Psychiatric aspects of traumatic brain injury

PSYCHIATRY IN THE MEDICALLY ILL 0193–953X/02 $15.00 � .00

PSYCHIATRIC ASPECTS OFTRAUMATIC BRAIN INJURY

Vani Rao, MD, and Constantine G. Lyketsos, MD, MHS

EPIDEMIOLOGY

Traumatic brain injury (TBI) is defined as brain damage secondaryto an externally inflicted trauma. It is an ongoing pandemic with anannual incidence of 2 million cases per year in the US.28 Of these,approximately 500,000 require hospitalization and 80,000 suffer fromchronic disability of some kind.28 TBI is the leading cause of death anddisability in people younger than 45 years of age, with an overallmortality rate of 25 deaths per 100,000. The age of peak incidence ofhead injury is 15 to 24 years, with males being injured two to threetimes more frequently than females.56, 99

Tables 180 and 255, 59 illustrate the causes and classification of headinjury. Advances in acute trauma care have improved survival signifi-cantly. This has led to a substantial increase in morbidity in patients who

Table 1. CAUSES OF HEAD INJURY

Causes Frequency (%)

Motor vehicle accidents � 50Falls 21Violence 12Sports or recreational activities � 10

Data from McAllister TW: Neuropsychiatric sequelae of head injuries. Psychiatr Clin North Am15:395–413, 1992.

From the Neuropsychiatry Service, Department of Psychiatry and Behavioral Sciences, TheJohns Hopkins University, School of Medicine, Baltimore, Maryland

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Table 2. CLASSIFICATION OF HEAD INJURY*

Test Mild Moderate Severe

Glasgow Coma Scale (GCS) 13–15 9–12 � 8Loss of consciousness (LOC) � 0.5 h 1–24 h � 24 hPosttraumatic amnesia (PTA) � 1 h 1–24 h � 24 h

*Severity of head injury can be classified by combining the GCS, LOC, and PTA.3 Other systemsof classification include use of GCS alone4 or use of LOC and PTA.5

Data from references 55 and 59.

survive TBI with psychiatric sequelae being central to their morbidity.Although physical disabilities typically stabilize with time, mood, cogni-tive, and behavior changes become the more disabling long-term impair-ments because they frustrate the patient, overwhelm the caregiver, andchallenge the physician. Despite the common occurrence of psychiatricdisorders following TBI, very little literature about their epidemiology,pathophysiology, and management is available. Almost no randomizedcontrolled studies about treatments for these psychiatric sequelae areavailable.

This article reviews the common psychiatric conditions associatedwith TBI, highlighting two features: (1) the link between psychiatry andTBI and (2) the existing gaps in the literature regarding these disorders.We begin with a discussion of the pathophysiology and recovery fromTBI. This is followed by classification of the psychiatric disorders associ-ated with TBI and approaches to the evaluation and diagnosis of post-TBI patients. We conclude with a discussion of the clinical features andtreatment of the psychiatric disorders.

PATHOPHYSIOLOGY AND RECOVERYFROM TRAUMATIC BRAIN INJURY

This section is divided into (1) pathophysiology of brain injury and(2) recovery from brain injury.

Pathophysiology of Brain Injury

Brain injury can be classified into two types, as follows:

A. Primary injury: direct impact of trauma1. Focal injury

a. Contusionb. Hematomac. Hemorrhaged. Hypoxic–ischemic injury

2. Diffuse injurya. Diffuse axonal injury (DAI)

PSYCHIATRIC ASPECTS OF TRAUMATIC BRAIN INJURY 45

b. Edemac. Hypoxic–ischemic injuryd. Diffuse vascular injury

B. Secondary injury: indirect trauma related factors1. Hypoxia2. Anemia3. Metabolic abnormalities4. Fat embolism5. Release of excitatory amino acids6. Release of oxidative free radicals7. Disruption of neurotransmitters

Primary Injury

Primary injury caused by direct mechanical impact of trauma mightbe focal31 or diffuse.30, 51 Focal injuries include contusion, intracerebralhematoma, intracranial hemorrhage, or focal hypoxic–ischemic injury.Contusion is the most common focal injury and is the result of accelera-tion–deceleration forces and the angular and transitional movements ofthe head, causing the brain to impact on the bony protuberances of theskull producing coup (at the site of impact) and contre-coup (away fromthe site of impact) injury.6

Of the diffuse injuries, DAI is the most common and is caused byangular or rotational acceleration of the head producing shearing andtearing of the axons.31 A diagnosis of DAI is suspected when there is ahistory of acceleration injury with immediate loss of consciousness andneuroimaging findings of swelling, peticheal hemorrhages, subarachnoidhemorrhage, or normal scan. The severity of the axonal damage can beassessed by the depth and duration of coma, duration of posttraumaticamnesia, and presence or absence of rostral brain stem signs.51 Brainedema and swelling, hypoxic brain damage, and vascular injury areother types of diffuse brain injuries well described by Katz and Alexan-der51 and Gennarelli and Graham.31

Secondary Injury

At the neuronal level, brain injury is a complex phenomenon, associ-ated with a cascade of events from the time of injury and for a prolongedperiod. Gennarelli and Graham31 have provided an extensive discussionof the neuropathology of brain injury. The reader is encouraged to readthat article for a better understanding of this heterogenous disorder. Thisarticle provides a brief summary. Calcium influx into the cells, freeradical damage, receptor damage, and inflammation are the four distinctbut inter-related processes that occur after brain injury resulting invascular or neural injury with consequent focal or diffuse brain dam-age.31 The immediate cellular effect of trauma is ‘‘mechanoseparation,’’the transient separation of the lipid bilayers from the more rigid mem-brane inclusions, such as channels or receptors, causing a traumatic

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defect in the cell membrane.31 The membrane defect may last a fewminutes to hours, with closure either by a passive process or by an activeprocesses, such as calcium-mediated lysolecithin patching or fusion ofthe membrane.26

Other mechanisms, such as activation of voltage-dependent or re-ceptor-mediated channels, cause delayed calcium entry into the cells.Subsequently, following a pressure gradient, ions move into and out ofthe cell, followed by an increase in intracellular calcium and leading todeleterious effects, such as expression of immediate early genes and heatshock proteins98 or activation of the N-methyl-D-aspartate receptors andother secondary messengers causing alterations in cell metabolism,27

with resultant damage to the cytoskeletal and axonal elements.Following the acute membrane defect, a cascade of neurochemical

events occurs, leading to disturbance in ionic homeostasis, cerebral me-tabolism, and blood flow. This results in activation of the excitatoryamino acids—glutamate and aspartate receptors,49 oxidative free radicaldamage,54 release of cytokines,114 changes in the cholinergic system,90

catecholamine system,40 and serotonergic system.107 All of these distur-bances contribute to short-term and long-term neuronal dysfunctionand, in some cases, neuronal death from necrosis.

Recovery from Brain Injury

Recovery from brain injury is a complex and dynamic process thatcontinues for a prolonged period from the time of injury. Little informa-tion is available on the exact duration of recovery, the factors influencingrecovery, or the relationship between severity of injury and durationand nature of recovery.

Animal studies suggest that, because of plasticity of the brain,neuronal and axonal recovery occur within a few months after injury.20

Researchers have hypothesized similar mechanisms of recovery in thehuman brain; however, this information cannot be translated directly tohumans because differences exist in the nature and severity of injury,between human brain injury, and experimental brain injury.

In humans, recovery after focal brain injury differs from recoveryafter diffuse brain injury. Location, size, site, and other pathophysiologicfeatures, such as hemorrhage, edema, and mass effect determine thecourse of recovery in patients with focal lesions. The authors havebroadly divided the course of recovery from focal injury into threephases: (1) an acute phase lasting from a few seconds to hours, in whichthe patient is frankly confused; (2) a subacute phase, lasting two toseveral days, characterized by gradual clearing of confusion but withpersistence of several emotional and cognitive sequelae (common symp-toms include headache, dizziness, anxiety, depression, inattention, andmemory lapses); (3) a chronic phase, lasting for weeks to months andcharacterized by gradual improvement in symptoms. In a small percent-age of patients with focal TBI, some symptoms persist for months to


years after the injury. The reason for this is unclear but is probably dueto a combination of biological or psychosocial factors and premorbidpersonality traits.

Recover from diffuse injury is often dependent on the amountof diffuse axonal injury. The stages of recovery after such injury havebeen described using the Rancho Los Amigos scale of cognitivefunctioning.50, 52 These levels of recovery are neither clear-cut nor sepa-rated into well-defined stages. Overlapping between the stages is com-mon, and, in general, the duration of the stages is proportional to theseverity of injury, with each stage longer than the previous stage.52 Insome cases, progress may stop abruptly in one or the other stage withoutever reaching the stage of complete independence. This scale is usefulfor patients with severe head injury: but whether it can be applied topeople with mild to moderate head injury is unclear. Also, the scaledoes not correlate well with the onset or resolution of psychiatric distur-bances.

In the authors’ opinion, the stages of recovery, after mild to moder-ate diffuse head injury, are probably similar to what happens after focalinjury, with each stage more prolonged in duration and with residualmood and cognitive or behavioral disability in the chronic stage in manypatients.

Recovery from brain injury is a complex and dynamic process, withrapid improvement occurring over a few months after the injury, fol-lowed by gradual plateauing in recovery. No clear evidence shows whenrecovery slows down or stops in patients with focal or diffuse injury.Also, no linear relationship exists between the severity of head injuryand functional or emotional recovery.

CLASSIFICATION, ETIOLOGY, RISK FACTORS, ANDEPIDEMIOLOGY OF THE PSYCHIATRIC DISORDERSASSOCIATED WITH TRAUMATIC BRAIN INJURY

Classification

TBI is associated with several psychiatric disturbances that are notalways easy to classify. It may be possible to group together certainsigns and symptoms as specific syndromes, but others may occur inisolation. Disturbances, such as irritability, insomnia, or fatigue, may besecondary to a comorbid psychiatric disorder, such as major depression,or may be a direct consequence of brain injury. Literature review alsoreveals a lack of uniformity in classifying the psychiatric sequelae. Simi-lar psychiatric disturbances have been classified differently by variousresearch workers. For example, impulsivity, aggressiveness, disinhibi-tion, or cognitive deficits occurring together have been classified bysome according to the anatomic site of damage as ‘‘frontal or temporallobe’’ syndromes,59 according to their clinical presentation as ‘‘personal-ity changes,’’60 or ‘‘aggressive disorder,’’63 and according to the time

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of occurrence, duration, and functional dependency as ‘‘delirium’’60 or‘‘dementia.’’10 Similarly, the term postconcussive syndrome has been usedto describe certain presentations. This term is confusing and controver-sial because it is seen in a number of TBI patients with or without a‘‘concussion.’’ The authors prefer to classify the neuropsychiatric distur-bances associated with TBI according to their phenomenology as follows:

1. Cognitive deficits, 20% to 80% of patients2. Mood disorders

a. Major depression, 6% to 77% of patientsb. Mania, 3% to 9% of patients

3. Anxiety disorders, 11% to 70% of patients4. Apathy, 10% of patients5. Psychosis, 2% to 20% of patients6. Behavioral dyscontrol disorder

a. Major variant, 11% to 98% of patientsb. Minor variant, 80% to 100% of patients

The authors have reported this in one an earlier review article.88 Theauthors have used the term behavioral dyscontrol disorder to describe aconstellation of cognitive, physical, and emotional signs and symptomsthat can occur together. The authors have subclassified this disorder intomajor and minor variants based on the severity of the signs and symp-toms. The clinical features of these disorders are discussed later.

Etiology and Risk Factorsfor Neuropsychiatric Disorders

The etiology of the psychiatric disturbances after TBI involves inter-action of postinjury biological changes, premorbid personality traits, andpsychosocial and environmental factors. Regarding premorbid personal-ity factors, little information about the correlation between the differentpersonality traits and the post TBI psychiatric sequelae is available. Riskfactors17, 24, 74 for the development of psychiatric sequelae include:

A. Highly significant risk factors1. Preinjury history of psychiatric illness2. Preinjury poor social functioning3. Increased age4. Alcoholism5. Arteriosclerosis

B. Less significant risk factors1. Lower Glasgow Coma Scale2. Lower Mini Mental State Examination (MMSE)3. Marital discard4. Financial instability5. Poor interpersonal relationship6. Pre-injury levels of education7. Compensation claims


The authors have divided them into two: (1) highly significant riskfactors, in which sufficient enough evidence suggests their role in thedevelopment of psychiatric sequelae, and (2) less significant factors, inwhich the evidence is still controversial.

Epidemiology of the Neuropsychiatric Sequelae

Depending on the study, 10% to 80% of people who sustain a TBIsuffer from a psychiatric disturbance at some point in their recoveryperiod.111 This wide range in estimates is probably the result of differ-ences in defining various syndromes; lack of standardized diagnosticcriteria; differences in TBI severity among participants; and selectiondifferences with patients seen in various locations, such as community,rehabilitation facilities, acute trauma centers, and psychiatric clinics. Theprevious list reports the frequency of some of the common disorders.The authors have listed the lowest and the highest quoted frequenciesso that the reader can get an idea of how common these disturbancesmight be.

EVALUATION AND DIAGNOSIS OFPSYCHIATRIC DISORDERS ASSOCIATEDWITH TRAUMATIC BRAIN INJURY

The psychiatric evaluation of an individual with brain injury shouldbe comprehensive and includes:

I. HistoryA. Demographic informationB. Family history of psychiatric illnessC. Personal history

1. Birth and development2. Childhood health and behavior history3. Education4. Pre- and postinjury employment5. Pre- and postinjury marital status6. Pre- and postinjury living situation

D. Drug and alcohol historyE. Pre and post injury legal historyF. Medical history

G. Current medicationsH. Past psychiatric history

1. History of hospitalization2. History of outpatient treatment3. History of self injurious behavior/suicide attempt4. History of treatment with psychotropics

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I. Details regarding premorbid personality for collateral infor-mants.

J. History of patient illness1. Details of head injury

a. Open versus closedb. Mechanism of injuryc. Glasgow Come Scale at the time of injuryd. Duration of loss of consciousness (LOC)e. Duration of past traumatic amnesia (PTA)f. Hospitalization versus outpatient treatmentg. Treatment of surgical or medical complications

2. Details regarding current psychiatric illness3. Review of old medical records

II. Mental status examinationIII. Neurologic examinationIV. Brief cognitive assessment (MMSE)V. Neuroimaging studies

VI. Neuropsychological testsVII. Occupational therapy assessment of functional skills and safety

The key components include obtaining a detailed history from the pa-tient and collateral informants, and review of old medical records, per-forming a mental status, physical, and neurologic examination and con-ducting a brief test of global cognitive functioning, such as the MMSE.This should help in formulating a working diagnosis. If deemed neces-sary and not done previously, other tests, such as neuropsychologicalassessment to characterize cognitive deficits, neuroimaging scans to as-sess neuroanatomic deficits, and occupational therapy evaluation toassess functional and motor skills and safety, also should be performed.

A complete diagnosis should include the type, nature, and severityof brain injury, the associated neuropsychiatric sequelae, comorbid psy-chiatric diagnosis, medical illnesses that may be present, psychosocialstressors, and current functional capacity. The patient’s stage of recoveryand short- and long-term prognosis also should be noted.51

CLINICAL FEATURES AND MANAGEMENTOF PSYCHIATRIC SEQUELAE AFTERTRAUMATIC BRAIN INJURY

This section provides an only overview of the psychiatric distur-bances associated with TBI because it is beyond the scope of this articleto discuss in detail all the different psychiatric sequelae. The reader isencouraged to read the textbook Neuropsychiatry of Traumatic Brain Injury,edited by Silver et al96 for more information. This section has beendivided into two parts: (1) general guidelines on the management ofpsychiatric sequelae and (2) clinical features.


General Guidelines on the Managementof Psychiatric Sequelae

Management of the psychiatric disorders of TBI is both complexand challenging. Approach to care should be multifaceted and interdisci-plinary, with the psychiatrist working in close collaboration with theother physicians and colleagues of other disciplines. The treatment planshould be holistic and practical and include (1) pharmacotherapy, (2)psychotherapy, and (3) caregiver and family education and support.Rabins et al87 have discussed the essential attributes of a treatment planin the care of patients with dementia. The authors suggest using thesame approach to the care of TBI patients with psychiatric disorders.The essential elements include (1) having a rational and realistic plantaking into account the severity of head injury, the stage of recovery, thepsychosocial situation, and psychiatric and medical complications; (2)keeping the plan flexible and dynamic according to the changing condi-tion and needs of the patient and family; (3) anticipating problems orchanges and educating patient and family about these; (4) having acohesive and comprehensive plan focusing on the many needs of thebrain-injured patient; and (5) instilling hope and emphasizing the impor-tance of maximizing the patient’s potential and minimizing disability.This section briefly outlines the general principles regarding (1) pharma-cotherapy, (2) psychotherapy, and (3) caregiver education and support.

Pharmacotherapy

Knowledge regarding pharmacologic interventions in brain-injuredpatients is derived mainly from the authors’ experience in caring forpatients with primary psychiatric disorders, anecdotal reports, and smallcase series studies; however, unlike primary psychiatric disorders, psy-chiatric symptoms associated with TBI are not always syndrome specific,and some of them may need to be treated independently. Therefore,treatment can be aimed at observable symptoms or syndromes, basedon hypotheses regarding biological dysfunction, or both.68 In general,TBI patients are very sensitive to medications; hence, one should followthe golden rule of ‘‘start low and go slow.’’ Other rules include (1)minimize medications; (2) avoid medications that may have a deleteriouseffect on the CNS, such as phenytoin, halperidol, barbiturates, andbenzodiazepines25, 86; (3) monitor serum levels if necessary; and (4) al-ways discuss indications, risks, and benefits with patient and familymembers. Table 3 depicts the various psychotropics based on theirclinical utility. Arciniegas et al5 have provided an extensive literaturereview on the medications useful for the treatment of various psychiatricdisorders following TBI, which the reader is encouraged to read.

Psychotherapy

Psychotherapy is as important as pharmacotherapy in the rehabilita-tion of patients with psychiatric disorders secondary to TBI. In addition

Table 3. MEDICATIONS FOR PSYCHIATRIC DISORDERS FOLLOWING TBI

Pathologic Risk forLaughter/ Agitation/ Adverse Side

Medications Depression Mania Apathy Crying Psychosis Anxiety Aggression Cognition Effects

Tricyclic antidepressants �� Selective serotonin reuptake ��

inhibitorsSerotonin and norepinephrine ��

reuptake inhibitors(venlafaxine)

Serotonin antogonists and � � � � � � �� reuptake inhibitors(trazodone)

Lithium � �� Carbamazepine and � ��

valproateTypical antipsychotics � � � � �� Atypical antipsychotics � �� Psychostimulants �� Amantadine � � �� Dopamine agonists �� Cholinesterase inhibitors � � � � � � � �� Benzodizopines � � � � � � � � ��Buspirone � � � � � � � � �Beta-blockers � � � � � � ��

� Potential benefit; � No/poor benefit; � Mild side effects; �� Moderate side effects; �� Severe side effects.Adapted from Arciniegas DB, Topkoff F, Silver JM: Neuropsychiatric aspects of traumatic brain injury. Curr Opin Neurol 2:160–186, 2000; with permission.

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to education and hope, supportive psychotherapy should include recom-mendations on nutrition, regular exercise, importance of maintainingroutine, and scheduling daily activities. Patients should be encouragedto attend brain injury support groups available in their area and tomaintain contact with the local and national brain injury associations.

It is beyond the scope of this article to discuss the extensive arrayof psychotherapeutic measures; hence, only the common varieties oftherapy are named. Psychotherapy may be individual, group, or familytherapy, or a combination. The different types of therapies include occu-pational therapy, physical therapy, behavior therapy, cognitive rehabilita-tion, reality orientation, speech therapy, social skills training, recreationtherapy, vocational training, and substance abuse counseling. Eventhough some of these interventions have been useful for some patients,their use is largely empiric, with a lack of scientific validation. The bigproblem is that no standardized criteria enumerate the indications, risks,and benefits of these forms of therapy. Cicerone et al13 conducted anextensive literature review on the effectiveness of the different forms ofcognitive rehabilitation for people with TBI and stroke and have foundan overall effectiveness. The authors recommend this paper because itprovides information on the various types and effectiveness of cognitiverehabilitation and methodologic success and flaws of different studies.

Caregiver Support and Education

A caregiver may be the spouse, parents, family member, a friend,or even a professional care provider. Whoever they may be, addressingtheir needs is important because they often experience intense stress,depression, and anxiety as a result of caring for a person with TBI.79

Often, these adverse effects are present for years after the TBI. Thefrequency of psychiatric illness, such as anxiety and major depression,among care providers of TBI patients ranges from 16% to 51%.89 Inaddition, other problems, such as financial difficulties, role changes,social isolation, and impaired family functioning79 are common. Hence,support of the family and of the caregivers is an essential component oftreatment of the brain-injured patient. Each family is unique, and so aretheir problems, and the needs should be addressed individually. Thegeneral approach to caregiver support includes (1) providing education;(2) instilling hope; (3) providing emotional support; (4) if symptoms ofanxiety or low mood are persistent, recommending professional help;(5) encouraging the use of available resources, such as local and nationalbrain injury association centers; (6) discussing importance of respite careand the need to have personal time; and (7) always providing emergencycontact numbers.

Clinical Features

This section discusses the common psychiatric disorders, whichinclude cognitive deficits, mood disorders, anxiety disorder, apathy, psy-

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chosis, and behavioral dyscontrol disorder. For each of these disorders,its definition, prevalence, clinical picture, pathology, and pharmacologictreatment are described in sequence.

Cognitive Deficits

Definition. Cognition may be defined as the sum total of processesinvolved in the acquisition, analysis, and management of information.This includes acquiring data through sensory inputs, analyzing datausing a predefined set of criteria, choosing alternatives by weighing thepros and cons, and executing the chosen option.85

Prevalence. Cognitive deficits are very common among TBI patients.Almost anyone who sustains a brain injury, regardless of the severity,suffers from some kind of cognitive deficit; however, the actual fre-quency of these deficits is unknown. Levin67 reported that memorydisturbance following closed head injury is the most common cognitivedeficit; the prevalence ranges from 23% to 79%

Clinical Picture. Cognitive activities include attention, memory, lan-guage, abstraction, executive function, and perceptual skills. All of theseactivities may be affected in brain injury to a varying degree, withdeficits lasting for a variable duration. The common cognitive deficitsthat persist after the resolution of the acute confusional state and post-traumatic amnesia include disturbances of memory, attention, language,and executive functions. Each of these deficits is briefly described.

Memory Disturbances. Memory loss is the most common complaintof patients after TBI. Quantifiable deficits occur in both verbal andnonverbal domains. The immediate postacute TBI phase is often associ-ated with problems in the acquisition and retrieval of new information,which often resolves as the confusion clears. Persistent memory changeis related to the severity of TBI and the diffuse nature of the injury.Short-term memory deficits, such as misplacing things, inability to recallrecent conversations, or trouble remembering grocery lists, are the mostcommon complaints during both the early and late recovery phases.O’Shanick and O’Shanick85 found that, after TBI, memory impairment isgreater for ‘‘effortful’’ rather than ‘‘incidental’’ memory, with patientsdoing better with open-ended questions rather than with ‘‘fill-in-the-blank’’ questions. Neuropsychological tests in brain-injured patients re-veal impaired episodic or declarative memory, with relative preservationof procedural memory.22, 85

Disturbances of Attention. Attentional disorders are also commonin patients with brain injury and often predict return to work.82 Learningis central for recovery after brain injury, and attention is the principalcomponent for adequate learning. Selective attention, sustained atten-tion, and divided attention are some of the functions of the attentionsystem. Patients with brain injury often have problems with sustainedand divided attention.100 They often report problems with concentration,difficulty in focusing, easy distractibility, or inability to focus on morethan one task at a time. In some patients, the attention deficit is probably


caused by impaired sensory gating or a sensation of ‘‘shutting off’’ in anoisy environment.4 The P50 evoked waveform response to paired audi-tory stimuli is a useful test to measure auditory gating. Arciniegas et al8

compared 20 TBI patients with memory and attention problems to 20control subjects and found that the P50 ratio was significantly greater inTBI patients indicating P50 nonsuppression or impaired gating. Cholin-ergic dysfunction has been hypothesized to be one of the key factorsresponsible for the impaired gating mechanism.4 The Brief Test of Atten-tion93 and the Paced Auditory Serial Addition Test34 are excellent testsof divided attention, and both have been found to be useful measuresof recovery from brain injury and outcome.

Language Disturbances. Language problems are also common afterTBI and occur with both focal frontotemporal damage and or diffusebrain injury.80 They may range from minor deficits, such as a lack ofspontaneity of speech, to severe forms of expressive, receptive, or globalaphasia. Common language deficits include motor and sensory prosodicdysfunction, word-finding problems, difficulty in expressing ideas, dys-arthria, and inability to understand sarcasm or follow simple com-mands.63, 108, 109

Executive Disturbances. Executive function involves planning, or-ganizing, and sequencing; concept formation; abstraction; and set shift-ing. Patients with executive dysfunction display perseveration, stimulusbound behavior, concrete thinking, impulsivity, poor initiation, and moti-vation and a general unawareness of self and others.79

Pathology. Cognitive deficits result from both focal and diffusecortical brain damage. These are believed to be the results of damage tothe anterior temporal and the orbitofrontal lobes, which are most vulner-able sites for injury secondary to their localization over the bony protu-berances of the skull. The severity of cognitive deficits depends on thesize and location of injury, the severity of injury, duration of posttrau-matic amnesia, brain stem dysfunction, and the degree of diffuse axo-nal injury.60

Treatment. Dopamine agonists, psychostimulants, amantadine, andcholinesterase inhibitors have been used to treat disturbances of atten-tion, arousal, memory, and executive functions.8, 58, 102, 110 A single casereport and small case series studies have suggested the beneficial effectsof methylphenidate and dextroamphetamine for the treatment of inatten-tion, distractibility, disorganization, hyperactivity, hypersomnia, hypo-arousal, and apathy.21, 38 Mood and cognitive improvement was noted ina double-blind, placebo-controlled cross-over study using methylpheni-date.21 The same agent has also been found useful in the postacuterecovery trauma period for the treatment of attention46 and cognitiveand physical function.84

Small, uncontrolled case studies also have suggested beneficial ef-fects of dopamine agents. Cognitive and behavioral improvement wasseen in open-labeled trial with L-dopa/carbidopa in 12 moderate orsevere brain-injured patients.61 Bromocriptine was found to be useful inthe treatment of apathy and executive dysfunction.81 Cognitive impair-

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ment in patients with TBI have been hypothesized to be secondary toacetylcholine deficiency. Case reports are available on the effectivenessof procholinergic agents to treat memory deficts. Goldberg et al32 usedoral physostigmine (1.5 mg) and lecithin (20 g suspended in cranberryjuice) to treat posttraumatic amnesia. Improvement was seen in verbalbut not visual memory. Additionally, the risk for neurologic and cardio-vascular side effects is high at this dose, and hence it may not be useful.Taverni et al102 reported on the use of donepezil, which is a central-acting selective acetylcholinesterase inhibitor, in two patients with mem-ory deficits months after they had sustained severe head injury. Bothshowed ‘‘improvement’’ in their memory problems at a dose of 5 mg, 3weeks after the medication was started. Because cognitive deficits arethe most common consequence of TBI, more studies need to be done toprove the effectiveness, tolerance, and safety of these medications.

Mood Disorders

Disturbances of mood range from transient episodes of sadness orhappiness to persistent periods of low or elevated mood associatedwith several neurovegetative symptoms. Major depression and bipolardisorder are the two most common mood disorders, as described later.Major depression should be differentiated from demoralization, adjust-ment disorder, apathy syndrome, and pathologic crying. Similarly, thedifferential diagnosis for bipolar disorder includes behavioral dyscontroldisorder and pathologic laughter.

Major Depression. Definition. Major depression is a persistent,sustained feeling of sadness associated with neurovegetative and cogni-tive disturbances, such as changes in sleep; appetite; energy; concentra-tion; interests; and feelings of worthlessness, guilt, hopelessness, or sui-cide.

Prevalence. The prevalence of major depression after TBI varieswidely because of a lack of standardized criteria in diagnosing depres-sion. Fedoroff et al,24 in their longitudinal study of 66 inpatients withacute TBI of mild, moderate, and severe degree, reported a cumulativeprevalence of 26% in the first year after TBI using the DSM-IIIR diagnos-tic criteria for major depression.

Clinical Picture. The clinical picture of post-TBI depression is simi-lar to that of primary depression. Post-TBI depression may be transient,lasting for a few days to weeks, or enduring, lasting for months. Thediagnosis of post-TBI major depression is difficult because a number ofsymptoms of major depression, such as changes in sleep, appetite, orlibido, could be secondary to the brain injury itself or a nonspecificreaction to an acute medical illness. Jorge et al41 examined longitudinallythe specificity of depressive symptoms at 3 months and 1 year afterhead injury and found that a lack of energy and symptoms related tochanges in self-attitude, such as a lack of self-confidence, low self-esteem, feeling of hopelessness, poor interest in surroundings, and sui-cidal thoughts differentiated the depressed from the nondepressed


group. Suicide is of concern in patients with post-TBI depression becauseapproximately 65% report suicidal ideation.62 No data are available oncompleted suicide in post-TBI, depressed patients. Major depressionshould be differentiated from demoralization, adjustment disorder, andapathy (Table 4).

Pathology. A number of studies have suggested that early onsettransient depression may be caused by the disruption of brain physiol-ogy associated with the injury, whereas prolonged, persistent depressionis probably a psychological reaction to physical and cognitive impair-ment.42, 74 Lesions in the left dorsolateral frontal or left basal gangliaregions have been associated with early onset major depression (1–3months after injury) but not late-onset depression (after 3 months ofinjury)43; however, more studies need to be done to confirm or refutethis hypothesis. Until then, post-TBI depression should be considered tohave a multifactorial etiology associated with biological, psychological,and environmental factors.

Treatment. Treatment of post-TBI major depression is very similarto the treatment of primary depression. Case reports are available onthe successful use of selective serotonin reuptake inhibitors (SSRIs), suchas sertraline23 and fluoxetine,11 trazadone;115 buspirone;39, 115 psychstimu-lants,38, 57 such as dextroamphetamine and methylphenidate; and evenelectroconvulsive therapy (ECT).48 Fann et al23 reported improvement intwo thirds of mild TBI depressed patients treated with sertraline in asingle-blind, placebo run-in trial; however, no other randomized, pla-cebo-controlled, double-blind studies support the effectiveness of any ofthese medications.

Monoamine oxidase inhibitors and tricyclic antidepressants gener-ally are not favored because of their drug food interactions and anticho-linergic side effects. Agents such as venlafaxine and paroxetine havebeen used with great success by the authors for the treatment of majordepression and insomnia, even though no studies guide the use of theseagents. ECT may be safely used for the treatment of psychiatric disordersfollowing TBI. Kant et al48 studied 11 closed-head injury patients withvarious psychiatric disorders, such as major depression, mood disordersecondary to TBI, chronic delirium, and delusional disorder. Eight re-sponded to an index course of ECT; 2, to continuation ECT after theindex course; and 1 was a nonresponder. Cognitive side effects were notsignificant in any of the patients except for the nonresponder. Otherstudies also have demonstrated the beneficial effect and safety of ECTin TBI patients with depression.14

Bipolar Disorder. Definition. Post-TBI bipolar disorder is definedas intermittent periods of major depression and mania. A manic episodeis characterized by periods of persistent elevated or irritable moodassociated with increased energy, racing thoughts, decreased sleep, gran-diose ideas, impulsivity, or aggressive behavior.

Prevalence. Literature on TBI-associated bipolar disorder is sparse.Only case reports or small series studies are available. The largest seriesis from Jorge,44 who studied 66 acute TBI patients for 1 year after their

Table 4. DIFFERENTIAL DIAGNOSIS OF MAJOR DEPRESSION

Signs and Symptoms Major Depression Adjustment Disorder Demoralization Apathy

Depressed mood Pervasive and persistent Often transient Often transient Not presentIdentifiable stressor Not always present Often present Often present Not presentResolution of symptoms Symptoms persist Symptoms resolve as Symptoms resolve as Symptoms persist despite

despite termination of stressor terminates stressor terminates termination of stressorstressor

Changes in sleep, appetite, Often present Often present Often not present Often not presentconcentration

Changes in self-attitude Often global and Related to the stressor Related to the stressor No changepersistent

Feeling of hopelessness Often global and Related to the stressor Related to the stressor No changepersistent

Suicidal thoughts May be present If present transient Not present Not presentAnhedonia Present May be present May be present Present and severeInitiation Decreased May be decreased May be decreased Markedly decreasedMotivation Decreased May be decreased May be decreased Markedly decreased

58


injury. Approximately 10% (6 of 66) met the DSM-IIIR diagnostic criteriafor manic episode at some point during the follow-up. Only 1 metcriteria for bipolar disorder.

Clinical Picture. The symptoms displayed by the six patients whodeveloped mania secondary to TBI in Jorge’s study44 included expansivemood (6 of 6), irritability, increased motor or verbal activity, and thoughtdisorder (5 of 6) increased sexual interests and aggressive behavior (3 of6), decreased need for sleep (2 of 6), and grandiose delusions (1 of 6). Ingeneral, the manic episodes lasted for approximately 2 months. Shuklaet al94 reported on 20 mild, moderate, and severe TBI patients referredto psychiatric clinics for evaluation for mania or schizoaffective disorder.Eighty-five percent had an irritable form of mania, and 70% had ahistory of assaultive behavior. Psychotic symptoms were found in only15%. Other symptoms included impaired and decreased need for sleep(100%), grandiosity (90%), pressured speech and flight of ideas (70% to80%), and hyperactivity (65%). They found a significant relationshipbetween mania and partial complex seizures (40%). Recurrent maniawithout depression was found in 70% of patients. It is difficult todistinguish mania from labile, aggressive, or disinhibited behavior sec-ondary to TBI. Symptoms such as impulsivity, disinhibition, or aggres-sion may be common to the two conditions; however, the core symptomsof mania include persistent, elevated, or irritable mood; mental andphysical overactivity (e.g., increased energy, decreased need for sleep,pressured speech with racing thoughts); and grandiose or persecutorybeliefs. Pathologic laughter is another common but less reported condi-tion characterized by inappropriate and uncontrollable laughter out-bursts. These outbursts are either not associated with changes in moodor, if associated, is out of proportion to mood changes. The other neuro-vegetative symptoms of mania are usually not present.

Pathology. Anterior temporal lesions have been associated with agreater risk for mania.44 Other studies of secondary mania have revealedan association with lesions involving the right hemisphere, particularlyorbitofrontal regions, inferior temporal areas, thalamus or basal gan-glia.89 No association has been found between mania and other factors,such as family history of mood disorder, personal history of psychiatricillness, severity of brain injury, degree of physical or cognitive impair-ment, social support, social functioning level, or posttraumatic epilepsy.44

Treatment. Literature is sparse in the treatment of mania followingTBI. Valproate or carbamazepine is preferable to lithium; the latter maycause worsening of cognitive deficits.59

Thus, post-TBI mania is relatively understudied despite its substan-tial frequency. More studies need to be done to elucidate specific riskfactors and to determine lesion location and effective treatment.

Anxiety Disorder

Definition. Anxiety is an intermittent or persistent feeling of appre-hension or dread with or without associated cardiovascular, gastrointes-tinal, or autonomic signs and symptoms.

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Prevalence. Anxiety is commonly reported after TBI (range, 11%–70%).53, 71 Epstein and Ursano19 compiled 12 studies comprising morethan 1000 head-injured patients and reported an overall prevalence ofanxiety disorder of 29%. Jorge et al,45 in their study of 66 TBI patients,reported a syndrome of anxious depression in 11%.

Clinical Picture. All types of anxiety disorder including generalizedanxiety disorder, panic disorder, obsessive-compulsiv disorder, and post-traumatic disorder have been reported after TBI57, 73; however, the mostcommon post-TBI anxiety symptoms include free-floating anxiety, fear-fulness, intense worry, generalized uneasiness, social withdrawal, inter-personal sensitivity, and anxiety dreams.71

Pathology. Both right33 and left72 hemispheric injuries have beenassociated with the development of anxiety disorders. Jorge et al45 foundanxious depression to be associated with right hemispheric lesions andmajor depression, with left-sided brain lesions suggesting that the twodisorders are different in their etiopathology.

Treatment. Small case series studies and anecdotal reports point tothe effectiveness of SSRIs, naltrexone,104 and buspirone39 in the treatmentof anxiety disorders. Antipsychotics25 and benzodiazepines86 should beavoided secondary to adverse side effects, such as delayed neuronalrecovery, paradoxic rage, and memory impairment. No controlled stud-ies of treatment for anxiety disorders after TBI are available.

Apathy

Definition. Apathy may be a symptom of major depression, delir-ium, or dementia (secondary apathy), or it may occur in isolation as aseparate syndrome (primary apathy).76 Marin defined primary apathyas lack of motivation emotionally, cognitively, and behaviorally notattributable to intellectual impairment, emotional distress, or diminishedlevel of consciousness.77

Prevalence. Kant et al,47 in a study of 83 patients with closed-headinjury attending a neuropsychiatric clinic, reported the prevalence of(primary) apathy to be 10% and of apathy in association with depression(secondary) to be 60% of all patients.

Clinical Picture. Apathetic patients usually do not complain of anysymptoms. They often are brought to treatment by a family memberwith the history of ‘‘laziness.’’ On further questioning of both the patientand the family member, symptoms such as disinterest, disengagement,lack of motivation, reduced emotional responsivity, inertia, lack of curi-osity, and decreased productivity become apparent. Table 4 comparesapathy to depression and depicts the salient features of these two condi-tions.

Pathology. Damage to the medial frontosubcortical circuit,15 basalganglia, and thalamus9 have been associated with the pathogenesisof apathy.

Treatment. Psychostimulants, dopamine agonists and amanta-


dine8, 36, 58, 110 have found to be beneficial in the treatment of apathy.Again, only anecdotal reports and small case series studies are available.

Psychosis

Definition. Psychosis refers to disturbances in form and content ofthought, frequently associated with hallucinations and delusions.

Prevalence. Psychotic syndromes are more common among subjectswho sustain TBI than in the general population. In their review, Davisonand Bagley16 reported that 0.7% to 9.8% of subjects with TBI developedschizophrenia-like psychosis. More recent studies have shown a preva-lence of 3.4% to 8.9%.2 Davison and Bagley16 also found that 15% ofschizophrenics had sustained TBI before the onset of their first psychoticepisode. In a study of multiple schizophrenia pedigrees, Malaspina etal75 reported that a family history of schizophrenia is associated withincreased risk for TBI, with head trauma further increasing the risk forTBI. In a retrospective study of 659 consecutive admissions to a psychiat-ric hospital, Wilcox and Nasrallah112 demonstrated that a history of headtrauma was significantly more common among the schizophrenics thanamong patients with major depression, mania, or surgical controls.

Clinical Picture. Post-TBI psychosis is a complex heterogeneousdisorder and may present with one or several of the core symptomsof schizophrenia, such as delusions, hallucinations, abnormal thoughtprocess, abnormal behavior, or ‘‘negative’’ symptoms. It may also mani-fest as impulsivity, aggressive behavior, expression of odd ideas, grimac-ing, inappropriate giggling, or ideas of reference. Psychotic symptomsmay be acute or delayed, relapsing or chronic, and might occur anytimeafter TBI. They also may be seen in association with posttraumaticamnesia,105 epilepsy,106 and mood disorders related to TBI.94, 103 Riskfactors for the development of psychosis include severe closed-headinjury, temporal lobe epilepsy,16 presence of a congenital neurologiccondition, and head injury before adolescence.29

Pathology. Both right69 and left hemisphere72 damage have beenassociated with posttraumatic psychosis.

Treatment. Animal studies have shown impaired neuronal recoverywith the use of ‘‘typical’’ neuroleptics, such as haloperidol.25 Hence,these agents should be used with caution and in low doses. Studiesabout the effectiveness of ‘‘atypical’’ neuroleptics are few. Risperidone92

and clozapine91 have been found to be useful in the treatment of post-TBIpsychotic symptoms, such as hallucinations, delusions, and catatonia.

Our clinical experience also indicates that medications such asrisperidone, olanzapine and quetiapine can be used effectively to treatparanoid delusions, auditory hallucinations and/or disorganizedthought process. Aggressive outbursts and delusion like signs and symp-toms associated with cognitive impairment or behavior dyscontrol maybenefit from dopaminergic agents.59

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Behavioral Dyscontrol Disorder

Definition. This is a complex syndrome characterized by distur-bance in mood, behavior, and cognition. Because the core feature of thissyndrome is dyscontrol of emotion and behavior, the authors haveprovided the term behavioral dyscontrol disorder. The authors have sub-classified this disorder into two variants: (1) major variant, in which thesymptoms are chronic, persistent, and severe and (2) minor variant, inwhich the symptoms are acute and transient. The authors describe theprevalence, clinical features, and treatment of the two variants sepa-rately.

Major Variant. Prevalence. The prevalence of agitation, impulsivebehavior, and aggressive outbursts are very common after brain injury,with a frequency ranging from 11% to 98%.6

Clinical Picture. The salient clinical features of this syndrome in-clude:*

MoodIrritabilityRageAngerCognitionImpaired attentionImpaired memoryPoor executive functionImpaired judgmentDistractabilityConceptual disorganizationBehaviorImpulsivityAggressivityHyperactivityImpaired judgmentHyperphagiaPica

Patients often are referred to a psychiatrist by their physician or familymembers for the management of verbal or physical aggression, impulsiv-ity, and anger or rage outbursts. This condition should be differentiatedfrom major depression, mania, and psychosis. The characteristic symp-toms of these disorders were described earlier in the relevant sections.The core feature of behavioral dyscontrol disorder is the intermittent,uncontrollable outburst of mood or behavior in contrast to the persis-tence of symptoms in other disorders. Patients have very little insight

*Adapted from Rao V, Lyketsos C: Neuropsychiatric sequelae of traumatic brain injury.Psychosomatics 41:95–103, 2000; with permission.


into their problem and may deny all complaints. The caregivers areoften overwhelmed and frustrated.

Pathology. The underlying abnormality probably is the result ofdamage to the frontotemporal regions, causing emotional lability, execu-tive dysfunctioning, disinhibition, memory lapses, and social inappropri-ateness.18, 36

Treatment. Management includes treatment of the patient and sup-port and education of the caregiver. Pharmacologic interventions for thetreatment of behavioral dyscontrol includes use of high-dose �-blockers,dopamine agents, SSRIs, and mood stabilizers.36, 97 Silver et al95 havereported the efficacy of high-dose blockers in the treatment of aggressionin chronically hospitalized inpatients. Carbamazepine has been shownto be useful for the treatment of aggression in the acute12 and chronic70

phases of recovery. Several reports have suggested the beneficial effectsof lithium in the treatment of aggression, but it is not favored secondaryto its potential neurotoxic side effects.7

Amantadine was first used in the 1960s as an antiviral agent andlater as an antiparkinsonian agent; however, over the past decade, it hasbeen used as a ‘‘frontal lobe agent’’ secondary to its dopamine-enrichingproperty. The effectiveness of amantadine was studied by Gualtieri in30 severely brain-injured patients approximately 2 to 144 months afterinjury.37 Two thirds of them showed improvement in symptoms of agita-tion, emotional lablity, distractibility, and aggression.

Minor Variant. The authors have used the term minor variant todescribe the most common and controversial condition followingTBI—the postconcussion syndrome. It refers to a constellation of mood,cognitive, and somatic signs and symptoms that occur soon after TBI ofany severity. Clinically, this condition resembles the major variant inthat patients present with a multitude of symptoms involving severaldomains but differs in that, in most patients, the symptoms are oftennot persistent and resolve spontaneously. Also, the other big differencebetween the major and minor variants is the presence of aggressivebehavioral symptoms in the former and physical or somatic symptomsin the latter.

Prevalence. Eighty to one hundred percent of patients who sustainmild closed-head injury suffer from a multitude of symptoms affectingseveral systems in the first month of injury.64 The prevalence of thisdisorder in patients with moderate and severe head injury is largelyunknown, although several researchers have reported their occurrence.Numerous studies suggest that several of these symptoms spontane-ously resolve by 3 and 6 months after injury; however, approximately15% of patients with mild TBI have symptoms lasting longer than1 year.83

Clinical Picture. The clinical picture of this disturbance includes:*

*Adapted from Rao V, Lyketsos C: Neuropsychiatric sequelae of traumatic brain injury.Psychosomatics 41:95–103, 2000; with permission.

64 RAO & LYKETSOS

MoodDepressionAnxietyIrritabilityCognitionImpaired memoryDecreased attentionDecreased concentrationDysexecutive functionConceptual disorganizationSomatic SymptomsHeadacheNauseaDizzinessVertigoDiplopiaInsomniaDeafnessTinnitusLight sensitivityNoise sensitivityFatigueDyscoordination

Drowsiness, blurred vision, nausea, and vomiting usually are seenwithin the first 48 hours. Other symptoms, such as headache, fatigability,dizziness, impaired memory, poor concentration, depression, slow think-ing, anxiety, and irritability often occur after 48 hours.101 Levin65 evalu-ated 155 patients 1 week after they had experienced a minor head injuryand found that headache and dizziness were reported by more than 50%of patients. Somatic complaints, such as dizziness and visual distur-bances, were also commonly reported symptoms but were more com-mon among in females than males.66

Pathology. The underlying abnormality of this perplexing disorderis unclear; however, a generally accepted hypothesis is that it may bethe result of rotational sheer strains and diffuse axonal injury.3 Interest-ingly, a number of patients have normal neurologic examination andstructural brain scans; however, single-photon emission CT and positronemission tomography case reports have revealed focal abnormalities ofregional cerebral blood flow and glucose uptake.1, 35 More studies usingfunctional neuroimaging techniques need to be done to identify specificabnormalities.

Treatment. It is crucial to maintain a practical and holistic approach.Persistent emotional or cognitive problems requires a thorough psychiat-ric evaluation to rule out mood and anxiety disorders. Disruptive andabnormal behavior should be redirected. Education, patient and familysupport, and psychotherapy are other essential rehabilitative interven-tions.


SUMMARY

TBI is a complex heterogenous disease that can produce a varietyof psychiatric disturbances, ranging from subtle deficits in cognition,mood, and behavior to severe disturbances that cause impairment insocial, occupational, and interpersonal functioning. With improvementand sophistication in acute trauma care, a number of individuals areable to survive the trauma but are left with several psychiatric sequelae.It is important for psychiatrists to be aware of this entity because anincreasing number of psychiatrists will be involved in the care of thesepatients. Treatment should be interdisciplinary and multifaceted, withthe psychiatrist working in collaboration with the patient, caregiver,family, other physicians, and therapists. The goal of treatment should beto stabilize symptoms; maximize potential; minimize disability; andincrease productivity socially, occupationally, and interpersonally.

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Psychiatric aspects of traumatic brain injury