseless ventricular tachycardia and ventricular fibrillation.5 Good outcome can be expected if a dose less than 20 mg/kg is ingested. After awakening, patients should remain in the intensive care unit for at least 24 hours to monitor for cardiac arrhythmias.8

A CONCLUDING NOTE

In comatose patients with prolongation of the QRS complex on EKG, there should be a high level of suspicion of self-poisoning with TCA’s. This drug may produce coma and even absence of many brainstem reflexes in the most severely affected patients.

REFERENCES

1. Bailey B, Buckley NA, Amre DK. A meta-analysis of prognostic indicators to predict seizures, arrhyth-mias or death after tricyclic antidepressant overdose. J Toxicol Clin Toxicol 2004;42:877–888.


2. Blaber MS, Khan JN, Brebner JA, McColm R. “Lipid rescue” for tricyclic antidepressant cardiotoxicity. J Emerg Med 2012;43:465–467.

3. Boehnert MT, Lovejoy FH, Jr. Value of the QRS duration versus the serum drug level in predicting seizures and ventricular arrhythmias after an acute overdose of tricyclic antidepressants. N Engl J Med 1985;313:474–479.

4. Caksen H, Akbayram S, Odabas D, et al. Acute amitriptyline intoxication: an analysis of 44 children. Hum Exp Toxicol 2006;25:107–110.

5. Deegan C, O’Brien K. Amitriptyline poisoning in a 2-year old. Paediatr Anaesth 2006;16:174–177.6. Eyer F, Stenzel J, Schuster T, et al. Risk assessment of severe tricyclic antidepressant overdose. Hum Exp

Toxicol 2009;28:511–519.7. Fleischman A, Chiang VW. Carbamazepine overdose recognized by a tricyclic antidepressant assay.

Pediatrics 2001;107:176–177.8. Kerr GW, McGuffie AC, Wilkie S. Tricyclic antidepressant overdose: a review. Emerg Med J

2001;18:236–241.9. Knudsen K, Abrahamsson J. Epinephrine and sodium bicarbonate independently and additively increase

survival in experimental amitriptyline poisoning. Crit Care Med 1997;25:669–674.10. Liebelt EL, Francis PD, Woolf AD. ECG lead aVR versus QRS interval in predicting seizures and arrhyth-

mias in acute tricyclic antidepressant toxicity. Ann Emerg Med 1995;26:195–201.11. McKenzie MS, McFarland BH. Trends in antidepressant overdoses. Pharmacoepidemiol Drug Saf

2007;16:513–523.12. Teece S, Hogg K. Gastric lavage in tricyclic antidepressant overdose. Emerg Med J 2003;20:64.13. Thanacoody HK, Thomas SH. Tricyclic antidepressant poisoning: cardiovascular toxicity. Toxicol Rev

2005;24:205–214.14. Watson WA, Leighton J, Guy J, Bergman R, Garriott JC. Recovery of cyclic antidepressants with gastric

lavage. J Emerg Med 1989;7:373–377.

719

A CONVERSATION

AN EXPLANATION

Overdose with antidepressants is not uncommon in patients with major depression. For many years tricyclic antidepressants overdose were more commonly seen in sui-cide attempts, but now the selective serotonin reuptake inhibitors (SSRIs) should be strongly considered. The drugs that are currently in use are sertraline, fluoxetine, flu-voxamine, paroxetine, and citalopram.3 Any SSRI ingestion may lead to a serotonin syn-drome, but also if “serotonin enhancing” drugs are taken at the same time (odansetron,

Comatose and ssRi Toxicity/ / / 102 / / /


metoclopramide, opioids).1,2,8 This can also occur within days of SSRI ingestion as a result of co-ingestion of a drug that reduces its clearance or as a result of a suicide attempt. Early studies have found that mortality can be substantial, and the condition continues to be problematic because it can lead to metabolic acidosis, rhabdomyolysis, acute liver failure, renal failure, and, in the most extreme cases, disseminated intravascu-lar coagulation.9,10

Serotonin syndrome should be considered in any patient taking SSRIs but seldom is in the differential in an elderly patient. Acute agitated delirium is often attributed to a prior dementia or some mixed metabolic disturbance. The patient will not improve if the drug is continued. In the most extreme situations, care is de-escalated and then the patient surprisingly improves. The serotonin pathways and reuptake mechanisms are shown in Figure 102-1.

Most patients initially present with fine tremors followed by myoclonus and hyperthermia. Core temperature is increased and can reach 40° to 41°C, but that is highly unusual. In addition, the patient has other dysautonomic features, such as diaphoresis and mydriasis.

FIGURE 102-1 Serotonin pathways.

Comatose and ssRi Toxicity / / 721

On examination, clonus and hyperreflexia in the lower extremities are typical but non-specific because they are seen in many intoxications.7 Patients may experience an episode of extreme vigilance followed by impaired consciousness, in particular when there is co-ingestion with antipsychotics. This combination of drugs is especially worrisome because it can cause both a neuroleptic malignant syndrome and serotonin syndrome.

The causes of coma in SSRI overdose are shown in Table 102-1. Possible explanations for serotonin syndrome are shown in Table 102-1.


Cyproheptadine is used for serotonin syndrome mostly in patients with severe dysauto-nomia. It involves 20 to 32 mg of cyproheptadine for the first 24 hours; some experts have suggested an initial dose of 20 mg cyproheptadine followed by 2 mg every two hours.4–6 Intramuscular administration of 100 mg chlorpromazine is often considered. Most of the is be focused on controlling the autonomic instability, as the patient may have fluctuat-ing blood pressure. Hypertensive episodes are additionally treated with IV esmolol or labetalol. Aggressive cooling using cooling devices is necessary to control hyperthermia. Liberal use of fluids is essential to avoid rapid dehydration and to reduce the effect of rhabdomyolysis on the kidneys. If there is severe rigidity, benzodiazepines are the drugs

TABLE 102-1 Causes of Coma in ssRi Toxicity

• Toxic neuronal cortical depression• Anoxic-ischemic encephalopathy• Lithium co-ingestion and overdose• Atypical alcohol ingestion

TABLE 102-2 explanations for ssRi Toxicity

Situation Associated drugs

Excess of precursors of serotonin or its agonists Buspirone, l-dopa, lithium, LSD, l-tryptophan, trazodoneIncreased release of serotonin Amphetamines, cocaine, MDMA (Ecstasy), fenfluramine,

reserpineReduced reuptake of serotonin SSRI, TCA, trazodone, venlafaxine, meperidineSlowing of serotonin metabolism MAOI (e.g., isocarboxazid, selegiline)

LSD = lysergic acid diethylamide, MDMA = methylenedioxy-methamphetamine,

SSRI = selective serotonin reuptake inhibitors, TCA = tricyclic antidepressants,

MAOI = monoamine oxidase inhibitors.



of choice. Severe rigidity can also cause poor movement of the chest wall, compromis-ing ventilation. Propranolol, bromocriptine, and dantrolene are not recommended. The prognosis of serotonin syndrome is typically very good and most patients recover.

A CONCLUDING NOTE

With increased use of SSRIs, overdose may occur more often. SSRI intoxication is one of the most important and problematic acute hyperthermia syndromes.

REFERENCES

1. Birmes P, Coppin D, Schmitt L, Lauque D. Serotonin syndrome: a brief review. CMAJ 2003;168:1439–1442.

2. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005;352:1112–1120. 3. Brosen K, Naranjo CA. Review of pharmacokinetic and pharmacodynamic interaction studies with cita-

lopram. Eur Neuropsychopharmacol 2001;11:275–283. 4. Iqbal MM, Basil MJ, Kaplan J, Iqbal MT. Overview of serotonin syndrome. Ann Clin Psychiatry

2013:24:310–318. 5. Kapur S, Zipursky RB, Jones C, et al. Cyproheptadine: a potent in vivo serotonin antagonist. Am

J Psychiatry 1997;154:884. 6. Lappin RI, Auchincloss EL. Treatment of the serotonin syndrome with cyproheptadine. N Engl J Med

1994;331:1021–1022. 7. LoCurto MJ. The serotonin syndrome. Emerg Med Clin North Am 1997;15:665–675. 8. Pedavally S. Fugate JE, Rabinstein AA. Serotonin syndrome in the intensive care unit: clinical presenta-

tions and precipitating medications. Neurocrit Care 2013:epub ahead of print. 9. Mason PJ, Morris VA, Balcezak TJ. Serotonin syndrome. Presentation of 2 cases and review of the litera-

ture. Medicine (Baltimore) 2000;79:201–209.10. Sternbach H. The serotonin syndrome. Am J Psychiatry 1991;148:705–713.

723

A CONVERSATION

AN EXPLANATION

It is a shame, but alcohol intoxication is a common cause of coma in many emergency departments.1,2 Alcohol is a common cause of death too, with many unfortunate exam-ples. It is a very serious (and definitely underappreciated) intoxication. Alcohol inhib-its gamma-aminobutyric acid (GABA) and blocks the N-methyl-d-aspartate (NMDA) receptor and reduces level of consciousness. Patients with alcohol intoxication typically

Comatose and Alcohol intoxication

/ / / 103 / / /


present with flushed faces, diaphoresis, tachycardia, hypothermia, hypotension, hypoven-tilation, mydriasis, nystagmus, dysarthria, and eventually stupor and coma.

The absorption of alcohol continues from 20 minutes on an empty stomach to 2½ hours on a full stomach after last consumption, but peak absorption usually is seen within one hour. It may be due to binge drinking on a single occasion or due to repeated drunkenness in a prior habitual drinker. Binge drinking has become a known drinking behavior and is loosely defined as having four or five drinks within a brief period of time. In reality, often 20 drinks are consumed within an hour, and these situations are virtually always associated with coma and respiratory difficulties.7

Severe intoxication with a blood alcohol concentration of more than 250 mg/dL (54 mmol/L) results in coma, assuming the person is alcohol naïve. Markedly increased blood alcohol levels can be found in chronic alcoholics. Alcohol is mostly detected by a simple sniff.5 However, when studied, up to 7% of patients were falsely suspected of being intoxicated. If there is no alcohol whiff, this usually is due to vodka ingestion.

The causes of coma after alcohol intoxication are listed in Table 103-1. Most impor-tantly, coexisting traumatic brain injury needs to be excluded, and trauma from fall-ing or fights may result in traumatic brain injury or acute subdural hematoma. Acute heavy alcohol drinking may also precipitate acute hypoglycemia when glucose stores are rapidly depleted by poor dietary intake, insufficient hepatic glycogen, and shuttling away of pyruvate. During alcohol ingestion, alcohol converts into acetate via the NADH cycle, and this switches pyruvate into lactate, reducing gluconeogenesis (Fig. 103-1).6 Alcoholic hypoglycemia is often not recognized, but usually occurs only in malnour-ished alcoholics.4

Blood alcohol concentration is important, and the correlation with neurologic symptomatology is shown in Table 103-2. Acute alcohol ingestion can cause so-called “holiday heart syndrome” that includes acute atrial fibrillation but also other supraven-tricular tachydysrhythmias.4,11 It may precipitate myocardial ischemia in patients with prior angina pectoris.

TABLE 103-1 Causes of Coma in Alcohol intoxication

• Toxic neuronal cortical depression• Hypoglycemia• Seizures• Coexisting atypical alcohol ingestion• Coexisting traumatic brain injury• Acute Wernicke-Korsakoff syndrome

Comatose and Alcohol intoxication / / 725

It is questionable whether the effect of alcohol on examination of traumatic brain-injured patients is significant (unless in extreme cases), and some studies doubt that alcohol intoxication could be a confounding factor in coma assessment.9,10 Therefore, simply attributing coma to alcohol intoxication in trauma may potentially delay diagnos-tic investigation even if the initial CT scan is normal.


The treatment of alcohol intoxication is largely immediate airway assessment and preven-tion of aspiration. Patients may be mechanically ventilated, and unfortunately we have seen an emergency tracheostomy after complicated intubations in a single bout of alcohol intoxication. Intravenous solution administration to correct or prevent hypoglycemia and electrolyte imbalances is necessary—IV dextrose, magnesium, folate, thiamine, and multivitamins are added. It is important to administer antiemetic drugs if emesis has occurred to prevent recurrent vomiting and aspiration. Physical restraints are not

TABLE 103-2 effects of Various Blood Alcohol Concentrations

BAC (mg/dL) Clinical Manifestations

0–50 Diminished fine motor control, relaxation, increased talkativeness50–100 Impaired judgment and coordination100–200 Ataxia/gait instability; slurred speech; mood, personality, and behavioral changes200–400 Amnesia, diplopia/nystagmus, dysarthria, hypothermia, nausea/vomiting>400 Respiratory depression, coma, death

Data from reference.3

Hepaticglycogen

Glucose Dietary intake

Pyruvate

Lactate

Ethanol

FIGURE 103-1 Mechanism of alcohol-induced hypoglycemia.


necessary; but improving patients, may need brief administration of haloperidol to con-trol their behavior.

A randomized trial found that a single intravenous injection of metadoxine (900 mg) significantly reduces the half-life of ethanol in blood, but it is rarely used.8 Other therapies such as naloxone or flumazenil have not been successful. The only other option is hemodialysis, which will rapidly enhance elimination of ethanol in patients who have marked systemic manifestations. In any patient, a co-ingestion with an atypi-cal alcohol should be considered. (Management of ethylene glycol toxicity is discussed in Chapter 104.) Alcohol-induced hypoglycemia is associated with hypothermia and tachypnea. Laboratory findings will demonstrate not only severe hypoglycemia but also ketonuria without glucosuria and mild acidosis. Alcoholic ketoacidosis can be severe, causing marked volume depletion, and patients require adequate treatment with crystal-loid fluid replacement, dextrose, and IV thiamine.

In-hospital mortality is rare from ethanol-induced ketoacidosis. The morbidity of hypoglycemia is rarely severe. Fatality usually occurs before the patient reaches the hos-pital. The prognosis is typically excellent; most patients are discharged from the hospital, but only after being seen by a psychiatrist for further counseling.

A CONCLUDING NOTE

Alcohol intoxication may lead to violence, falls, and traumatic brain injury. Acute ethanol intoxication may be associated with other alcohol co-ingestion, and inebriated patients should be examined for both.

REFERENCES

1. Allely P, Graham W, McDonnell M, Spedding R. Alcohol levels in the emergency department: a worry-ing trend. Emerg Med J 2006;23:707–708.

2. Haberkern M, Exadaktylos AK, Marty H. Alcohol intoxication at a university hospital acute medicine unit—with special consideration of young adults: an 8-year observational study from Switzerland. Emerg Med J 2010;27:199–202.

3. Kleinschmidt K. Ethanol. In: Shannon MW, Borron SW, Burns M, eds. Haddad and Winchester’s Clinical Management of Poisoning and Drug Overdose, 4th eds. Philadelphia: Saunders, 2007.

4. Lieber CS. Medical disorders of alcoholism. N Engl J Med 1995;333:1058–1065.5. Malhotra S, Kasturi K, Abdelhak N, Paladino L, Sinert R. The accuracy of the olfactory sense in detecting

alcohol intoxication in trauma patients. Emerg Med J 2013:30:923–925.6. Molina PE, Sulzer JK, Whitaker AM. Alcohol abuse and the injured host: dysregulation of counterregu-

latory mechanisms review. Shock 2013;39:240–249.7. Pitzele HZ, Tolia VM. Twenty per hour: altered mental state due to ethanol abuse and withdrawal. Emerg

Med Clin North Am 2010;28:683–705.

Comatose and Alcohol intoxication / / 727

8. Shpilenya LS, Muzychenko AP, Gasbarrini G, Addolorato G. Metadoxine in acute alcohol intoxication: a double-blind, randomized, placebo-controlled study. Alcohol Clin Exp Res 2002;26:340–346.

9. Sperry JL, Gentilello LM, Minei JP, et al. Waiting for the patient to “sober up”: Effect of alcohol intoxica-tion on glasgow coma scale score of brain injured patients. J Trauma 2006;61:1305–1311.

10. Stuke L, Diaz-Arrastia R, Gentilello LM, Shafi S. Effect of alcohol on Glasgow Coma Scale in head-injured patients. Ann Surg 2007;245:651–655.

11. Vonghia L, Leggio L, Ferrulli A, et al. Acute alcohol intoxication. Eur J Intern Med 2008;19:561–567.

728

A CONVERSATION

AN EXPLANATION

In 2002, the Poison Control Centers in the United States reported more than 6,000 exposures to ethylene glycol, but much less poisoning in children. In about 25% of all cases, these exposures were intentional, with substantial mortality. Ethylene glycol is a polyhydric alcohol solvent. It has a sweet taste (“a long sweet sleep”)6 and is not infrequently ingested diluted. It has no distinctive breath odor.6,7 Its presence in anti-freeze solution is known, but more recently hand sanitizers have provided a source for

Comatose and ethylene Glycol ingestion

/ / / 104 / / /

Comatose and ethylene Glycol ingestion / / 729

self-inflicted poisonings.3 The damaging effects of ethylene glycol, in addition to sei-zures and coma, include renal injury, shock, and respiratory depression. Within four to six hours after ingestion, signs are clinically apparent and serum concentrations greater than 20 mg/dL are found. However, the serum concentration peaks early after inges-tion, so it may be low in patients who present later. The time to peak clinical effect is about 120 hours.

A large osmolar gap is characteristic in patients who have self-poisoning with eth-ylene glycol, methanol, and isopropanol (Chapter 7).4,12 Metabolic acidosis is severe in all atypical alcohol intoxications, with a demonstrable large anion and osmolar gap. Ketones are often documented in urine. (An anion-gap metabolic acidosis can be seen in early sepsis or diabetic ketoacidosis, but the gap is typically small and less than 15 mOsm.) Ethylene glycol intoxication is confirmed indirectly with an osmo-lar gap and also by screening of urine for fluorescence under ultraviolet light (Woods lamp). Crystals2,9 can be easily missed with perfunctory viewing, so urine fluorescent screening is not an infallible test (Fig. 104-1).9 This is particularly relevant because drug screens, while they test for methanol and isopropyl alcohol, do not usually test for ethylene glycol.

The causes of coma in ethylene glycol ingestion are shown in Table 104-1. Much of the presentation is due to severe metabolic depression of cortical function. Patients are flaccid and hypoventilating with intact brainstem reflexes. Nonconvulsive status epilep-ticus may be a confounder but this is rare. When seizures occur, renal failure is expected or soon follows.

FIGURE 104-1 Ethylene glycol crystal in urine sample.



Treatment of ethylene glycol poisoning involves correction of metabolic acidosis.8,13 The use of high-dose ethanol as a treatment has been abandoned due to its own toxic-ity. Current standard therapy is fomepizole. Although it can produce severe side effects, when administered early it will prevent renal injury. Fomepizole is given in an intrave-nous dose of 15 mg/kg followed by 10 mg/kg every 12 hours for 48 hours.8,10 The dose can then be increased to 15 mg/kg every 12 hours. Hemodialysis is another option; the criteria are shown in Table 104-2.1 Poor prognosis is likely when coma, severe acidosis, seizures, and hyperkalemia are present.5 Bilateral facial palsy or multiple cranial nerve deficits have been reported in survivors.11

A CONCLUDING NOTE

Metabolic acidosis with a large osmolar gap and coma should immediately point toward poisoning with atypical alcohols. Fomepizole has emerged as an important new therapy to treat this very serious toxicity and has reduced renal failure and the need for hemodialysis.

TABLE 104-1 Causes of Coma in ethylene Glycol ingestion

• Toxic cortical neuronal suppression• Seizures• Hypercarbia from hypoventilation• Coexisting illicit drug ingestion• Coexisting alcohol ingestion

TABLE 104-2 indications for hemodialysis in Deteriorating Patients with ethylene Glycol ingestion

Initial plasma concentration ≥0.5 g/L (8.1 mmol/L)Arterial pH <7.10Inability to maintain arterial pH >7.3 despite bicarbonate therapyDecrease in bicarbonate concentration >5 mmol/L, despite bicarbonate therapyAcute renal failure (creatinine >2.0 mg/dL)


Comatose and ethylene Glycol ingestion / / 731

REFERENCES

1. Caravati EM, Heileson HL, Jones M. Treatment of severe pediatric ethylene glycol intoxication without hemodialysis. J Toxicol Clin Toxicol 2004;42:255–259.

2. Casavant MJ, Shah MN, Battels R. Does fluorescent urine indicate antifreeze ingestion by children? Pediatrics 2001;107:113–114.

3. Doyon S, Welsh C. Intoxication of a prison inmate with an ethyl alcohol-based hand sanitizer. N Engl J Med 2007;356:529–530.

4. Geoghegan J. Ethylene glycol poisoning and the osmolal gap. Anaesthesia 2012;67:924.5. Hylander B, Kjellstrand CM. Prognostic factors and treatment of severe ethylene glycol intoxication.

Intensive Care Med 1996;22:546–552.6. Jaffery JB, Aggarwal A, Ades PA, Weise WJ. A long sweet sleep with sour consequences. Lancet

2001;358:1236.7. Jammalamadaka D, Raissi S. Ethylene glycol, methanol and isopropyl alcohol intoxication. Am J Med Sci

2010;339:276–281.8. Megarbane B, Borron SW, Baud FJ. Current recommendations for treatment of severe toxic alcohol poi-

sonings. Intensive Care Med 2005;31:189–195.9. Parsa T, Cunningham SJ, Wall SP, Almo SC, Crain EF. The usefulness of urine fluorescence for suspected

antifreeze ingestion in children. Am J Emerg Med 2005;23:787–792.10. Sivilotti ML, Burns MJ, McMartin KE, Brent J. Toxicokinetics of ethylene glycol during fomepizole ther-

apy: implications for management. For the Methylpyrazole for Toxic Alcohols Study Group. Ann Emerg Med 2000;36:114–125.

11. Spillane L, Roberts JR, Meyer AE. Multiple cranial nerve deficits after ethylene glycol poisoning. Ann Emerg Med 1991;20:208–210.

12. Takayesu JK, Bazari H, Linshaw M. Case records of the Massachusetts General Hospital. Case 7-2006. A 47-year-old man with altered mental status and acute renal failure. N Engl J Med 2006;354:1065–1072.

13. Vasavada N, Williams C, Hellman RN. Ethylene glycol intoxication: case report and pharmacokinetic perspectives. Pharmacotherapy 2003;23:1652–1658.

732

A CONVERSATION

AN EXPLANATION

Salicylate poisoning is usually unintentional and involves toddlers and very young chil-dren. Salicylates are found in most homes and are often contained in other products; therefore, the exposure is considerable.4–6 Salicylate overdose has a mortality of up to 20%, and this may be due to lack of appreciation of its potential severity. Salicylates directly stimulate the inspiratory neurons in the respiratory centers of the medulla oblongata and increase minute ventilation. Extremely high doses can cause respiratory

Comatose and salicylate Toxicity/ / / 105 / / /

Comatose and salicylate Toxicity / / 733

depression. Therefore, salicylate poisoning should be considered in any patient with the combination of a suspicious ingestion and respiratory alkalosis.1,7 Purpura and rapidly developing hypoglycemia are other useful clinical clues.

The causes of coma in salicylate poisoning are shown in Table 105-1. Salicylate over-dose may cause multiple cerebral hemorrhages, and this has been a cause of death.11 Cerebral edema is a more common manifestation, but it is likely from co-ingestion with acetaminophen. Severe hypoglycemia is a potential cause of coma, and recognition requires serial blood samples.


Plasma salicylate concentrations can be measured, and the severity of poisoning is determined by this level. A salicylate level of 600 mg/L or higher is considered to be of such severity that it would require aggressive management.12 A recently proposed algo-rithm is shown in Figure 105-1.3 Urine alkalinization increases the elimination of salicy-late and remains the first-line treatment in patients with severe salicylate poisoning.8,9 Administration of sodium bicarbonate will produce urine with a pH of more than 7.5, and pH manipulation is far more important than diuresis. Both urine alkalinization and high urine flow (>600 mL/h) are, however, ultimate goals of management.2,5 Potassium supplementation is necessary to prevent hypokalemia.

Another method to eliminate salicylates is hemodialysis.10,13 This treatment has improved outcome but is considered only when the plasma concentration is greater than 800 mg/mL.13 Continuing urinary alkalinization remains important while the patient is undergoing hemodialysis.

A CONCLUDING NOTE

Salicylate poisoning is one of the most important poisonings in young children, and treatment is based on the salicylate level. Rapid urinary alkalinization is standard man-agement, but hemodialysis may be needed.

TABLE 105-1 Comatose from salicylate Toxicity

• Toxic cortical neuronal depression• Hypoglycemia• Cerebral hemorrhages• Cerebral edema (co-ingestion with acetaminophen)

FIG

URE

105

-1 F

low

char

t fo

r m

anag

emen

t o

f sa

licyl

ate

po

iso

nin

g. A

dap

ted

fro

m D

arga

n e

t al

.3 w

ith

per

mis

sio

n.

Comatose and salicylate Toxicity / / 735

REFERENCES

1. Bora K, Aaron C. Pitfalls in salicylate toxicity. Am J Emerg Med 2010;28:383–384.2. Chase P, Walter F, James S. Whole bowel irrigation, hemodialysis, and continuous venovenous

hemodiafiltration in the successful treatment of severe salicylate poisoning. Case report. Dialysis & Transplantation 2002;31:387–391.

3. Dargan PI, Wallace CI, Jones AL. An evidence based flowchart to guide the management of acute salicy-late (aspirin) overdose. Emerg Med J 2002;19:206–209.

4. Davis JE. Are one or two dangerous? Methyl salicylate exposure in toddlers. J Emerg Med 2007;32:63–69.5. Done AK. Aspirin overdosage: incidence, diagnosis, and management. Pediatrics 1978;62:890–897.6. Flomenbaum NE. Salicylates. In: Nelson L, Lewin N, Howland MA, et al. eds. Goldfrank’s Toxicologic

Emergencies, 9th ed. McGraw-Hill, 2010:508–519.7. Krenzelok EP, Kerr F, Proudfoot AT. Salicylate toxicity. In: Haddad LM, Shannon MW, Winchester

JF, eds. Clinical Management of Poisoning and Drug Overdose, 3rd ed. Philadelphia: WB Saunders, 1998:675–687.

8. Proudfoot AT, Krenzelok EP, Brent J, Vale JA. Does urine alkalinization increase salicylate elimination? If so, why? Toxicol Rev 2003;22:129–136.

9. Proudfoot AT, Krenzelok EP, Vale JA. Position paper on urine alkalinization. J Toxicol Clin Toxicol 2004;42:1–26.

10. Satar S, Alpay NR, Sebe A, Gokel Y. Emergency hemodialysis in the management of intoxication. Am J Ther 2006;13:404–410.

11. Thisted B, Krantz T, Stroom J, Sorensen MB. Acute salicylate self-poisoning in 177 consecutive patients treated in ICU. Acta Anaesthesiol Scand 1987;31:312–316.

12. Wood DM, Dargan PI, Jones AL. Measuring plasma salicylate concentrations in all patients with drug overdose or altered consciousness: is it necessary? Emerg Med J 2005;22:401–403.

13. Wrathall G, Sinclair R, Moore A, Pogson D. Three case reports of the use of haemodiafiltration in the treatment of salicylate overdose. Hum Exp Toxicol 2001;20:491–495.

736

A CONVERSATION

AN EXPLANATION

Heroin is far more toxic than morphine. The presentation of opioid-related emergency department visits can be fairly dramatic, and heroin is commonly responsible for respira-tory depression, delayed gastrointestinal motility, miosis, and terminal cardiac arrest.5,6,8,10 Every inner-city police officer recognizes the barely breathing, emaciated person with pinpoint pupils as another heroin intoxication.

Comatose and opioid Toxicity/ / / 106 / / /

Comatose and opioid Toxicity / / 737

The diagnosis of heroin intoxication is relatively simple and is based on a respiratory rate less than 10 breaths per minute, miotic pupils, and circumstantial evidence or history of heroin use. Heroin is diacetyl morphine, and its metabolites anchor the mu receptors.

Use of heroin creates tolerance, and higher doses are needed over time. A common problem is when addicted persons detoxify and, after a period of abstinence, start up again with a dose similar to that they used before, may cause an accidental overdose (Fig. 106-2). Other problems are concomitant alcohol use, which reduces judgment regarding the amount taken. Fatal heroin overdose is often a result of mixed drug use.

Heroin overdose is a major cause of mortality and morbidity worldwide. Free admin-istration of naloxone—an opioid antagonist for intravenous, intramuscular, subcutane-ous, and intranasal administration—can reduce deaths because many opioid overdoses are witnessed. Active heroin users could potentially survive an overdose if naloxone is administered by a bystander heroin addict. Naloxone programs have reported reversal of opioid overdose as a result of this important and simple observation.1,3 In some studies, it has been found that the first 12 months after discontinuation of addiction therapy and the first two weeks after release from incarceration were higher-risk periods for heroin overdose and death, again arguing for take-home naloxone to prevent these lethal events.

Another major opioid is methadone. Methadone has been protective against death from heroin overdose. It is a substitute drug that is used in medication-assisted therapy for drug dependency. The drug has been associated with MR signal abnormalities in the white matter, with sparing of the subcortical U fibers.7 (These findings are mostly seen after methadone intoxication).

High

Low

Inexperienced Experienced

Intoxicatingdose

Lethaldose

User

Her

oin

do

se

FIGURE 106-1 Bioconversion of heroin (diacetylmorphine). The boxed components are the ago-

nists at the mu receptor. Adapted from reference 10.


Another major known intoxication is oxycodone, a mu-opioid receptor agonist often used for chronic pain management. Overdose here again is associated with respiratory depression. Oxycodone prescribing patterns are worrisome and there have been multiple cases of suicide attempts involving overdose of prescribed oxycodone.

The most notorious and difficult to recognize intoxication is the one associated with opioid patches. Unexpected high blood levels may occur in susceptible patients, and the patch may not have been spotted—at least initially—by physicians during examination.

Opioid overdose (with major consequences) does occur from time to time in postop-erative patients often after recent orthopedic surgery. Inadvertent dosing in patient con-trolled analgesia (PCA) pumps is fortunately rare and is often recognized early.

The causes of coma in opioid intoxication are shown in Table 106-1. Because respira-tory arrest and cardiopulmonary resuscitation are common after acute heroin overdose, failure to awaken may be a result of anoxic-ischemic brain injury.


The treatment of acute opioid overdose involves providing adequate ventilation with bag-valve-mask ventilation with 100% oxygen or intubation if oxygenation is poor and the patient is pooling secretions. Endotracheal intubation is necessary in many patients who have persistent hypoventilation. Naloxone (0.2 to 0.4 mg) is given intravenously, subcutaneously, or intramuscularly, with repeated dosing with naloxone 2 mg if there is no improvement in 10 minutes.9 Full support in the ICU is necessary in many patients, and many patients need further psychiatric help. Noncardiogenic pulmonary edema is a complication of heroin overdose and may have led to permanent anoxic injury. In some patients, repeated use (and repeated episodes of overdose with less-than-pure heroin) will lead to a delayed, possibly reversible, leukoencephalopathy.2 Long-term devastating injury, however, is possible with both heroin and methadone use, with reports of akinetic mutism.4

TABLE 106-1 Causes of Coma and opioid Toxicity

• Toxic cortical neuronal depression• Acute leukoencephalopathy• Traumatic brain injury• Coexisting benzodiazepine overdose• Anoxic-ischemic encephalopathy• Sepsis and endocarditis

Comatose and opioid Toxicity / / 739

A CONCLUDING NOTE

Opioid intoxication causes coma and pinpoint pupils. It may be caused by a patch, injec-tion by a drug addict, or cumulative doses administration in postoperative patients.

REFERENCES

1. Baca CT, Grant KJ. What heroin users tell us about overdose. J Addict Dis 2007;26:63–68.2. Barnett MH, Miller LA, Reddel SW, Davies L. Reversible delayed leukoencephalopathy following intra-

venous heroin overdose. J Clin Neurosci 2001;8:165–167.3. Coffin PO, Sullivan SD. Cost-effectiveness of distributing naloxone to heroin users for lay overdose

reversal. Ann Intern Med 2013;158:1–9.4. Gheuens S, Michotte A, Flamez A, De Keyser J. Delayed akinetic catatonic mutism following methadone

overdose. Neurotoxicology 2010;31:762–764.5. Jones CM. Heroin use and heroin use risk behaviors among nonmedical users of prescription opioid

pain relievers—United States, 2002–2004 and 2008–2010. Drug Alcohol Depend 2013;132:95–100.6. Jones JD, Mogali S, Comer SD. Polydrug abuse: a review of opioid and benzodiazepine combination use.

Drug Alcohol Depend 2012;125:8–18.7. Salgado RA, Jorens PG, Baar I, et al. Methadone-induced toxic leukoencephalopathy: MR imaging and

MR proton spectroscopy findings. AJNR Am J Neuroradiol 2010;31:565–566.8. Sporer KA. Acute heroin overdose. Ann Intern Med 1999;130:584–590.9. Warner-Smith M, Darke S, Lynskey M, Hall W. Heroin overdose: causes and consequences. Addiction

2001;96:1113–1125.10. White JM, Irvine RJ. Mechanisms of fatal opioid overdose. Addiction 1999;94:961–972.

740

A CONVERSATION

AN EXPLANATION

Benzodiazepine overdose is a common intentional drug ingestion, and these drugs have a long duration of action. Lorazepam can therefore markedly suppress an EEG for many hours. Time to peak CSF concentration in lorazepam is approximately seven minutes and is about twice rapid as in diazepam and midazolam. Its effects on EEG activity may last four times more than diazepam and midazolam.

Comatose and Benzodiazepine Toxicity

/ / / 107 / / /

Comatose and Benzodiazepine Toxicity / / 741

Neurologic presentation is typically marked flaccidity and hypoventilation. The airway often collapses and patients pool secretions. Depending on when the patient is found after ingestion, there may be associated hypothermia, and that may lead to profound bradycardia. It is also highly possible that severe hypoxemia, in combination with hypotension, may have occurred, increasing the risk for hypoxic-ischemic encephalopathy.

The causes of coma after a benzodiazepine overdose are shown in Table 107-1. In clinical practice, co-ingestion with other proconvulsants has been noted in quite a few patients, mostly in patients who have ventilatory failure. It is estimated that one in five patients with benzodiazepine overdose had co-ingested tricyclic antidepressants.8 Most concerning is that benzodiazepine overdose can result in transient atrioventricular block, and this cardiac arrhythmia cannot be corrected by flumazenil.1


Patients with a benzodiazepine overdose are often intubated and supported for 24 to 48 hours on a mechanical ventilator until they awaken. Flumazenil remains very effective in reversing the need for ventilatory failure.6 Flumazenil has usually been administered intravenously at 0.2 mg in 30 seconds and can be followed by additional doses.7 Clinical experience has shown that flumazenil results in a substantial number of patients in awak-ening from benzodiazepine overdose.2 Most remarkable, the risk of seizures does not appear to be higher after flumazenil use; it is estimated at approximately 1%.2 However, the incidence of seizures is much higher in patients who have co-ingested tricyclic antide-pressants. The recent experience with flumazenil is that it is usually used in less than 2% of patients with benzodiazepine poisoning.8 Moreover, seizures can be totally unrelated to flumazenil.5 The mechanism of action in flumazenil is shown in Figure 107-1. In general, flumazenil is contraindicated if there is additional ethanol intoxication and when there is evidence of co-ingestion of tricyclics.

An interesting disorder has been named idiopathic recurrent stupor.4 This disorder initially was described as an episodic transient unconsciousness of unknown cause with subsequent detection of a benzodiazepine-like factor, endozepine, in CSF and dramatic improvement with flumazenil. Whether this entity exists remains unclear, and we have

TABLE 107-1 Causes of Coma and Benzodiazepine Toxicity

• Toxic neuronal cortical depression• Anoxic-ischemic encephalopathy• Flumazenil-induced seizures• Co-ingestion with opioids


not been able to diagnose this disorder. Exogenous benzodiazepine administration by proxy has been described in patients suspected of this disorder.3

A CONCLUDING NOTE

Benzodiazepine overdose is best treated with supportive care. Flumazenil is an effective antidote, but has questionable benefit and should be used sparingly.

REFERENCES

1. Arroyo Plasencia AM, Ballentine LM, Mowry JB, Kao LW. Benzodiazepine-associated atrioventricular block. Am J Ther 2012;19:e48–52.

2. Barnett R, Grace M, Boothe P, et al. Flumazenil in drug overdose: randomized, placebo-controlled study to assess cost effectiveness. Crit Care Med 1999;27:78–81.

3. Granot R, Berkovic SF, Patterson S, Hopwood M, Mackenzie R. Idiopathic recurrent stupor: a warning. J Neurol Neurosurg Psychiatry 2004;75:368–369.

4. Lugaresi E, Montagna P, Tinuper P, et al. Endozepine stupor. Recurring stupor linked to endozepine-4 accumulation. Brain 1998;121(Pt 1):127–133.

5. Spivey WH. Flumazenil and seizures: analysis of 43 cases. Clin Ther 1992;14:292–305.6. Spivey WH, Roberts JR, Derlet RW. A clinical trial of escalating doses of flumazenil for reversal of sus-

pected benzodiazepine overdose in the emergency department. Ann Emerg Med 1993;22:1813–1821.7. Thomson JS, Donald C, Lewin K. Use of flumazenil in benzodiazepine overdose. Emerg Med J 2006;23:162.8. Veiraiah A, Dyas J, Cooper G, Routledge PA, Thompson JP. Flumazenil use in benzodiazepine overdose

in the UK: a retrospective survey of NPIS data. Emerg Med J 2012;29:565–569.

GABA

GABA

Benzodiazepines

FlumazenilZolpidem

Barbiturates

CI-

αα

β

β γ

FIGURE 107-1 Chlorine channel and multiple receptors (including flumazenil).

743

A CONVERSATION

AN EXPLANATION

Lithium is a mood-stabilizing agent used to treat bipolar affective disorders. Lithium is absorbed within six to eight hours and distributed in total body water, does not bind to plasma proteins, and is excreted mostly by the kidneys. The elimination half-life is long, averaging 24 hours, but is doubled in the elderly or in patients with prolonged use.

Lithium intoxication is mostly nonintentional and has a gradual clinical presentation.9 Most patients start with a fine tremor and muscle weakness; when initially examined, they have generalized hyperreflexia. When lithium toxicity worsens, the patient develops

Comatose and Lithium Toxicity/ / / 108 / / /


dysarthria, ataxia, increased tone and myoclonus, and eventually widespread fascicula-tion and rigidity.3,4 Gastrointestinal symptoms are the first signs of acute lithium toxicity, and diarrhea may emerge, leading further to marked dehydration. The effect of lithium on the heart is typically bradycardia with a prolonged QT interval on EKG. Lithium does not cause an acid–base abnormality, but it is often co-ingested with other drugs such as cocaine or phencyclidine. This syndrome, due to its marked rigidity, looks identical to serotonin syndrome or neuroleptic malignant syndrome, which should be recognized as such, particularly when the patient is taking additional psychiatric medications. Causes of coma in lithium toxicity are shown in Table 108-1.

Serum lithium concentrations are necessary to determine the severity of an overdose. Lithium has a narrow therapeutic index, and normally lithium concentrations are between 0.8 and 1.2 mEq/L; levels above 4 mEq/L are necessary to impair level of consciousness.8 Because nephrogenic diabetes insipidus is a complication of lithium overdose, marked hypernatremia may be seen concomitantly. Lithium affects thyroid function, and both hypothyroidism and hyperthyroidism are described (Chapter 75). A serum T4 level con-centration is mandatory.


Treatment is mostly supportive care, but because of the marked dehydration, aggressive hydration is necessary. Suggested treatment is shown in Figure 108-1.

Isotonic saline may be needed, particularly if there is marked associated hyperna-tremia.6 Because lithium can induce nephrogenic diabetes insipidus, a large amount of fluids is needed to control the water deficit with hypernatremia. If the time of ingestion was within one hour, gastric lavage should be considered. Whole-bowel irri-gation is indicated only for large ingestions, in particular ingestion of sustained-release products. The use of oral activated charcoal does not result in a reduction of lithium absorption, and hemodialysis might be the only option if the serum lithium concen-tration is above 4 mEq/L. Again, normal saline solution should be administered intra-venously to reverse and prevent volume depletion and to maintain adequate urine output. Forced diuresis does not increase lithium clearance.

TABLE 108-1 Causes of Coma in Lithium Toxicity

• Toxic cortical neuronal depression• Nonconvulsive status epilepticus• Hypothyroidism• Severe hypernatremia

Comatose and Lithium Toxicity / / 745

Major lithium toxicity is best managed with hemodialysis and as soon as possible, usually within 8 hours. Hemodialysis should be started in patients who present with coma or renal failure Hemodialysis is also strongly recommended for patients with serum lithium levels above 4 mEq/L or for those undergoing chronic lithium therapy whose levels are between 2.5 and 4 mEq/L. Often two sessions of hemodialysis are necessary to reduce the lithium levels.2

A reversible neurotoxicity has been described after lithium intoxication, and these persistent symptoms have been called “syndrome of irreversible lithium-effectuated neu-rotoxicity” (SILENT). There is marked cerebellar dysfunction with truncal ataxia and appendicular ataxia.1,5 These symptoms may last for years after the initial lithium intoxi-cation. Fortunately, most other patients have full recovery of neurologic function after lithium intoxication has been treated.

A CONCLUDING NOTE

Lithium overdose is usually recognized early, but intoxication is serious with marked dehydration, hypernatremia, and EKG abnormalities. Long-term ataxia is possible.

Type of lithium preparation?

Liquid lithiumSustained-release lithium

tablets

Nasogastric aspirationIf patient presesnt within 1 hr ofingestiona) Acute overdose for >50 mg/kg

b) Acute-on-chronic overdose for any amount in excess of normal dose

Gastric lavageIf patient presesnt within 1 hr ofingestiona) Acute overdose for >50 mg/kg


Take blood for lithium level and U & E at 6 hr post-ingestion

Repeat lithium level every 6-12 hr depending on clinical situation(see text)

Consider hemodialysis if lithium level greater than

• 7.5 mmol/L in acute overdose in a patient not normally on lithium

• 4 mmol/L in acute overdose in a patient on lithium

• 2.5 mmol/L in chronic accumulation

• Coma, convulsions, respiratory failure, renal failure

And in patients with severe clinical features

Whole bowel irrigationIf patient presesnt within 12 hr ofingestiona) Acute overdose for >50 mg/kg


Non-sustained-releaselithium tablets

Acute lithium overdose

FIGURE 108-1 Treatment algorithm for lithium intoxication. U&E: renal function tests and electro-

lytes. Adapted from references 4,6.


REFERENCES

1. Adityanjee, Munshi KR, Thampy A. The syndrome of irreversible lithium-effectuated neurotoxicity. Clin Neuropharmacol 2005;28:38–49.

2. Beckmann U, Oakley PW, Dawson AH, Byth PL. Efficacy of continuous venovenous hemodialysis in the treatment of severe lithium toxicity. J Toxicol Clin Toxicol 2001;39:393–397.

3. Fetzer J, Kader G, Danahy S. Lithium encephalopathy: a clinical, psychiatric, and EEG evaluation. Am J Psychiatry 1981;138:1622–1623.

4. Hansen HE, Amdisen A. Lithium intoxication. (Report of 23 cases and review of 100 cases from the literature). Q J Med 1978;47:123–144.

5. Kores B, Lader MH. Irreversible lithium neurotoxicity: an overview. Clin Neuropharmacol 1997;20:283–299.

6. Okusa MD, Crystal LJ. Clinical manifestations and management of acute lithium intoxication. Am J Med 1994;97:383–389.

7. Olson K. Poisoning and Drug Overdose (6ed.) McGraw-Hill Professional. 2011.8. Sadosty AT, Groleau GA, Atcherson MM. The use of lithium levels in the emergency department. J Emerg

Med 1999;17:887–891.9. Simard M, Gumbiner B, Lee A, Lewis H, Norman D. Lithium carbonate intoxication. A case report and

review of the literature. Arch Intern Med 1989;149:36–46.

747

A CONVERSATION

AN EXPLANATION

“Rave parties” are characterized by an uninterrupted dance using glowsticks while wearing colorful rings and other flashy jewelry.19 The use of MDMA (3,4-methylamphetamine) also called Ecstasy (Fig. 109-1) has become popular at raves in many Western countries. Usually, a dose of 100 to 150 mg provides euphoria, but at low doses it provides marked alteration of color perception and texture and magnification of “fantasy states.” Repeated doses may result in hallucinations, tachycardia, hypertension, and hyperthermia.

Comatose After a Rave Party/ / / 109 / / /


Tachycardia may also be due to interaction with caffeine.15 Marked diaphoresis can occur; in poorly ventilated areas, this can lead to hyperthermia and even heatstroke. Major adverse events are rare,10 but the drug is far less innocuous than advertised and can lead to significant systemic and neurologic manifestations.16,17 Systemic manifestations include tachyarrhythmias, myocardial ischemia, pulmonary edema, hyperpyrexia, disseminated intravascular coagulation, renal failure, and rhabdomyolysis.6,7,9,11,12,14 Hyponatremia and hypoglycemia are secondary effects that cause concern.

The causes of coma after a rave party are shown in Table 109-1. The circumstances are favorable for heatstroke. Comatose patients typically have temperatures about 40°C. Marked dilutional hyponatremia may occur if participants drink large amounts of liquids to prevent fluid loss. Ecstasy-induced brain death associated with severe hyponatremia has been described.3 Some patients develop a catatonic stupor after Ecstasy ingestion, and this manifestation has also been linked to hyponatremia.3,13 Moreover, MDMA is a potential hepatotoxic drug that may cause fulminant hepatic failure. Neurologic manifestations of MDMA overdose have included cerebral infarction and intracranial hemorrhage associated with marked hypertension, but this has been rarely reported. However, several cases of acute

Polydrugs

Fluid loss

High ambienttemperature

CH3

NH.CH3

FIGURE 109-1 The circumstances of a rave party. Structure shown is Ecstasy (3,4-methylenedioxy-

N-methylamphetamine [MDMA]).

TABLE 109-1 Causes of Coma After a Rave Party

• Toxic cortical neuronal depression• Hyperthermia• Hyponatremia• Seizures• Multiple ischemic strokes due to aortic dissection

Comatose After a Rave Party / / 749

aortic dissection are on record.4,18 Cerebral venous thrombosis may occur and is possibly as a consequence of severe dehydration and hyperthermia. The central nervous system (CNS) hyperexcitability may lead to seizures. Polydrug ingestion may be a confounding issue, and some patients take cocaine and amphetamines in combination with MDMA, causing a syn-ergistic increase in dopaminergic and serotonergic stimulation2 (Table 109-2). The usual toxicology screens fail to detect MDMA unless large doses have been ingested. Thin-layer chromatography would be necessary to detect metabolites in urine.

TABLE 109-2 Characteristics of Drugs Associated With Raves

DrugStreet Names Mechanism Clinical Features Toxicities

3-4 Methylenedioxy-

methylamphetamine

(MDMA, Ecstasy)

E, X, XTC,

Love,

Adam

5-HT release Heightened perception

and sensual

awareness, mydriasis,

sympathomimetic,

bruxism, and ataxia

Dysrhythmias,

hyperthermia,

rhabdomyolysis,

disseminated

intravascular

coagulation (DIC),

hyponatremia, and

seizures

Lysergic acid

diethylamide (LSD)

Acid, Hits,

Blotters

5-HT2 receptor

agonist

Sympathomimetic

symptoms, mydriasis,

nausea, visual

hallucinations, and

agitation

Persistent psychosis,

hallucinations, persisting

perception disorder, and

“flashbacks”

Ketamine Kit-Kat,

Special K

NMDA receptor

antagonist

Sympathomimetic

symptoms, nystagmus,

rigidity, and hallucinations

Loss of consciousness,

respiratory depression,

and catatonia

Phencyclidine (PCP) Angel dust,

peace

Glutamate

agonist at

NMDA receptor

Sympathomimetic and

cholinergic symptoms,

miosis, nystagmus,

hypertension

Coma, seizures,

hyperthermia,

rhabdomyolysis,

hypoglycemia, and

hypertension

Crystal

methamphetamine

Speed,

crystal,

crys, jib,

meth

Enhances

release and

blocks uptake of

catecholamines

Tachycardia, tachypnea,

hypertension,

hyperthermia, mydriasis,

and diaphoresis

Dysrhythmias, seizures,

hypertension, and

hyperthermia

Gamma-

hydroxybutyrate

(GHB)

G, liquid Biphasic

dopamine

response

Agitation, nystagmus,

ataxia, hypotonia,

vomiting, and muscle

spasms

Seizures, apnea, sudden

reversible coma with

abrupt awakening and

violence, and bradycardia

(continued)



Management of intoxication from MDMA is supportive care alone and consists of treat-ment of dehydration.1,5 Hyperthermia should be treated with cooling blankets, and car-diac arrhythmias should be treated using typical management algorithms.8 Dantrolene has been advocated, but its effect is uncertain.8 If hypertension remains, it responds well to sedation with lorazepam or midazolam.

A CONCLUDING NOTE

MDMA intoxication is on the rise and should be considered in intoxicated young adults. Other party drugs may have been co-ingested. There are serious medical and neurologic complications associated with Ecstasy use, with the potential for long-term morbidity.

REFERENCES

1. Ben-Abraham R, Szold O, Rudick V, Weinbroum AA. “Ecstasy” intoxication: life-threatening manifesta-tions and resuscitative measures in the intensive care setting. Eur J Emerg Med 2003;10:309–313.

2. Boys A, Lenton S, Norcross K. Polydrug use at raves by a Western Australian sample. Drug Alcohol Rev 1997;16:227–234.

3. Caballero F, Lopez-Navidad A, Cotorruelo J, Txoperena G. Ecstasy-induced brain death and acute hepa-tocellular failure: multiorgan donor and liver transplantation. Transplantation 2002;74:532–537.

4. Duflou J, Mark A. Aortic dissection after ingestion of “ecstasy” (MDMA). Am J Forensic Med Pathol 2000;21:261-263.

5. Emde K. MDMA (Ecstasy) in the emergency department. J Emerg Nurs 2003;29:440–443.6. Greene SL, Dargan PI, O’Connor N, Jones AL, Kerins M. Multiple toxicity from

3,4-methylenedioxymethamphetamine (“ecstasy”). Am J Emerg Med 2003;21:121–124.

DrugStreet Names Mechanism Clinical Features Toxicities

Cannabis

Oil-resin = hashish

Oil-herb = marijuana

herb Binds to

cannabis

receptor

Mild hallucinations,

paranoia, tachycardia,

conjunctival injection

Rare

Cocaine Coke, dust,

blow, snow,

flake

Inhibits

uptake of

catecholamines

Tachycardia,

hypertension, pyrexia,

mydriasis, ataxia,

diaphoresis, agitation,

delusions, and rapid

euphoria

Hyperthermia,

hallucinations, seizures,

and death

Adapted from reference 20. (See also Chapter 7 for toxidromes.)

TABLE 109-2 Continued

Comatose After a Rave Party / / 751

7. Guillot CR, Berman ME. MDMA (Ecstasy) use and psychiatric problems. Psychopharmacology (Berl) 2007;189:575–576.

8. Hall AP, Henry JA. Acute toxic effects of “Ecstasy” (MDMA) and related compounds: overview of pathophysiology and clinical management. Br J Anaesth 2006;96:678–685.

9. Klein M, Kramer F. Rave drugs: pharmacological considerations. Aana J 2004;72:61–67.10. Krul J, Sanou B, Swart EL, Girbes AR. Medical care at mass gatherings: emergency medical services at

large-scale rave events. Prehosp Disaster Med 2012;27:71–74.11. Libiseller K, Pavlic M, Grubwieser P, Rabl W. Ecstasy—deadly risk even outside rave parties. Forensic Sci

Int 2005;153:227–230.12. Liechti ME, Kunz I, Kupferschmidt H. Acute medical problems due to Ecstasy use. Case-series of emer-

gency department visits. Swiss Med Wkly 2005;135:652–657.13. Maxwell DL, Polkey MI, Henry JA. Hyponatraemia and catatonic stupor after taking “ecstasy”. BMJ

1993;307:1399.14. McCann UD, Slate SO, Ricaurte GA. Adverse reactions with 3,4-methylenedioxymethamphetamine

(MDMA; “ecstasy”). Drug Saf 1996;15:107–115.15. McNamara R, Maginn M, Harkin A. Caffeine induces a profound and persistent tachycardia in response

to MDMA (“Ecstasy”) administration. Eur J Pharmacol 2007;555:194–198.16. Schifano F. A bitter pill. Overview of ecstasy (MDMA, MDA) related fatalities. Psychopharmacology

(Berl) 2004;173:242–248.17. Schwartz RH, Miller NS. MDMA (ecstasy) and the rave: a review. Pediatrics 1997;100:705–708.18. Swalwell CI, Davis GG. Methamphetamine as a risk factor for acute aortic dissection. J Forensic Sci

1999;44:23–26.19. ter Bogt TFM, Engels RC. “Partying” hard: party style, motives for and effects of MDMA use at rave

parties. Subst Use Misuse 2005;40:1479–1502.20. Weir E. Raves: a review of the culture, the drugs and the prevention of harm. CMAJ 2000;162:1843–1848.

752

A CONVERSATION

AN EXPLANATION

When rapidly demented patients underwent brain biopsy for diagnostic purposes, Creutzfeldt-Jakob disease (CJD)—both classical and variant type—was found in 12% of patients and Alzheimer’s disease in 18%, but many other disorders were also seen, such as vasculitis, Behçet’s disease, neurosarcoidosis, granulomatous encephalopathy, paraneo-plastic encephalopathy, Whipple’s disease, progressive multifocal leukoencephalopathy, or a less defined chronic encephalitis.9 Nondiagnostic gliosis was found in more than a third of

Comatose and Rapid Dementing illness

/ / / 110 / / /

Comatose and Rapid Dementing illness / / 753

the cases.11 Other rare progressive dementias, eventually culminating in comatose states, to consider are Huntington’s disease, familial insomnia, and Gerstmann-Straussler-Scheinker syndrome, and many of the inherited metabolic diseases of infancy.

The diagnostic criteria of CJD include progressive dementia with myoclonus, visual disturbances, pyramidal or extrapyramidal signs, a characteristic EEG, or increased 14-3-3 protein in cerebrospinal fluid (CSF). Sporadic CJD often involves patients aged 50 or younger, with younger age at onset also indicating a more severe clinical course. Depression with accusatory behavior is often seen in younger individuals, but patients may, in a matter of months, progress to a minimally conscious state.1,11 Patients with most other dementing illnesses do not develop an early marked decline in consciousness but only insomnia or apathy. Alzheimer’s disease progresses, but some arousal remains. A persistent vegetative state in Alzheimer’s is highly unusual, and many years pass before this terminal manifestation.10

Currently, there are at least six phenotypes in sporadic CJD, including an encephalitic variant with predominant white matter involvement. A Heiden-Hain variant is character-ized by cortical blindness and visual apraxia and an Oppenheimer variant with marked ataxia.5 Other classifications include patients with sporadic CJD and predominant cere-bral cortical involvement. Variants that have more notable ataxia as a clinical presentation have subcortical neuropathological changes on MRI. These sporadic variants also have more characteristic basal ganglia abnormalities or cerebral cortical involvement.2

The causes of coma in patients with acute dementing illness are shown in Table 110-1. Coma may be due to widespread rapid cortical involvement in CJD or nonconvulsive status epilepticus but is not infrequently confounded by overuse of atypical antipsychotic drugs to treat aggression, paranoia, and hallucinations. Depression during the course of illness is common and may lead to suicide attempts using drug ingestion.

MRI findings in sporadic CJD have recently been redefined. The posterior thalamus or pulvinar region shows hyperintensities, also known as the pulvinar sign. In sporadic CJD, gray matter abnormalities are seen in neocortex, limbic cortex,7 striatum, and thalamus (Fig. 110-1). The posterior and medial thalamus is more involved in the variant of CJD. Serial EEG recordings are helpful, showing frontal intermittent rhythmical delta activity

TABLE 110-1 Causes of Coma and Rapid Dementing illness

• Diffuse cortical damage• Nonconvulsive status epilepticus• Overuse of atypical antipsychotic drugs• Suicide attempt with antidepressants


(FIRDA) and periodic sharp-wave complexes. These periodic sharp waves may originate from the thalamus or frontal cortex.6 An increased cell count or protein and the presence of oligoclonal bands are highly unusual in CJD. CSF-14-3-3 protein immunoassay is a sen-sitive test to confirm the clinical diagnosis but has a specificity of not more than 60%.3

Criteria for the new variant of CJD have been recently proposed (Table 110-2).4 The diagnosis of CJD is ideally confirmed after a brain biopsy. This involves creating a burr

FIGURE 110-1 MRI with cortical hyperintensity signals in CJD.

TABLE 110-2 Diagnostic Criteria for new Variant Creutzfeldt-Jakob Disease (nvCJD)

I A. Progressive neuropsychiatric disorderB. Duration of illness >6 monthsC. Investigations do not suggest alternative diagnosisD. No history of potential iatrogenic exposure

II A. Early psychiatric symptoms such as depression, anxiety, apathy, withdrawal, or delusionsB. Persistent painful sensory symptoms such as frank pain or dysesthesiaC. AtaxiaD. Myoclonus, chorea, or dystoniaE. Dementia

III A. EEG does not show generalized triphasic periodic complexes at approximately 1/s or no EEG

performedB. Bilateral pulvinar high signal on MRI

Diagnosis: Definite nvCJD: IA and neuropathological confirmation of nvCJD (i.e., spongiform change and

extensive prion protein deposition with florid plaques throughout cerebrum and cerebellum)Probable nvCJD: I and 4/5 of II and IIIA and IIIB Possible nvCJD: I and 4/5 of II and IIIA

From reference 12.

Comatose and Rapid Dementing illness / / 755

hole with opening of the dura and excision en bloc of at least a 10-mm cube of leptomen-inges and gray and white matter. In most instances, the nondominant right frontal lobe is taken or a biopsy is performed at the location of abnormalities on MRI. Tonsillar biopsy has also been suggested as a way to detect the abnormal protein, but positive staining has been found only in new variant of CJD and not in other forms. The typical neuropatho-logical changes in a brain biopsy are spongiform changes that involve fine vacuole-like appearances.


All health care workers in contact with the patient should be informed, and precautions are needed for handling of equipment and specimens. There is no specific therapy for CJD—only symptomatic treatment and supportive care—but clinical trials that could work against receptors of prion protein are in development.8 Levodopa may improve extrapyramidal symptoms. Benzodiazepines, antidepressants, and atypical antipsychotic drugs (e.g., quetiapine and olanzapine) are useful, but sedation is a major limiting factor. Clonazepam in high doses may be needed to control myoclonus.

A CONCLUDING NOTE

The relentless progression into a minimally conscious state preceded by myoclonus is a common occurrence in CJD. CJD is now more easily diagnosed with CSF biomarkers and is recognized by typical MRI findings. Brain biopsy is preferred to exclude the remote possibility of a treatable disorder.

REFERENCES

1. Boesenberg C, Schulz-Schaeffer WJ, Meissner B, et al. Clinical course in young patients with sporadic Creutzfeldt-Jakob disease. Ann Neurol 2005;58:533–543.

2. Collins SJ, Sanchez-Juan P, Masters CL, et al. Determinants of diagnostic investigation sensitivities across the clinical spectrum of sporadic Creutzfeldt-Jakob disease. Brain 2006;129:2278–2287.

3. Green A, Sanchez-Juan P, Ladogana A, et al. CSF analysis in patients with sporadic CJD and other trans-missible spongiform encephalopathies. Eur J Neurol 2007;14:121–124.

4. Hill AF, Butterworth RJ, Joiner S, et al. Investigation of variant Creutzfeldt-Jakob disease and other human prion diseases with tonsil biopsy samples. Lancet 1999;353:183–189.

5. Hilton DA. Pathogenesis and prevalence of variant Creutzfeldt-Jakob disease. J Pathol 2006;208:134–141.6. Jung KY, Seo DW, Na DL, et al. Source localization of periodic sharp wave complexes using independent

component analysis in sporadic Creutzfeldt-Jakob disease. Brain Res 2007;1143:228–237.7. Lin YR, Young GS, Chen NK, Dillon WP, Wong S. Creutzfeldt-jakob disease involvement of rolandic cor-

tex: a quantitative apparent diffusion coefficient evaluation. AJNR Am J Neuroradiol 2006;27:1755–1759.


8. Ludewigs H, Zuber C, Vana K, et al. Therapeutic approaches for prion disorders. Expert Rev Anti Infect Ther 2007;5:613–630.

9. Murray K. Creutzfeldt-Jacob disease mimics, or how to sort out the subacute encephalopathy patient. Pract Neurol 2011;11:19–28.

10. Volicer L, Berman SA, Cipolloni PB, Mandell A. Persistent vegetative state in Alzheimer disease. Does it exist? Arch Neurol 1997;54:1382–1384.

11. Warren JD, Schott JM, Fox NC, et al. Brain biopsy in dementia. Brain 2005;128:2016–2025.12. Will RG, Zeidler M, Stewart GE, et al. Diagnosis of new variant Creutzfeldt-Jakob disease. Ann Neurol

2000;47:575–582.

757

A CONVERSATION

AN EXPLANATION

Malignant catatonia is rare and is frequently associated with affective disorders and schizophrenia, but it may occur with the use of psychotropic drugs and in catastrophic neurologic injuries. If unrecognized, malignant catatonia can be fatal because of rhab-domyolysis, renal failure, and cardiac arrhythmias.12 Acute catatonia typically begins with subtle features such as insomnia, anxiety, and mood changes, followed by agitation, delusional thinking, and hallucinations. Acute catatonia (DSM-IV) is characterized by

Comatose and malignant Catatonia

/ / / 111 / / /


rigidity, psychosocial withdrawal (mutism), and repetitious behavior.6,11 Acute catatonia can show bizarre signs, such as the compulsive repetition of meaningless words, and can progress to psychogenic unresponsiveness (catatonic stupor). Immobility alternating with grasping can occur.17

Similarly, malignant catatonia is preceded by behavioral symptoms such as agitation and excitement. More importantly, malignant catatonia may emerge from a catastrophic neurologic disorder, but its symptoms may be misinterpreted as belonging to the primary central nervous system disorder and thus go unnoticed.8–10,14 Traumatic brain injury, encephalitis, and anoxic-ischemic encephalopathy have been most commonly linked to these acute dysautonomias. The emergence of hyperthermia, dysautonomia, and extreme agitation heralds a rapid decline in the patient’s medical condition. Even more complex are patients with paranoid schizophrenia who attempt suicide resulting in acute brain injury (e.g., suicidal hanging or jumping out of a window, causing traumatic brain injury) and then develop a clinical picture of catatonia.1,2,6,14

Malignant catatonia is part of a group of acute dysautonomias. Again, these patients become mute and rigid and develop significant dysautonomic symptoms. The autonomic instability involves a persistent tachycardia, labile blood pressure, and tachypnea, and these symptoms occur at the time there is a sudden rise in temperature. Temperatures of greater than 40°C have been described14,20 (Fig. 111-1).

The causes of coma in malignant catatonia are shown in Table 111-1. The underlying brain injury often confounds neurologic examination. Acute uremia associated with rhabdomyolysis may become an additional confounding factor. Nonconvulsive status epilepticus has been reported in association with catatonia.15,18 Eventually, multiple doses of benzodiazepines or opioids to control agitation may contribute a great deal.

Temperature high41

40

39

Tem

pera

ture

(C

)

38

37

36

351 3 5 7 9 11 13 15 17

Hospital day

19 21

ECT

23 25 27 29 31

Temperature low

FIGURE 111-1 Marked temperature fluctuation. Note temperature decrease with electroconvulsive

therapy (ECT) and relapse of hyperthermia.

Comatose and malignant Catatonia / / 759

A similar clinical picture has been described with a neuroleptic malignant syndrome. Here, any class of neuroleptic drugs can trigger symptoms, which usually occur within the first 2 weeks of starting medication. A third major acute dysautonomic syndrome that should be considered is a serotonin syndrome related to the use of selective serotonin reuptake inhibitors. However, serotonin syndrome presents more often with shivering and myoclonus and less often with rigidity and hyperthermia. Obviously, the clinical diag-nosis of each of these disorders (malignant catatonia, malignant neuroleptic syndrome, serotonin syndrome) is considered when the clinician is knowledgeable about these dis-orders, and there is concern that many physicians are unaware of these presentations. Important supportive diagnostic tests are increased serum creatinine phosphokinase lev-els; levels may easily reach more than 10,000 IU/L. Rhabdomyolysis in malignant cata-tonia can result in worsening serum creatinine, proteinuria, and myoglobulinuria. Acute leukocytosis is a consistent finding, and lactate dehydrogenase, alkaline phosphatase, and liver transaminase levels are elevated.3,20


Severe catatonia without dysautonomic features responds well to a lorazepam chal-lenge.9,18 More recently, a trial with zolpidem has been proposed, resulting in improve-ment of symptoms within an hour after a 10-mg dose.19 (Although there is a different affinity at certain units, both drugs act at GABA receptors and thus modulate the inhibit-ing neurotransmitter GABA.)

Malignant catatonia with dysautonomia is an emergency. The treatment is to stop the causative agent (Fig. 111-2)8 followed by supportive care that should include rehydra-tion, prevention of acute renal failure due to rhabdomyolysis, and thus correction of elec-trolyte imbalances and treatment of cardiac arrhythmias. Specific urine alkalinization is necessary in addition to high-volume intravenous fluids, all to minimize renal failure from rhabdomyolysis. Mechanical ventilation may be required if there is marked chest wall rigidity or evidence of aspiration pneumonia, and under these circumstances, neuromus-cular blockers may be needed. Cooling blankets with ice packs in the axillae and gastric lavage should be ordered. The use of dantrolene, a direct-acting skeletal muscle relaxant

TABLE 111-1 Causes of Coma in malignant Catatonia

• Major psychiatric disorders• Underlying acute catastrophic brain injury• Accumulation of benzodiazepines• Seizures (nonconvulsive)


(doses of 0.25 to 2 mg/kg intravenous every 12 hours), is a first measure (see Fig. 111-2). Dantrolene should be considered for at least five days. Electroshock therapy (ECT) is generally used in patients who do not respond to supportive therapy (see Fig. 111-2) such as lorazepam5,13,16 or clonidine.4 Bromocriptine (maximal dose of 40 mg/d) and amantadine (maximal dose of 200 mg every 12 hours) have been used but with vari-able success. The mortality of malignant catatonia has decreased to 20% due to aggressive supportive care.7

A CONCLUDING NOTE

Hyperthermia, rigidity, and dysautonomic features in any patient, including those with underlying structural brain injury, should prompt the diagnosis of malignant catatonia. Lorazepam or zolpidem may be very successful in uncomplicated catatonia. In malignant catatonia, dantrolene is the first-line treatment and ECT may be needed.

REFERENCES

1. Ainsworth P. A case of ‘lethal catatonia’ in a 14-year-old girl. Br J Psychiatry 1987;150:110–112.2. Bush G, Fink M, Petrides G, Dowling F, Francis A. Catatonia. I. Rating scale and standardized examina-

tion. Acta Psychiatr Scand 1996;93:129–136.3. Chandler JD. Psychogenic catatonia with elevated creatine kinase and autonomic hyperactivity. Can J

Psychiatry 1991;36:530–532.

Stopsuspicious drug

Fluidreplacement

Sedation(lorazepam)

Cooling

Urinealkalizing

Dantrolene sodium0.25–2 mg/kg IV q12h

Clonidine hydrochloride25 mg po q6h

Morphine sulfate2.5–10 mg IV q6h

ECT 3–5 days

Bromocriptine mesylate10–40 mg/d

FIGURE 111-2 Algorithm for the treatment of malignant catatonia or neuroleptic malignant syndrome.

Comatose and malignant Catatonia / / 761

4. Cizadlo BC, Wheaton A. Case study: ECT treatment of a young girl with catatonia. J Am Acad Child Adolesc Psychiatry 1995;34:332–335.

5. Consoli A, Benmiloud M, Wachtel L, et al. Electroconvulsive therapy in adolescents with the catatonia syndrome: efficacy and ethics. J Ect 2010;26:259–265.

6. Cottencin O, Warembourg F, de Chouly de Lenclave MB, et al. Catatonia and consultation-liaison psy-chiatry study of 12 cases. Prog Neuropsychopharmacol Biol Psychiatry 2007;31:1170–1176.

7. Ferro FM, Janiri L, De Bonis C, Del Carmine R, Tempesta E. Clinical outcome and psychoendocrino-logical findings in a case of lethal catatonia. Biol Psychiatry 1991;30:197–200.

8. Fink M, Taylor MA. Catatonia: A Clinician’s Guide to Diagnosis and Treatment. Cambridge, UK: Cambridge University Press, 2003.

9. Fink M, Taylor MA. Catatonia: subtype or syndrome in DSM? Am J Psychiatry 2006;163:1875–1876.10. Freudenreich O, McEvoy JP, Goff DC, Fricchione GL. Catatonic coma with profound bradycardia.

Psychosomatics 2007;48:74–78.11. Jaimes-Albornoz W, Serra-Mestres J. Catatonia in the emergency department. Emerg Med J 2012;29:

863–867.12. Mann SC, Caroff SN, Bleier HR, et al. Lethal catatonia. Am J Psychiatry 1986;143:1374–1381.13. Petrides G, Divadeenam KM, Bush G, Francis A. Synergism of lorazepam and electroconvulsive therapy

in the treatment of catatonia. Biol Psychiatry 1997;42:375–381.14. Philbrick KL, Rummans TA. Malignant catatonia. J Neuropsychiatry Clin Neurosci 1994;6:1–13.15. Primavera A, Fonti A, Novello P, Roccatagliata G, Cocito L. Epileptic seizures in patients with acute

catatonic syndrome. J Neurol Neurosurg Psychiatry 1994;57:1419–1422.16. Rosebush PI, Mazurek MF. Catatonia and its treatment. Schizophr Bull 2010;36:239–242.17. Saddawi-konefka D, Berg SM, Nejad SH. Catatonia in the ICU: an important and underdiagnosed cause

of altered mental status. Crit Care Med 2013:42:e234–e241.18. Suzuki K, Miura N, Awata S, et al. Epileptic seizures superimposed on catatonic stupor. Epilepsia 2006;47:

793–798.19. Thomas P, Rascle C, Mastain B, Maron M, Vaiva G. Test for catatonia with zolpidem. Lancet 1997;349:702.20. Wijdicks EFM. Neuroleptic malignant syndrome. UpToDate. Waltham, MA, 2007.

762

A CONVERSATION

AN EXPLANATION

The diagnosis of psychogenic unresponsiveness (“hysterical coma,” “feigned coma,” or “dissociative stupor”) is not truly a diagnosis of exclusion. Psychogenic unresponsive-ness may occur after surgery or after a major spat at home or work. Prior unexplained clinical symptoms have been evaluated and may have even resulted in exploratory surgery.1,5,9,13 Moreover, factitious disorders commonly include “neurologic” presen-tations.4 During examination, there are recognizable clinical findings, often changing

Comatose and Conversion Disorder

/ / / 112 / / /

Comatose and Conversion Disorder / / 763

over time and not following “the rules” of neurologic localization. The neurologic examination is normal, but some skill is needed to demonstrate inconsistencies with-out embarrassing the patient. Patients with psychogenic unresponsiveness are flaccid, although with passive motion brief periods of tone can be felt. Eyes remain closed even after noxious stimuli, but a wisp of cotton tickling the vermilion border of the lip and nose hairs results in eye opening.7 Another maneuver is brief tipping of the eyelashes.12 Obstructing the airway at the nose will immediately open the mouth. If still uncertain, a face mask with outlets obstructed usually results in a purposeful grab at the mask after 60 seconds8 (Fig. 112-1).

FIGURE 112-1 Examination of psychogenic unresponsiveness: touching nose hairs or upper lip,

extreme eye deviation, arm staying in position after being elevated by examiner, mouth opening

with closing of nose passage or grasping mask.


Downward gaze with no visualization of the upper pupil rim is typical and does not change with head turning.3,6,10 Elevating an arm may stay only to flop onto the bed gradu-ally and in a stuttering fashion. When held in front of the patient’s head, the arm will fall but will avoid direct facial contact when suddenly let loose (“hand-drop test”). It remains an unreliable sign, and we have seen patients having their arms fall flat on their face with very little grimace or other response.

Psychogenic status epilepticus is recognized by several clinical signs. Patients have their eyes closed (as opposed to open or half-open in true status epilepticus), show abrupt starting-and-stopping movements, may hyperventilate, and even may produce a loud scream during convulsions rather than in the early ictal phase. Another helpful sign is stertorous (snoring-like) breathing.11 Flailing arms, shaking in two extremities alone (often alternating), hip thrusts, and rolling movements are other features. (VC 112-1)

The EEG may be difficult to read due to artifacts, but it has no sharp waves or an epi-leptic focus. Measurement of the serum prolactin level could differentiate between true seizure and pseudoseizure; the level is elevated in a true seizure when measured 10 to 20 minutes after a single seizure. The test is rarely used in clinical practice, and the level is not elevated in status epilepticus.2

The causes of unresponsiveness in a conversion disorder are shown in Table 112-1. The diagnosis is not always straightforward. Complex partial status epilepticus, prolonged postictal state, and the first presentation of frontal lesions or frontal glioma may result in bizarre behavior that may be virtually identical to psychogenic unresponsiveness.


Perseverance with painful stimuli should be avoided; many patients are able to tolerate “extraordinary degrees of pain.” Management should include avoiding self-inflicted injury to the patient using pads. Avoidance of repeated doses of benzodiazepines is very impor-tant. Resolution is spontaneous and often dramatic (“what happened to me?”) but in some patients the symptoms last for days.

TABLE 112-1 Causes of Psychogenic Unresponsiveness

• Unknown defense mechanism• Dissociative or other psychiatric disorder• Malingering• Frontal lesion

Comatose and Conversion Disorder / / 765

A CONCLUDING NOTE

Psychogenic unresponsiveness is not common but resolves quickly in most cases. Psychogenic status epilepticus should be considered when no effect of antiepileptic drugs is seen. (EEG monitoring is normal if it can be reliably read despite the artifacts.)

The professional help of a psychiatrist is needed. Long-term prognosis can be poor, with more functional signs and symptoms in the future.

REFERENCES

1. Albrecht RF, 2nd, Wagner SRt, Leicht CH, Lanier WL. Factitious disorder as a cause of failure to awaken after general anesthesia. Anesthesiology 1995;83:201–204.

2. Chen DK, So YT, Fisher RS. Use of serum prolactin in diagnosing epileptic seizures: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2005;65:668–675.

3. Dhadphale M. Eye gaze diagnostic sign in hysterical stupor. Lancet 1980;2:374–375.4. Fliege H, Grimm A, Eckhardt-Henn A, et al. Frequency of ICD-10 factitious disorder: survey of senior

hospital consultants and physicians in private practice. Psychosomatics 2007;48:60–64.5. Haller M, Kiefer K, Vogt H. [Dissociative stupor as a postoperative consequence of general anesthesia].

Anaesthesist 2003;52:1031–1034.6. Henry JA, Woodruff GH. A diagnostic sign in states of apparent unconsciousness. Lancet 1978;2:920–921.7. Maag FF. Detection of feigned coma. N Engl J Med 1973;289:811.8. Maddock H, Carley S, McCluskey A. An unusual case of hysterical postoperative coma. Anaesthesia

1999;54:717–718.9. Meyers TJ, Jafek BW, Meyers AD. Recurrent psychogenic coma following tracheal stenosis repair. Arch

Otolaryngol Head Neck Surg 1999;125:1267–1269.10. Rosenberg ML. The eyes in hysterical states of unconsciousness. J Clin Neuroophthalmol 1982;2:259–260.11. Sen A, Scott C, Sisodiya SM. Stertorous breathing is a reliably identified sign that helps in the differentia-

tion of epileptic from psychogenic non-epileptic convulsions: an audit. Epilepsy Res 2007;77:62–64.12. Wiggs JW. Detection of feigned coma. N Engl J Med 1973;289:379.13. Young JL, Rund D. Psychiatric considerations in patients with decreased levels of consciousness. Emerg

Med Clin North Am 2010;28:595–609.

INDEX

α coma patterns, 178abciximab, 534abscess of brain

causes of coma, 398ttreatment plan and prognosis, 399

abuse, contusions and subdural hematomas from, 188, 188–190

accommodation stage of medullary compression, 20acetaminophen overdose, 711–713

causes of coma, 712treatment plan and prognosis, 713

acetylcholine, 70involved with awake state, 71

acetylcholine esterase inhibitors, 73Acinetobacter acinus, 246Acinetobacter baumannii, 230acupuncture, 268acute aortic regurgitation, 616acute catatonia, 757–758acute confusional state, 83acute dementing illness, causes of coma, 753tacute disseminated encephalomyelitis (ADEM),

193, 465–568causes of coma, 466ttreatment plan and prognosis, 467–468triggers, 466t

acute epidural hematoma, 336–338causes of coma, 337ttreatment plan and prognosis, 338

acute fatal alcohol intoxication, 195acute hemorrhagic leukoencephalitis (AHL), 412acute hydrocephalus, 478–482

causes, 480tcauses of coma, 479t

acute hypercarbic respiratory failure, 225acute leukemia, 666–669acute leukoencephalopathy

in demyelinated tissue, 193MR image, 172, 173

acute myelogenous leukemia, 666classification, 669

acute necrotizing encephalitis, 423–424causes of coma, 424ttreatment plan and prognosis, 424

acute porphyria, 670–673treatment plan and prognosis, 671–673

acute subdural hematoma, 340–343causes of coma, 342tCT scan, 341CT scan of septum pellucidum displacement,

171evacuation, 342

acute thrombocytopenia, 662–665, 664causes of coma, 664t

acute thyroid disease, emergency management, 605t

acute uremia, 581–584causes of coma, 582ttreatment plan and prognosis, 583

Adams, R.D., 31, 32, 42, 44ADEM. See acute disseminated

encephalomyelitis (ADEM)adrenal crisis, treatment, 222tadvance directives, 251, 280, 289advanced care protocol, 269African Americans, religious beliefs, 289AHL (acute hemorrhagic leukoencephalitis), 412air embolism, 573–576

causes of coma, 575ttreatment plan and prognosis, 575–576

airway, supportive care, 235–240akinetic mutism, 37, 77, 118–119, 282

causes, 119talcohol, 137

delirium from withdrawal, 83alcohol-induced hypoglycemia, 725t, 726alcohol intoxication, 723–726

acute fatal, 195

Page numbers in italics refer to figures and page numbers followed by t refer to tables page numbers.

768 / / INDEX

alcohol intoxication (Cont.)causes of coma, 724ttreatment options for coma due to, 222ttreatment plan and prognosis, 725–726

alcoholism, Wernicke-Korsakoff syndrome and, 679alertness, 76alkalosis, 27ALL (acute lymphoblastic leukemia), 666Alquier, M., 7alternative medicine, 268Alzheimer’s disease, 752amantadine, 264–265, 265tAmerican Academy of Neurology, 46, 113, 289

guidelines, prognostication in comatose patients following CPR, 558

American Academy of Pediatrics and Child Neurology Society, 147

American College of Critical Care Medicine, 289amitriptyline, 265

overdose, EKG of, 716AML (acute myelogenous leukemia), 666

classification, 669ammonia, 596amniotic fluid embolization, 226amphetamines, 70–71anencephaly, 148anesthesia, awakening from, 496aneurysmal subarachnoid hemorrhage (SAH), 118,

366–370causes of coma, 367

angiogram, 146cerebral, 523–525

De Anima Brutorum (Willis), 3animals, close contact with, 427–430anion gap, 220anoxic-ischemic injury, 184, 186anterior cingulate cortex, 68, 78, 118anti-freeze solution, ethyl glycol in, 728antibiotics, 230

neurotoxicity from, 708anticoagulated patient, enlarging hematoma in, 348anticoagulation, risk in infective endocarditis, 613antidotes for toxins, 221antiepileptics, 265

treatment options for coma due to, 222tantihistamine drugs, 71, 75antineuronal-antibody-associated, 458taorta dissection, 615–617


aortic regurgitation, acute, 616apallia, 35Das Apallische Syndrom, 35, 36apnea, 28

test procedure, 46, 132in brain death determination, 140–142

apneusis, 29apneustic breathing, 95apraxia of eyelid opening, 378ARAS. See ascending reticular activating

system (ARAS)Arieff, A.I., 30–31arousal, disturbance of, 82arterial hypertension, 21artery occlusion, basal, 386–389ascending reticular activating system (ARAS), 60,

64, 69, 78Aspen Consensus Conference Working Group, 116aspergillosis infection

after near-drowning, 550CT scan of abscesses, 434

Aspergillus fumigatus, 438, 438tinfection, 192, 192

aspiration pneumonia, 230Association of Health Care Journalists, 300asterixis, 31, 582asthmaticus, status, 577–580astrocytoma, high-grade, 441–444ataxia of respiration, 29autoimmune encephalitis, 461–464

treatment plan and prognosis, 463autopsy, 201–202autoresuscitation, 295awake state

anatomical structures and dorsal and ventral pathways involved with, 67

anatomy of, 64–70chemistry of, 70–76key structures in maintaining, 76neuroscience of, 60–78

early studies, 61–64translation into clinical practice, 76–77

neurotransmitter pathways involved with, 71–73physiology, 75

awakening from coma, 111, 260awareness, 76awareness without behavioral evidence, 53axonal injury, demonstrating, 189

Babinski signs, 139baclofen, 234

accidental intoxication, 705–707causes of coma, 706tintoxication and withdrawal, clinical features,

706tbacterial meningitis, 190–191, 193, 391–394

causes of coma, 392tmacroscopic view of, 191treatment plan and prognosis, 392–394

BAEPs (brainstem auditory evoked potentials), 183barbiturate, GABAergic transmission and, 71, 73basal forebrain, awake state and, 64

INDEX / / 769

basilar artery aneurysm, rupture of, 367basilar artery occlusion, 386–389basilar artery sign, hyperdense, 217battered child, subdural hematoma, 190Beecher, Dr., 42, 44benzodiazepine, 234

overdose, 740–742causes of coma, 741ttreatment plan and prognosis, 741–742

Bergmann, P.S., 23, 24Bernoulli’s law, 5beta-blockers, 234Bickerstaff encephalitis, 193bihemispheric cortical injury, 85bihemispheric stroke, 383–385, 384

causes of, 384tbihemispheric syndrome pattern, 101, 102, 105bilateral diencephalic impairment, 15Bing, Lehrbuch der Nervenkrankheiten, 3binge drinking, 724bioethics. See law and bioethicsBiot breathing, 27, 28black hole, 471bladder care, 246blink reflex, 86, 87blinking, 82blood alcohol concentration, 724

effects, 725tblood glucose control, 232–233blood pressure, assessment of, 207blood transfusions, 207Boissier de Sauvages de Lacroix, François, Nosologia

methodica sistens morborum classes, genera et species, 3

bone metastases, hypercalcemia and, 638bradycardia, in neurologic examination, 90tbrain

common origins of metastases, 449hypertonic dehydration of, 635injury

anoxic-ischemic, 31and breathing rhythm, 27judging outcome after, 54

lateral displacement of, 18testing for absence of function, 294traumatic injury, 315–320, 318t

CT scans and MR example, 318treatment plan and prognosis, 319–320

tumors, tissue displacement from, 7–8brain abscess


brain biopsy, 514–518causes of coma, 515ttreatment plan and prognosis, 516–517

brain death, 38, 105

arguments against, 294classifying, 45clinical diagnosis of, 131–152clinical examination, 134–150, 135

bedside examination, 138–142prerequisites and confounding factors,

134–138code of practice for, 132–134confirmatory testing, 142–144, 144t, 146definition of, 42documentation of, 144–146family refusal to accept, 149–150first description, 41histopathology of, 200tneuropathology of, 199–201and organ procurement, 151–152pathophysiological response, 150–151percentage of moderate to severe neuronal

ischemic changes, 201pitfalls of confirmatory tests for, 143trejecting concept of, 291tests to diagnose, 136transition to, 292UK and US positions on, 45withdrawal of support after, 254

brain displacement syndromes, 100–107brain edema

from acute necrotizing encephalitis, 424, 425

ketotic hyperglycemia of, 625, 625brain herniation, 4–17

early historical landmarks, 5tpathology of, 195–197

brain tissue shiftCT images of, 162diagnostic imaging of, 160–168

brainstemabsence of reflexes, 139–140compression, 13displacement, 14

downward, 163from hemispheric infarct, 381lateral, 17, 348

emergent evaluation and care after injury, 211examination of function in neonates, 147–148hemorrhages in, 10histopathology in brain death, 200tinjury, 4–5

hypersynchronous EEG from, 64localized, 77

loss of reflexes, 45lower lesions, 29lymphomas, central neurogenic hyperventilation

from, 29monoaminergic nuclei, awake state and, 64syndromes, 105–106

770 / / INDEX

brainstem (Cont.)traumatic lesion, 327–329

causes of coma, 328tserial CT scan images, 329treatment plan and prognosis, 328

upper compression, 14–15brainstem anesthesia, 498brainstem auditory evoked potentials (BAEPs), 183brainstem death, 43brainstem reticular formation, stimulation of, 66brainstem stroke, 68breathing patterns, 27, 29

brain injury and rhythm of, 27clinical observations in neurologic exam,

94–95, 96tBremer, Frédéric, 62“Bremer’s cats,” 62Bright, R., 30British Medical Journal, 45bromocriptine, 234, 262, 265tBrophy, Paul Sr., 281brucellosis, 429bruxism, 235Buddhism, 291bulldog reflex, 116bypass surgery, coronary artery, 505–508

Cairns, R., 37–38, 63calcineurin inhibitor neurotoxicity, 501

MRI of abnormalities associated with, 502caloric testing, 98Candida albicans, oral infection, 235cannabis, 750tcarbon dioxide challenge, 140carbon dioxide, transcutaneous partial pressure

monitoring, 141carbon monoxide (CO) poisoning, 175, 194, 541–543

causes of coma, 542tmechanism of, 542preferential locations of MR lesions due to, 176ttreatment options for coma due to, 222ttreatment plan and prognosis, 543

cardiac arrhythmias, in neurologic examination, 88cardiac care, 240–243, 241, 242tcardiac surgery

causes of coma after, 506tCT scan after, 507

cardiac troponin, 242cardiomyopathy, stress, 241cardiopulmonary resuscitation (CPR), 31, 554–559

for accidental hypothermia, 539causes of coma after, 555tCT scan after, 556treatment plan and prognosis, 557–558

catatonia, acute, 757–758Catholic Church

on medical science, 290position on brain death, 293

cefepime toxicity, 708–710causes of coma, 709ttreatment plan and prognosis, 709–710

central brainstem displacement syndrome, 104, 106central herniation, 196

clinical signs, 16central nervous system (CNS)

infection, 215, 221–223, 401causes of coma, 438tfungal, 432pathology characteristics, 193

lymphoma, 445–447, 447causes of coma, 446ttreatment plan and prognosis, 446–447

vasculitis, 656–659, 659causes of coma, 657ttreatment plan and prognosis, 658–659

central neurogenic hyperventilation, 27, 29central spinal fluid (CSF), abnormalities, 50–51central syndrome, 15cephalosporin-resistant Escherichia coli, 231cerebellar hemorrhage, 17

suggestions to surgically manage, 364cerebellar herniation, 7cerebellar infaret, 506cerebellar tonsillar herniation, 170cerebellum, 186

histopathology in brain death, 200tcerebral aneurysm

endovascular coiling, causes of coma, 533truptured, clipping of, 527–530treatment plan and prognosis, 533–534

cerebral angiogram, 145t, 523–525, 525causes of coma after, 524ttreatment plan and prognosis, 524

cerebral angiographyfor brain death determination, 143for PVS, 120

cerebral artery, on contrast CT, 161cerebral blood flow, after resuscitation, 555cerebral cortex, 292cerebral edema, 217

hepatic encephalopathy and, 31cerebral hematoma, 165, 345–350


cerebral hemorrhage, 360–364, 362causes of coma, 361tintracranial lesions in, 5treatment plan and prognosis, 361–363

cerebral lupus, 652cerebral salt-wasting syndrome, 629cerebral spinal fluid (CSF) hypotension, 483–485cerebral tumor, 453

INDEX / / 771

cerebral vasoconstriction, fulminant, 692–695cerebral vasodilation hypothesis, 592cerebral venous thrombosis, 372–376

causes of coma, 373conditions associated with, 375in puerperium, 697–698treatment plan and prognosis, 374–376

cerebritis, 652cerebrospinal fluid (CSF) polymerase chain

reaction (PSR), 406cervical spine injuries, 551Charcot, J.M., 32, 33–34, 35chemo brain, 701chemotherapy

causes of coma, 703ttoxicity, 701–704treatment plan and prognosis, 703

Cheyne-Stokes respiration (CSR), 27, 28, 95chikungunya, 430childbirth, acute coma after, 226children

dehydrated brain in, 635diagnosis of brain death in, 147–150salicylate overdose in, 733

chronic liver disease, 596–599, 598causes of coma, 597tmanagement of patient, 599treatment plan and prognosis, 598–599

chronic obstructive pulmonary disease (COPD), 238cinema, perspective on coma from, 307–308, 308tcirculation, assessment of, 207CJD (Creutzfeldt-Jakob disease), 752–755

diagnostic criteria, 753clinical diagnosis, 205–227

neuroimaging interpretationCT scan abnormal findings, 210–215CT scan normal findings, 215–216

neurologic examination, 209–210questions to family, 208–209respiratory and hemodynamic stabilization,

206–208in various hospital locations, 216–226

emergency department, 217–223ICU, 223–225on the ward, 225–226

clonidine, 234Clostridium difficile, 230cluster breathing, 29, 95CMV (cytomegalovirus encephalitis), 192CNS. See central nervous system (CNS)CO poisoning. See carbon monoxide (CO)

poisoningcode of practice, for brain death, 132–134coenzyme Q10, 685Collier, J., 7, 24coma

awakening from, 111, 260classifying, 43, 47–53, 216tclinical signs, 21–29

breathing patterns, 27, 29decerebrate rigidity, 21–23fixed dilated pupil, 23–26vestibular ocular reflex, 26–27

determining cause of, 101early descriptions, 3–4emergent evaluation and care of patient, 214prognostication of, 53–55prolonged states, 35–47

coma scales, 89–94. See also Glasgow Coma Scaleideal, 90

coma vigile, 35communicating hydrocephalus, 478, 480tcommunication with family, 229, 249–253compresseur ovarien, 35Cone, W.V., 11–12, 25Conference of Royal College of Physicians, 43confusional state, acute, 83conjugate gaze deviation, 98consciousness, 60. See also prolonged impaired

consciousnessdisorders of, 3propofol induced loss of, 70

continuous positive airway pressure- pressure support (CPAP/PS) ventilation, 235

contractures, 262contrast toxicity, 524conversion disorder, 762–765convulsive status epilepticus, 487–491

treatment plan and prognosis, 489–490cooling methods for patients, 234cornea reflex, 87coronary artery bypass surgery, 505–508

treatment plan and prognosis, 508cortex, histopathology in brain death, 200tcortical function, 45cortical injury, bihemispheric, 85corticosteroids, 212

for CNS lymphoma, 446cough reflex, 87, 88CPR. See cardiopulmonary resuscitation (CPR)cranial nerve examination, 95–99craniotomy, 514–518


Creutzfeldt-Jakob disease (CJD), 752–755diagnostic criteria, 753

Cruz, Gloria, 305Cruzan, Nancy, 281–282cryptococcal meningitis, 652Cryptococcus, 438Cryptococcus neoformans, 438tcrystal methamphetamine, 749t

772 / / INDEX

CT scanof air embolization, 575tof brain, 156, 157

reading guide, 158tfor breath death assessment, 136impact, 4ischemic hemisphere swelling, 163of multiple shear lesions, 174for persistent vegetative state, 120of profound cerebral atrophy with ventricular

dilation, 120cultural differences, 289cuneus, 70, 78Cushing, H., 5, 7, 19, 19–20, 20Cushing’s law, 19cyproheptadine, 721cytomegalovirus encephalitis (CMV), 192

Dawson fingers, 471DCD (donation after cardiac death) protocols,

295–296decerebrate posturing, 50

vs. spinal reflexes or responses, 139decubitus ulcers, 246, 248, 249

description, 248tdeep brain stimulation, 75, 268deep vein thrombosis (DVT), 246–247default mode network (DMN), 122delirium, 83dementing illness, acute, causes of coma, 753tLes démoniaques dans l’art (Charcot and Richer), 32,

33–34, 35demyelination, 172, 193–194

osmotic, 474–476Descotes, J., 38–39desipramine, 265dexamethasone, 212, 392–393dexmedetomidine, 75, 234diabetes insipidus, 150

management of, in organ procurement, 151diabetic ketoacidosis (DKA), 624diazepam, 740diencephalon, histopathology in brain

death, 200tdiffuse encephalopathies, mechanisms of,

29–32dilated pupils, fixed, 23–26Disability Rating Scale, 272, 273tdisconjugate ocular responses, 26disconnection syndrome, 70dissection, aorta, 615–617disseminated encephalomyelitis, acute (ADEM),

193, 465–568causes of coma, 466ttreatment plan and prognosis, 467–468triggers, 466t

disseminated necrotizing leukoencephalopathy, 172dissociative agents, treatment options for coma due

to, 222tDKA (diabetic ketoacidosis), 624

diagnostic criteria, 625tDMN (default mode network), 112Dockary, Gary, 302doll’s eye response, 98dopamine, 70, 74

involved with awake state, 72dopaminergic agents, 265tdorsal attention network, 122dorsal pathway, 64

awake state involvement, 67drowsiness, 84drug-induced coma, 221

clinical neurologic signs in, 210tdrug screens, 137drugs

elimination half-life for, 137physical signs in comatose patient indicating

toxicity, 90tfor transport or induction of intubation,

clearance, 209tdry skin, in neurologic examination, 90tDunlap, Zach, 305Duret, H., 5Duret’s thesis, on brainstem lesions, 6

ear, water flushing of, 99eclampsia, 226, 698, 699ECMO (extracorporeal membrane oxygenation),

509–512causes of coma, 512tinjury after, 510treatment plan and prognosis, 512

ecstasy, 747EEG (electroencephalography), 146, 156

of assessment of encephalopathies, 176of awake state, 68continuous monitoring, 182–183evoked potentials, 183–184grading scale in coma, 178tisoelectric or low-voltage, 38, 40normal, 175patterns in coma, 176–182for sleep/awake mechanisms, 61

electrical stimulation, 267–269elimination half-life, for drugs, 137emergency department

coma in, 217–223CT scan review, 217–218EEG limitations, 220–221neurologic examination review, 217toxidromes, 218, 219, 220

MRI in, 218

INDEX / / 773

empyema, 401–403causes of coma, 403ttreatment plan and prognosis, 403

encephalitisacute necrotizing, 423–424autoimmune, 461–464EEG in diagnosis, 181herpes simplex, 405–409

in CT scan, 407MRI of, 408treatment plan and prognosis, 408–409

microscopy of, 192mumps, 419–422Nipah, 430paraneoplastic limbic, 456–460


rabies, 415–418causes of coma, 417ttreatment plan and prognosis, 417–418

encephalomyelitis, acute disseminated, 465–568encephalopathies

EEG changes, 177thepatic, 31mechanisms of metabolic and diffuse, 29–32multifactorial, 709septic, 607–608

encephalopathy syndrome, posterior reversible, 172, 215

end-stage renal disease, 581endocarditis, 611–614

treatment plan and prognosis, 613endotracheal intubation, 94endovascular treatment, 531–534, 532Enterobacter species, 230Enterococcus faecalis, 230Enterococcus spp., 246epidural empyema, 157epidural hematoma, 337

acute, 336–338causes of coma, 337ttreatment plan and prognosis, 338

epilepsy surgery, 519–522causes of coma, 521treatment plan and prognosis, 520, 522

Escherichia coli, 246cephalosporin-resistant, 231

esmolol, 209tethanol intoxication, 221Ethelberg, S., 26ethics. See law and bioethicsethylene glycol, 176t

causes of coma, 730tethylene glycol ingestion, 221, 728–730

indications for hemodialysis in deteriorating patients, 730t

ethylene glycol overdose, treatment plan and prognosis, 730

etomidate, 209tEuropean Society of Intensive Care Medicine, 182extracorporeal membrane oxygenation (ECMO),

509–512causes of coma, 512tinjury after, 510treatment plan and prognosis, 512

extubation, 254eye movements, 98, 126

abnormalities in coma, 100tin locked-in syndrome, 106in persistent vegetative state, 114spontaneous abnormalities, 99

failure to awaken after surgery, 223–224, 497family

communication with, 229, 249–253questions for, 208–209

family conference, 251fat embolism, causes of coma after, 570tfat embolism syndrome, 569–572fat embolization, criteria for, 571tfatal alcohol intoxication, acute, 195feeding tube, court case on, 284–285fentanyl, 209t, 562fever, 233, 545

in neurologic examination, 88Fisher-Brügge, E., 25Fisher, C.M., 17, 50–51, 84fluid attenuated inversion recovery (FLAIR), 159fluid compartment collapse, schematic

representation, 627flumazenil, 221, 741–742fMRI. See functional MRI (fMRI)Foley, J.M., 31, 32fomepizole, 730FOUR (Full Outline of UnResponsiveness) score,

84, 92, 93, 94, 101francisella tularensis, 428French, 64

experimental lesion studies, 65Friede, R.L., 10full recovery from prolonged coma, 112fulminant cerebral vasoconstriction,

692–695causes of coma, 694t

fulminant hepatic failure, 591–594, 593causes of coma, 592ttreatment plan and prognosis, 592–593

fulminant multiple sclerosis, 470–473causes of coma, 471ttreatment plan and prognosis, 472–473

functional anatomy, 85–88pathways, 87

774 / / INDEX

functional independence measure (FIM) instrument, 271t

functional MRI (fMRI), 70, 121in MCS and PVS, compared with control, 123

fungal infections, 432

gabapentin, 234gag reflex, 140

oropharyngeal function testing with, 99gamma-amino butyric acid (GABA), 71

alcohol and, 723gamma-hydroxybutyrate (GHB), 749tganglionic hemorrhage, 187gastrointestinal care, 243–244, 244tgeneralized periodic epileptiform discharges

(GPEDs), 177–178, 179Glasgow Coma Scale, 84, 91, 92t

vs. FOUR score, 94Glasgow Group, 54–55glioblastoma multiforme, 442gliomatosis cerebri, 453–454, 455

causes of coma, 454tglutamate, 71glutamine, 31Goulon, M., 39–41, 42GPEDs. See generalized periodic epileptiform

discharges (GPEDs)Graeb scale, 353tgrimacing, 114, 116Groeneveld, A., 7gulutamine-ammonia hypothesis, 592gunshot wounds, 322–325

causes of coma, 323tneurosurgical options, 325treatment plan and prognosis, 323

H1N1 infection, radiographic images of, 413H1N1 influenza, 411–414

treatment plan and prognosis, 412, 414Hallervorden-Spatz disease, 171Hammond, Treatise on Diseases of the Nervous System, 3hand sanitizer, ethyl glycol in, 728hanging, intentional, 565Harvard Medical School, 61

Ad Hoc Committee, 42, 44Hashimoto’s encephalopathy, 603, 604, 605thead tilt, 51heat illness risk assessment chart, 546heatstroke, 545–548

causes of coma, 546tcooling methods for patients, 547treatment plan and prognosis, 547

hematomaacute epidural, 336–338


acute subdural, 340–343causes of coma, 342tCT scan, 341evacuation, 342

cerebral, 345–350causes of coma, 346ttreatment plan and prognosis, 346–347

destructive thalamus, 347enlarging in anticoagulated patient, 348putaminal, 348

hemicraniectomy, decompressive, 380hemispheric stroke

causes of coma, 379treatment plan and prognosis, 379

hemodynamic stabilization, 206–208hemoglobin level, 207hemorrhage, 186–188

aneurysmal subarachnoid, 118at brain biopsy site, 515, 516–517cerebellar, 17

suggestions to surgically manage, 364cerebral, 360–364, 362

causes of coma, 361tintracranial lesions in, 5treatment plan and prognosis, 361–363

intracranial, 226intraventricular, 352–355


pontine, 356–358causes of coma, 357ttreatment plan and prognosis, 357–358

hemorrhagic border zone infarct, 187hemorrhagic infarct, 167hemorrhagic leukoencephalitis, acute, 412hemorrhagic necrosis, 433heparin, 247heparin-induced thrombocytopenia (HIT)

syndrome, 662–663hepatic encephalopathy, 31

stages, 597hepatic failure, fulminant, 591–594herniation, 108heroin, 736

bioconversion, 737theoretical model of intoxicating and

lethal, 737herpes simplex encephalitis, 191–192, 405–409

causes of coma, 406tin CT scan, 407MRI of, 408treatment plan and prognosis, 408–409

herpes simplex virus (HVS), 424herpes virus, reactivation, 437hesmipheric stroke, 378–382Heymans, C., 31

INDEX / / 775

HHS (hyperosmotic hyperglycemic state), 624diagnostic criteria, 625t

high-grade astrocytoma, 441–444causes of coma, 442ttreatment plan and prognosis,

442–443higher brain death, 45Hill, L., 19Hinduism, 291hippocampal system, 60

herniation of gyrus of, 13histamine, 70histaminergic cells, 75histopathology in brain death, 200thistoplasmosis, of central nervous system, 399Historiae apoplecticorum (Wepfer), 3HIT (heparin-induced thrombocytopenia)

syndrome, 662–663holiday heart syndrome, 724Horner’s syndrome, 97Howell, D.A., 13, 14–15human herpesvirus HHV -6, 424human life, view of sanctity of, 289Hurst’s disease, 412, 424Hutchinson, Jonathan, 24HVS (herpes simplex virus), 424hydrocephalus, 211, 403, 481

acute, 478–482causes, 480tcauses of coma, 479t

after surgical repair of aneurysm, 528thydrophobia, 416hyperammonemia, 675–676

treatment, 222thyperammonemia encephalopathy, causes of coma,

676hyperbaric chamber protocol, 575hyperbaric oxygen therapy, 268–269hypercalcemia

causes, 639tstrategies to treat, 640ttreatment, 222ttreatment plan and prognosis, 639–640

hypercalcemic crisis, 638–640causes of coma, 639t

hypercapnia, 319, 574, 642–644causes of coma, 643, 644tand MELAS, 684treatment plan and prognosis, 644

hypercarbic respiratory failure, acute, 225hyperdensity, on CT, 157hyperglycemia, 30–31, 506, 623–627

causes of coma, 624ttreatment, 222ttreatment plan and prognosis, 626

hyperglycemic coma, initial management, 627t

hyperglycemic hyperosmolar nonketotic syndrome, 626

hypermetamorphosis, 118hypernatremia, 475, 634–637

causes, 636tcauses of coma, 635Itformulas for use in managing, 636ttreatment plan and prognosis, 636–637

hyperosmotic hyperglycemic state (HHS), 624diagnostic criteria, 625t

hypersomnia, 82–83hypertension, 207

arterial, 21in neurologic examination, 88, 90tnormal CT scan and, 220t

hypertensive crisis, 585–589causes of coma, 586tconditions associated with, 587ttreatment plan and prognosis, 588–589

hypertensive encephalopathy, conditions associated with, 587t

hyperthermia, in neurologic examination, 90thyperthyroidism (thyroid storm), 605thypertonic saline, 212hyperventilation, 212

central neurogenic, 27, 29in neurologic examination, 90t

hypocapnia, 319hypodensity, on CT, 157hypoglycemia, 175, 619–621

alcohol-induced, 725t, 726and the brain, 620causes of coma, 620ttreatment, 222ttreatment plan and prognosis, 621

hypoglycemic agents, treatment options for coma due to, 222t

hyponatremia, 475, 629–632causes of coma, 630tformulas for use in managing, 630trecommendations for correction, 476ttreatment, 222ttreatment plan and prognosis, 631

hypophosphatemia, 225hypotension, 207

CSF, 483–485in neurologic examination, 88, 90t

hypothalamus, posteriorawake state and, 64neurotransmitters in, 75

hypothermia, 137, 207, 536–539after near-drowning, 549algorithm of management, 539causes of coma in, 537tclassification, 538tinduced, 557, 559

776 / / INDEX

hypothermia (Cont.)in neurologic examination, 88, 90ttherapeutic, 561–563treatment plan and prognosis, 538, 539

hypothyroidism, 601, 602clinical features, 602

hypothyroidism (myxedema coma), 605thypoventilation

coma from, 225in neurologic examination, 90t

hypoxemia, 184–186, 549from air embolization, 574from CO poisoning, 542

iatrogenic gas embolization, 573idiogenic osmoles, 31idiopathic recurrent stupor, 741–742immunosuppressive drugs after transplantation, 437indomethacin, 212infarction, 186–188infection, 190–193

control, 230–232infective endocarditis, 611

causes of coma, 612tinfluenza encephalitis, causes of coma, 414tinfluenza, H1N1, 411–414infratentorial empyema, 402infusate, characteristics, 632tinhalants, treatment options for coma due to, 222tinjury severity score (ISS), 316tinsomnia, serotonin depletion and, 74Institute of Neurological Sciences (Glasgow), 35intensive care unit (ICU), coma consultation, 76,

223–225intentional hanging, 565Internet, coma information from, 306–307intoxication, 218, 219, 220. See also toxins

managing with supportive care, 221intracranial hemorrhage, 226intracranial pressure (ICP)

increased, 10managing, 211–212options for treating, 213role of, 18–21

in neurologic examination, 88intrathecal baclofen overdose, 705–707

treatment plan and prognosis, 706–707intraventricular hemorrhage (IVH), 352–355

causes of coma, 354tin neonate, 688treatment plan and prognosis, 354–355

intrinsic brainstem syndrome, 102, 105intubation, 206ischemia, 184–186, 555

MRI showing, 556ischemic-hypoxic brain injury, prognosis, 54

ischemic lesions, 185ischemic stroke

cardiac surgery and, 506vs. herpes simplex encephalitis, 406

isoelectric EEG, 38, 40isolation guidelines, for infections, 232IVH. See intraventricular hemorrhage (IVH)

Jainism, 291jaundice, 31Jefferson, Geoffrey, 8, 10Jennett, Bryan, 25, 35, 53, 84Jobes, Nancy, 280–281Johnson, R.T., 14Jouvet, M., 38–39Judaism, 290–291juvenile Huntington’s disease, 171

Kernohan, J.W., 7Kernohan-Woltman syndrome, 8Kernohan’s notch, 8ketamine, 73, 209t, 749tketoacidosis, 623ketones, 220kidney disease, end-stage, 581kidney failure, 175

treatment, 222tKlebsiella pneumoniae, 230Klebsiella spp., 246Klingon, G.H., 26Das Klivus Kanten Syndrome, 25Kocher, Theodor, 19, 20–21Korein, J., 51Kretschmer, E., 35KULT mnemonic, 218

L-arginine, 685lamotrigine, 265Langfitt, T.W., 21lateral brainstem displacement syndrome, 103,

104, 106law and bioethics, 278–296

court cases, 279–289Brophy case, 281Cruzan case, 281–282Jobes case, 280–281lessons learned, 286–288Quinlan case, 279, 286Schiavo case, 283–286, 287tWendland case, 283

ethics, 289–294coma as bioethical controversy, 291–294

in organ donation, 294–296withdrawal of support, 288–289

Lazarus phenomenon, 295Leach, B.G., 54

INDEX / / 777

Legallois, J.J.C., 27leukemia, acute, 666–669leukoencephalitis, acute hemorrhagic, 412leukoencephalopathies

in demyelinated tissue, 193leukoencephalopathy

acutein demyelinated tissue, 193MR image, 172, 173

from chemotherapy, 701disseminated necrotizing, 172

Levine, D.E., 31levodopa/carbidopa, 265tlevofloxacin, 230Levy algorithms, 54lidocaine, 209tlight reflex, 87limbic encephalitis, paraneoplastic, 456–460limbic system, 60Lindsley, D.B., 64Listeria, 438Listeria monocytogenes, 438tlithium toxicity, 743–745

causes of coma, 744ttreatment algorithm, 745treatment plan and prognosis, 744–745

liver disease, chronic, 596–599liver failure, 175

from acetaminophen overdose, 711–713localization, 21–29, 81, 100locked-in syndrome, 45, 82, 92, 103, 106locus coeruleus, noradrenergic neurons located in,

73locus minoris resistentiae, 10lorazepam, 209t, 740low-voltage EEG, 38lumbar puncture, damage from, 5lung injury, mechanism based on fluid aspiration, 550lymphoblastic leukemia (ALL), acute, 666lymphoma, central nervous system (CNS), 445lysergic acid diethylamide (LSD), 749t

Macewen, William, 24Mack, David, 302magnetic resonance angiography, 159Magnus-De Kleijn tonic neck reflex, 24Magoun, H.W., 61, 63malignant catatonia, 757–760

algorithm for the treatment, 760causes of coma, 759ttreatment plan and prognosis, 759–760

mannitol, 212Marekwald, M., 29massive ganglionic hematoma, 164mathematical calculations, for outcome prediction,

54–55

McNealy, D.E., 15, 16MCS. See minimally conscious state (MCS)MDMA (3,4-methylamphetamine), 747media on coma

cinema, 307–308, 308tInternet, 306–307news writing, 299–300newspaper coverage, 301–304television, 304–306

medical care, 229–255supportive care, 230–248

airway and pulmonary care, 235–240bladder care, 246blood glucose control, 232–233bowel care regimen, 244cardiac care, 240–243, 241, 242tcirculation care, 243complications of immobilization, 246–248daily concerns, 231teye and mouth care, 234–235gastrointestinal care, 243–244, 244tinfection control, 230–232systemic approach, 230temperature control, 233–234

withdrawal of support, 253–255medical science, Catholic Church on, 290medical wards, coma in, 225–226medulla oblongata, 293

function testing, 38medullary collapse, 21medullary compression, stages of, 20–21MELAS, 683–686, 685

causes of coma, 684tmechanism, 685treatment plan and prognosis, 685

meningitisbacterial, 391–394cryptoccoccal, 652tuberculous, breathing patterns, 27tularemia, 428from zoonosis, 428

meningoencephalitis, 218mumps, 420from zoonosis, 428

mesencephaloncompression or ischemia of, 25destructive hematoma with extension

into, 347distortion of, 106

metabolic acidosis, 137metabolic disturbances

neuroimaging in, 175treatment options for coma due to, 222t

metabolic encephalopathies, mechanisms of, 29–30

metadoxine, 726

778 / / INDEX

metastasis, 449–450, 451causes of coma, 450ttreatment plan and prognosis, 450

methadone, 737methanol, 176tmethicillin-resistant Staphylococcus aureus, 231methotrexate therapy, 4463-4 methylenedioxy-methylamphetemine

(MDMA, ecstasy), 749tmethylenedioxymethamphetamine, treatment

options for coma due to, 222tmetrics, in neurorehabilitation, 269–272metronidazole, 230Meyer, Adolph, 7microorganisms, antibiotic-resistant, 232tmidazolam, 207, 490, 740middle ear infection, 402Milwaukee protocol, 417–418minimally conscious state (MCS), 38, 112,

116–119, 291criteria for, 117vs. persistent vegetative state, 118

miosis, 97miracles, 289modafinil, 74Mollaret, P., 39–41, 42monoaminergic systems, VLPO and, 74Moore, M., 10Morison, R.S., 61, 63mortality, from untreated infections, 125Moruzzi, G., 61, 63motor imagery, 122–123mouth, inspection, 99MR FLAIR imaging, 172MRI, 4, 156, 159, 164–165

of displacement of brainstem, 168of downward displacement, 169horizontal shift in, 167ischemic injury after cardiac surgery, 507orienting lines in, 165, 165–166postbiopsy, 516prebiopsy, 516in PVS, 121of rabies encephalitis, 417reading guide of, 161t

MRSA pneumonia, 239multifactorial encephalopathy, 709multiple sclerosis

demyelination in, 193fulminant, 470–473

mumps encephalitis, 419–422causes of coma, 421ttreatment plan and prognosis, 420

muscle shortening, 262music therapy, 267Muslim beliefs, 291

mutism, akinetic, 37, 77, 118–119, 282causes, 119t

mycophenolate mofetil, 501mycotic infections, 193mydriasis, 97myelogenous leukemia

acute, 666classification, 669

causes of coma, 667ttreatment plan and prognosis, 667, 669

myocardial function, and brain death, 150myocardium, damage to, 240myoclonus status epilepticus, 105myoinositol, 31myxedema coma. See also hypothyroidism

(myxedema coma)treatment, 222t

N-methyl-D-aspartate (NMDA), 723N-methyl-D-aspartate (NMDA) receptors,

ketamine block of, 73naloxone, 208, 221, 737Nathenson, M., 26National Institute of Health (NIH) Stroke scale, 378National Institutes of Neurologic Disorders

and Stroke (NINCDS)Multicenter Collaborative Study on Cerebral Death, 46

near-drowning, 549–552causes of coma, 550tfactors predictive of death or survival, 552ttreatment plan and prognosis, 551

near-hanging, 565–567causes of coma, 567ttreatment plan and prognosis, 566–567

neck, abnormal tonic reflex, 23necrotizing encephalitis

acute, 423–424causes of coma, 424ttreatment plan and prognosis, 424

necrotizing leukoencephalopathy, disseminated, 172

Negovsky, V.A., 31neocortical death, 35neonate, 688neuroaspergillosis, 432–434


neurogenic stress cardiomyopathy, 240neuroimaging, 156, 157–175

interpretation of abnormal CT scan findings, 210–215

neurologic disease, zoonosis causing, 428tneurologic examination, 81–108

clinical examination, 84–100coma scales and FOUR score, 89–94physical examination, 88–89

INDEX / / 779

clinical observations, 94–100breathing patterns, 94–95, 96tcranial nerve examination, 95–99spontaneous movements, 100

definitions, 82–84Neurologic Examiniation of the Comatose Patient

(Fisher), 50neuron-specific enolase (NSE), in septic patients, 609neuropathology of coma, 184neurophysiology of coma, 175–184neurorehabilitation, 269–274

metrics, 269–272neurotoxicity, 194–195neurotransmitter pathways, 70, 71

involved with awake state, 71–73neurotransmitters, 70new variant Creutzfeldt-Jakob disease (nvCJD),

diagnostic criteria, 754tnews writing, coma information from, 299–300newspaper coverage, of coma, 301–304Nipah encephalitis, 430NMDA encephalitis, causes of coma, 462tNocardia asteroides, 438tnocardiosis, 436–439

treatment plan and prognosis, 439nociception (pain) pathways, 68nonconvulsive status epilepticus, 367, 406, 488,

492–495causes of coma, 493tEEG of, 494ttreatment plan and prognosis, 495

norepinephrine, 70involved with awake state, 72

nosocomial pneumonia, 237–238criteria for, 238t

noxious stimuli, 89–90, 90, 138–139NSE (neuron-specific enolase), 609nuclear scan, 146nursing home, vs. rehabilitation center, 251nutrition, termination of, 282nvCJD (new variant Creutzfeldt-Jakob disease),

diagnostic criteria, 754t

obstructive hydrocephalus, 478, 480tocular dipping, 99ocular motor function, disturbances of, 14ocular signs, 50oculovestibular reflex, 26–27, 86, 87odor, in neurologic examination, 90topiates, treatment options for coma due to, 222topioid overdose, 736–738


optimism, in physicians, 252orexin-hypocretin, 70organ donation, 148

organ failure, MRI of major effects, 175organ procurement protocol, 152torgan transplantation, 291, 500–504

causes of coma, 502tChristian views on, 290ethics in, 294–296failure to awaken after, 224treatment plan and prognosis, 503–504

organic mercury poisoning, 176torganophosphates, treatment options for coma due

to, 222tornithine transcarbamylase (OTC) deficiency, 675,

676, 684oropharyngeal function, testing, 99, 140Osborn waves, 537Osler, W., 29, 30, 299osmotic demyelination, 474–476, 476


oxycodone, 738oxygen desaturation, 206

Page, I.H., 21pain, perception of, 53Pallis, C., 45, 51palsy, upward gaze, 14papilledema, 98paraneoplastic disorders, 458tparaneoplastic limbic encephalitis, 456–460


paratonia, 15paroxysmal hyperactivity syndrome, 416paroxysmal sympathetic hyperactivity (PSH)

syndrome, 233–234patient wishes, prior statements as evidence, 281PBG (porphobilinogen) deaminase, partial

deficiency, 670PCP (phencyclidine), 749tpeduncle V-shaped indentation, description, 9, 10penicillin, toxicity, 708pentobarbital, 489–490percutaneous dilatory tracheostomy (PDT), 236percutaneous endoscopic gastrostomy (PEG) tube,

243, 245pergolide, 265tperiodic alternating gaze, 99periodic breathing patterns, 27periodic lateralized epileptiform discharges

(PLEDs), 177, 179persistent vegetative state (PVS), 35, 37, 45, 51, 53,

111–112, 113–116, 250attorneys’ critique of neurologists in court cases,

288tcontractures in patients in, 262court case on, 280–281

780 / / INDEX

persistent vegetative state (PVS) (Cont.)diagnostic criteria, 114tEEG in, 119electrodes implanted in cervical spinal cord

to treat, 268ethics and, 294examining patients with, 86vs. minimally conscious state, 118pathological changes, 197–199pathology of, 199patient examination, 115tprediction of outcome, 124–126, 125t

PET (positron emission tomography), 121pharmaceutical interventions, 262–266phencyclidine (PCP), 749tphenytoin, 717physical examination, neurologic, 88–89physiotherapy, 262, 263–264pineal gland, displacement of, 171ping-pong gaze, 99pinpoint pupils, 86pituitary adenoma, 646–647pituitary apoplexy, 603, 646–649

causes of coma, 647tclinical features, 648MRI, 647treatment, 222ttreatment plan and prognosis, 648

pituitary function, deterioration of, 150pituitary, histopathology in brain death, 200tpituitary hormone replacement, 649tPius XII (pope), 42place, disorientation in, 83PLEDs (periodic lateralized epileptiform

discharges), 177, 179Plum, F., 15, 16, 24, 27, 29, 35, 47, 49, 83pneumonia

aspiration, 230MRSA, 239nosocomial, 237–238

criteria for, 238tpoisoning. See also toxins

coma due to, 194pons

displacement of, 170osmotic demyelination in, 194

pontine hemorrhage, 187, 356–358causes of coma, 357ttreatment plan and prognosis, 357–358

porphobilinogen (PBG) deaminase, partial deficiency, 670

porphyriaacute, 670–673causes of coma, 673t

positron emission tomography (PET), in PVS, 121Posner, J.B., 24, 29, 47, 49, 83

post resuscitation disease, 31posterior cingulate/precuneus, 122posterior hypothalamus

awake state and, 64neurotransmitters in, 75

posterior reversible encephalopathy syndrome (PRES), 172, 215, 585

postpartum cerebral vasoconstriction syndrome, 693prayer, 289precuneus, 78prefrontal cortex, 60pregnancy

arteriovenous malformation (AVM) rupture, 696–697

brain death during, 149causes of coma, 698tmajor neurologic complications, 699t

PRES. See also posterior reversible encephalopathy syndrome (PRES)

President’s Council on Bioethics, 293pressure cone, temporal, 10preterm newborn, 688–691

causes of coma, 689tprolonged impaired consciousness

categories of outcome, 112–113, 113clinical diagnosis, 111–127laboratory investigations, 119–124

propofol, 73, 209t, 212, 489, 562Proteus spp., 246proton-emission tomography (PET), for brain

neuronal activity study, 70Pseudomonas aeruginosa, 230, 246psychiatric medications, treatment options for

coma due to, 222tpsychogenic coma, examination, 763psychogenic unresponsiveness, 32–35, 223, 762

causes, 764tpuerperium, 696–699pulmonary edema, 239pulmonary emboli, 246pulmonary function

and brain death, 150supportive care, 235–240

pupilsabnormalities in neurologic exam, 96, 97, 98activity, 14in brain death assessment, 139changes, intracranial pressure and, 11–12, 11–12fixed dilated, 23–26light reflex, 86

putaminal hematoma, 348PVS. See persistent vegetative state (PVS)

quality of life, 283Quinlan, Karen Ann, 279, 286Qur’an, 291

INDEX / / 781

rabies encephalitis, 415–418causes of coma, 417ttreatment plan and prognosis, 417–418

range of motion, exercises to maintain, 262rapid dementing illness, 752–755rapid eye movement (REM) sleep, 64, 68, 119rave party

causes of coma after, 748circumstances of, 748comatose after, 747–750drugs associated, 749t–750t

recanalization, after basilar artery occlusion, 387

recovery and rehabilitation, 260–274early interventions, 261–269

electrical stimulation, 267–269pharmaceutical interventions, 262–266physiotherapy, 262, 263–264stimulation programs, 266–267

four major pillars of, 270neurorehabilitation, 269–274

metrics, 269–272technology and new options, 272, 274

recovery roomcauses of coma in, 498tcoma in, 496–499

red dead neurons, 185red nuclei displacement, 168refractory status epilepticus, 463Reid, W.L., 11–12, 25religion

differences, 289role of, 252

REM (rapid eye movement) sleep, 64, 68, 119renal disease, end-stage, 581renal failure, 175

treatment, 222trespiration, 49respirator brain, 38respiratory acidosis, 38, 137, 643respiratory drive, absence of, 140respiratory stabilization, 206–208resting state networks, 122resuscitation. See cardiopulmonary

resuscitation (CPR)reversible cerebral vasoconstriction syndrome,

factors associated with, 693treversible encephalopathy syndrome, posterior,

172, 215reversible posterior leukoencephalopathy syndrome,

antineoplastic agents associated with, 702trhabdomyolysis, hypernatremia and, 635Richer, Paul, 32, 33–34, 35rigidity, 21–23rocuronium, 209tRoessmann, U., 10

Romberg, Lehrbuch der nerven krankheiten des menschen, 3

Ropper, A.H., 26Ropper, Allan H., 17, 18Rosner, A., 13–14Rostan, L., 4rostrocaudal deterioration, 15rostrocaudal patterns, 49roving eyes, 98ruptured cerebral aneurysm, 531–534, 532

clipping of, 527–530, 529causes of coma, 528ttreatment plan and prognosis, 528

SAH (subarachnoid hemorrhage), aneurysmal, 118, 366–370

causes of coma, 367salicylate overdose, 220, 732–733

causes of coma, 733tflowchart for management, 734treatment plan and prognosis, 733

Scantlin, Sarah, 302Schaltenbrand, G., 7Schiavo, Theresa Marie, 117, 283–286, 287t

website on, 306Schwarz, G., 13–14sedative-hypnotic agents, treatment options for

coma due to, 222tselective serotonin reuptake inhibitors (SSRIs)

overdose, 719–722causes of coma, 721ttreatment plan and prognosis, 721–722

selegiline, 265tself-awareness, 82semen retrieval, brain death and, 149sensory stimulation, 266sepsis, 125, 224–225, 607–610


septic encephalopathy, 607–608septicemia, 402

in near-drowned patient, 551septum pellucidum

CT scan of development, 160displacement of, 171

serotonin, 70, 74involved with awake state, 73

serotonin syndrome, 74, 720, 721t, 759mechanism, 720

shaken-impact syndrome, 331–334“black brain” associated with, 333causes of coma, 333tclinical signs, 332t

Sherrington, Charles, 21transection experiments, 22

Shewmon, D.A., 293

782 / / INDEX

shivering, 100Sikhism, 291SILENT (syndrome of irreversible

lithium-effectuated neurotoxicity), 745sirolimus, 501SIRPIDs (stimulus-induced rythmic, periodic, or

ictal discharges), 178skin appearance, in physical examination, 88–89SLE, diagnostic considerations, 655sleep, 68

research into mechanisms, 61sleep-wake cycles, in persistent vegetative state, 116somatic integration theory, 293somatosensory evoked potentials (SSEPs), 183sound, response in persistent vegetative state, 114spinal cord, histopathology in brain death, 200tspinal reflexes or responses, vs. decerebrate, 139spirituality, and health care, 289spontaneous intracranial hypotension syndrome,

causes of coma, 485tSSRI. See selective serotonin reuptake inhibitors

(SSRIs)Staphylococcus aureus, 230, 403

endocarditis, 611methicillin-resistant, 231

status asthmaticus, 577–580causes of coma, 578ttreatment plan and prognosis, 579–580

status epilepticuscauses of coma, 488tconvulsive, 487–490and MELAS, 684myoclonic, 557nonconvulsive, 367, 406, 492–495refractory, 463treatment options, 490ttypes, 488

Steegmann, A.T., 29Stern, K., 10, 25stimulus-induced rythmic, periodic, or ictal

discharges (SIRPIDs), 178stress cardiomyopathy, 241stroke, 378–382

bihemispheric, 383–385, 384causes of, 384t

brainstem, 70in pregnancy, 226

la stupeur hypertonique post-comateuse, 35stupor, 83–84

idiopathic recurrent, 741–742subarachnoid hemorrhage (SAH)

aneurysmal, 118, 366–370causes of coma, 367

subdural hematomaacute, 340–343

causes of coma, 342t

CT scan, 341evacuation, 342

CT scan, 484subfalcine herniation, 195succinylcholine, 209tsuicide

from acetaminophen overdose, 711attempts, 215by hanging, 566, 567

supportive care, 229supratentorial empyema, 402surgery

delayed awakening after, 496failure to awaken after, 497

surgical wards, coma in, 225–226Swanson, A.G., 27sweating, in neurologic examination, 90tsyndrome of irreversible lithium-effectuated

neurotoxicity (SILENT), 745systemic illness, physical signs in comatose patient

indicating, 90tsystemic lupus erythematosus, 651–655, 654

causes of coma, 652tmajor antibodies, 653ttreatment plan and prognosis, 653–654

T1-Weighted Imaging (T1WI), MRI Signal Intensity Characteristics of Substances on, 160t

T2-Weighted Imaging (T2WI), 160ttachycardia, in neurologic examination, 90ttacrolimus neurotoxicity, MRI characteristics of,

503taurine, 31Taylor, R.D., 21Teasdale, G., 84technology, 272, 274television, perspective on coma from, 304–306temozolomide, 442temperature control, 233–234temporal lobes, 60temporal pressure cone, 10tentorial groove, 9tentorial pressure cone, 10tentorium, pressure changes at, 14teratomas, 462thalamic compression, 98thalamic reticular nucleus, 68thalamus, 61, 77, 85

awake state and, 64compression of, 348destructive hematoma, 347distortion of, 106

thalamus-brainstem compression, types, 101thallium, poisoning with, 194theophylline, 578

INDEX / / 783

therapeutic hypothermia, 561–563causes of coma, 562effects, 563treatment plan and prognosis, 562–563

thiamine deficiency, 680thiopental, 209tthrombocytopenia,

acute, 662–665, 664causes of coma, 664t

thrombocytopenic purpura (TTP), 662–663thyroid disease, 601–605


thyroid function, deterioration of, 150thyroid storm (hyperthyroidism), 602

treatment, 222tthyrotoxic coma, 175tigecycline, 230time, disorientation in, 83toluene, 176ttonic neck reflex, 22, 24tonsillar herniation, 7, 197

diagnostic imaging of disorders, 168–175MRI document of, 168

toxidromes, 84, 219toxins, 175, 215. See also intoxication

antidotes for, 221chemotherapy as, 701–704coma due to, 194mechanisms, 501preferential locations of MR lesions due to, 176ttreatment options for coma due to, 222t

Toxoplasma gondii, 438ttracheostomy, 236, 237

percutaneous dilatory (PDT), 236transcranial direct current stimulation, 268transcranial Doppler ultrasonogram, 146transcutaneous carbon dioxide partial pressure

monitoring, 141transplant recipients. See also organ transplantation

cerebral Aspergillus infection, 433transtentorial herniation, 17trauma

contusions and subdural hematomas from, 188, 188–190

failure to awaken after, 224traumatic brain injury, 315–320

causes of coma, 318tCT scans and MR example, 318treatment plan and prognosis, 319–320

traumatic brainstem lesion, 327–329causes of coma, 328ttreatment plan and prognosis, 328

Treatise on Diseases of the Nervous System (Hammond), 3

trichloroethane, 176t

tricyclic antidepressant, 265overdose, 715–717


triphasic waves, 179in EEG, 177

TTP (thrombocytopenic purpura), 602–603tuberculosis, 193tuberculous meningitis, breathing pattern, 27tularemia meningitis, 428turpentine, 176tTwining line, 165–166

uncal herniation, 7, 17, 51, 195–196progression, 15

unconsciousness, 82search for associated lesions, 63

uncus, sagittal depressions of, 8Uniform Determination of Death Act, 133tupward gaze palsy, 14urea cycle disorder, 675–677


uremiaacute, 581–584


uremic coma, 30urinary tract, care of, 246, 246turine osmolality, 631urine sample, ethylene glycol crystal in, 729

vaccine, for mumps, 420Vaernet, K., 26vagal nerve, and blood pressure, 20Van Gehuchten, P., 10vancomycin, 230vancomycin-resistant enterococci (VRE), 231varicella zoster virus (VZV), 424vasculitis, classification, 658tvasospasm, on cerebral angiogram, 694vecuronium, 209tvegetative state. See persistent vegetative state (PVS)venous thrombosis. See cerebral venous thrombosisventilators

auto-cycling, 148weaning from, 235

ventral midbrain syndrome, 51ventral pathway, 64

awake state involvement, 67vestibular ocular reflex, 26–27vie vegetative, 35vignettes, introduction to, 313viral infections, 193visual orienting reflex, 114visual tracking, 87

784 / / INDEX

VLPO, 74Von Bergmann, E., 18–19von Economo, C., 61von Frerichs, F.A., 31VZV (varicella zoster virus), 424

wakeful unconscious state, 35wakefulness

neuroimaging studies of, 68, 70reduced, 82

waking center, 74Walker, A.E., 17Wallis, Terry, 302warfarin-associated thalamic hemorrhage, 162Wendland case, 117Wendland, Robert, 283Wepfer, Johann Jakob, Historiae apoplecticorum, 3Wernicke-Korsakoff syndrome, 195


Wernicke’s encephalopathy, treatment, 222tWertheimer, P., 38–39, 41white matter

changes in SLF, 653diagnostic imaging of disorders, 168–175

whole brain death, 45Willis, Thomas, De Anima Brutorum, 3Willoughby, J.O., 54withdrawal of support, 253–255

legal aspects, 288–289Wolman, L., 10Woltman, H.W., 7wounds, from gunshots, 322–325wrong-side pupil, 107

Yates, P.O., 14

zoonotic disease, 427–430causes of coma, 428ttreatment plan and prognosis, 430

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The comatose patient