Journal ofNeurology, Neurosurgery, and Psychiatry 1989;52:387-391

Short report

Cerebellar degeneration in neuroleptic malignantsyndrome: neuropathologic findings and review of theliterature concerning heat-related nervous systeminjuryS LEE,* A MERRIAM,t T-S KIM,* M LIEBLING,* D W DICKSON,* G R W MOORE*

From the Department ofPathology (Neuropathology) and the Rose F Kennedy Centerfor Research in MentalRetardation and Human Development,* and the Departments ofPsychiatry and Neurology,t Albert EinsteinCollege ofMedicine, Bronx, New York, USA

SUMMARY A selective subtotal cerebellar neuronal degeneration was found in a patient who died 41months after suffering neuroleptic malignant syndrome (NMS), a rare, potentially fatal disorderassociated with neuroleptic medications. It is suggested that the cerebellar neuronal degeneration inthis case was due to hyperpyrexia, a cardinal clinical feature of NMS. Similar pathologic findingsappear not to have been previously reported inNMS but have been described in heat-induced centralnervous system (CNS) injury. The findings imply that a cerebellar syndrome might be encountered inpatients who survive NMS complicated by a particularly high febrile course.

Neuroleptic malignant syndrome (NMS) is a poten-tially lethal reaction to central dopamine blockingagents.' It is characterised clinically by hyperpyrexia,extrapyramidal rigidity, autonomic dysfunction, anddepressed sensorium. Elevation of serum creatininekinase (CK) secondary to rhabdomyolysis, abnormalliver function tests, and leukocytosis are commonaccompaniments. The disorder is rare, with anestimated incidence of 04 to 1-4%, and carries afatality rate of 4 to 22% in reported series.2The pathogenesis of the disorder remains

speculative. The current theory of the patho-physiological mechanism is extreme blockade ofdopamine receptors in both the basal ganglia andhypothalamus resulting in extrapyramidal musclerigidity with thermogenesis and in impaired centraltemperature regulation, respectively.2 Based on clin-ical similarities of NMS to malignant hyperthermia(MH), an alternative hypothesis proposes that

Address for reprint requests: DennisW Dickson, MD, Department ofPathology (Neuropathology), Albert Einstein College of Medicine,1300 Morris Park Avenue, K-438, Bronx, New York, 10461, USA.

Received 19 August 1988.Accepted 28 October 1988

neuroleptic medications induce abnormal calciumdisposition in the muscle cells of susceptibleindividuals and thereby trigger muscle rigidity,rhabdomyolysis, and fever.2 Observations in biopsyspecimens of muscle ofNMS survivors that caffeine,3halothane,4 and fluphenazine,4 neuroleptic, produceabnormal contracture patterns similar to that seen inMH, lends some support to the latter hypothesis.

Despite the voluminous literature on the clinicalmanifestations and management of NMS, neuro-pathologic examinations have seldom been reported.The postmortem examination of brain of a patientwho developed NMS-like illness after receivingneuroleptics, monoamine oxidase inhibitors, andnumerous electroconvulsive treatments, revealed fociof necrosis in the anterior and lateral hypothalamicnuclei.5 A previous case report by Morris et al revealedno pathologic findings in the brain or muscle of anindividual who succumbed to NMS.6The following report describes the neuropathology

of a patient who died 41 months after an episode offull-blown NMS. We discuss the relationship ofcerebellar degeneration to hyperpyrexia which is aninvariable component of NMS. A review of theliterature confirms the common occurrence ofcerebellar injury in other heat-related fatal disorders.

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388Case report

A 32 year old man with Klinefelter's syndrome and chronicschizophrenia was brought to the emergency room withdyspnoea and involuntary dystonic posturing of his limbs.The patient had required multiple psychiatric hospitalisa-tions over the previous 5 years and had been treated with avariety of neuroleptic medications. He had most recentlybeen maintained on haloperidol. Several years previously, hedeveloped involuntary movements of his oral, buccal, lin-gual, trunk, neck, and limb muscles and tardive dyskinesiawas diagnosed. One year prior to admission, in an effort todiminish the dyskinetic movements, he was prescribed theexperimental drug tetrabenazine. This was maintained at adose of25 mg p.o. four times daily, with an excellent responseand without side effects. In the week prior to his presentationhe once more sustained an increase in his psychotic symp-toms, and his haloperidol dose had accordingly beenincreased from 10mg p.o. twice daily to three times daily. Theanticholinergic antiparkinsonian agent benztropine wasmaintained without change at 1 mg p.o. twice daily.Although on initial presentation to the emergency room

the patient was alert and afebrile, he became progressivelymore rigid and mute over the next several hours as histemperature climbed to 40-1°C. On examination, the patientwas tachycardic to 120 beats/min, with a blood pressure of140/90mm Hg and respiration of 36/min. His chest was clearto auscultation and percussion, and his abdomen was soft;he had no lymphadenopathy, skin rash, or other signs ofinfection. The neurological examination showed him to beinitially fully oriented but he soon lapsed into a mute,stuporous state shortly after arrival in the emergency room.His optic discs were flat and the cranial nerve examinationshowed no abnormalities. He showed continuous dystonicposturing and choreiform movements of all four extremities.Muscle tone was increased, particularly in the lowerextremities. The deep tendon reflexes were diffusely hyper-active with sustained ankle clonus. The Babinski sign wasabsent bilaterally.The routine admission laboratory studies showed a leuk-

ocytosis of 16,200/mm3, with a normal differential. Thecreatinine kinase was 1,420 U/L initially and rose to 32,000U/L two days later; MB fraction was 0%. A chest radiographwas normal. Non-contrast CT of the head was normal. Thecerebrospinal fluid was acellular and sterile, with a protein of26 mg/100 ml and a glucose of 91 mg/100 ml. A diagnosis ofneuroleptic malignant syndrome (NMS) was made, and anintravenous infusion ofdantrolene 160 mg was administered,along with bromocriptine 2 5 mg by nasogastric tube. Thepatient responded by exhibiting less muscular hypertonia, bybecoming aware of his environment, and by defervescing to37 7°C.The following day his muscle rigidity returned and his

temperature rose to 38 8°C. Dantrolene was readministered,but the infusion was interrupted after 120 mg was adminis-tered when the patient suddenly developed bradycardia (47/min) and hypotension (70 mmHg/palpation). He becameunresponsive to verbal stimuli, became flaccid, and requiredmechanical ventilation. An EEG showed diffuse slowing withdelta and theta waves, with no lateralising or epileptiformfeatures. Neither dantrolene nor bromocriptine were re-administered.

Lee, Merriam, Kim, Liebling, Dickson, MooreHis remaining course was complicated by intercurrent

infections with candida, proteus, and klebsiella, and inter-mittent fever. He showed no major improvement in hismental status throughout the hospitalisation. He failed torespond to his environment. He had no documented episodeofclinical hypoxia, until he succumbed ofa cardiopulmonaryarrest 4j months after presentation, and he did not receiveanti-convulsant drugs, such as phenytoin.

Pathologic fiaiw

The general necropsy revealed multiple microabscesses in thekidneys, heart, and gastrointestinal tract. Necrotising absces-ses containing mixed bacterial flora were found in the lung,consistent with aspiration pneumonia. No microorganismswere demonstrated in other systemic organs.

NeuropathologyThe brain was unremarkable on inspection. It weighed 1 170 gafter fixation in 10% formaldehyde. No frank haemorrhagesor oedema was present. Microscopically, the most strikingpathology was in the cerebellum (fig a& b). There was almostcomplete loss of Purkinje cells, moderate reduction ofgranular neurons, and subtotal loss ofneurons in the dentatenucleus. Proliferating Bergmann's glia replaced the Purkinjecell layer, and were diffusely scattered throughout thethinned molecular layer. The cerebellar white matter waspale, vacuolated, and infiltrated by numerous macrophagesthat were most concentrated in the core of folia, deep whitematter, and adjacent to the dentate nucleus. The macro-phages contained myelin debris that stained blue with luxol-fast-blue (LFB). The white matter demonstrated loss ofmyelin and axons on LFB and Bodian's stain. Similarly, thesuperior cerebellar peduncle (SCP) and the dentatorubro-thalamic tract from the dentate hilum to the ventral thalamusdisplayed degeneration of axons and myelin associated withlipid-laden macrophages, characteristic of active Walleriandegeneration (fig c & d). The fibre tract degeneration was notpresent in other myelinated pathways and the cerebral whitematter was free of similar degeneration.The cerebral cortex, basal ganglia, and hippocampus were

free of anoxic-ischaemic changes. Neither dark shrunkenneurons nor neuronal loss were seen in any ofthe areas. Serialsections of hypothalamus taken at 3 mm intervals from theolfactory trigone to the level of pulvinar were free ofsignificant changes. The spinal cord was also unremarkable.The cerebrum, brainstem, and cerebellum had scattered

microabscesses of various ages in which rare yeasts withpseudohyphae consistent with candida were demonstrated.The muscles (deltoid and pectoralis major) were histo-

logically abnormal. Randomly scattered atrophic fibres werefocally surrounded by increased endomysial connectivetissue. Enzyme histochemical preparations performed onfrozen sections identified the atrophic fibres to be predomin-antly type II.

Discussion

Neuroleptic malignant syndrome (NMS), a rare com-plication of neuroleptic treatment, is fatal in up to22% of cases.2 Hyperpyrexia to a toxic degree (over

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Cerebellar degeneration in neuroleptic malignant syndrome

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Figure (a) The cerebellar cortex shows extensive loss ofPurkinje cells andproliferation ofBergmann 's glia. Moderate lossofneurons and gliosis is present in the internal granular layer and in the molecular layer. H&E ( x 90). (b) Macrophages ladenwith myelin debris in the cerebellar white matter that also shows loss offibres and vacuolation is indicative ofactive Walleriandegeneration secondary to cerebellar cortical degeneration. Luxol-fast-blue stain ( x 225). (c) The superior cerebellarpeduncle (SCP) at the level ofcaudal midbrain is pale and depleted ofmyelinatedfibres, in contrast to well-myelinatedfibretracts (medial longitudinalfasciculus: MLFand central tegmental tract: CTT). AQ: aqueduct ofSylvius. Luxol-fast-blue stain( x 9). (d) Numerous lipid-laden macrophages are present in the dentatorubrothalamic pathway in this sectionfrom rostralmidbrain. Oil-red-O ( x 360).

40"C) has been recorded in about a third of patientswith NMS in one series.2 Neuropathological studieshave been few, and to our knowledge, no cases sinilarto ours have previously been reported.The present patient suffered schizophrenia for many

years and had received multiple neuroleptics includingseveral phenothiazines and haloperidol, a butyro-phenone. Both groups are implicated in inducingNMS, the latter with a higher frequency. Our patienthad additionally been maintained on tetrabenazine, adopamine blocking and depleting agent used to treatmovement disorders. Tetrabenazine has also beenshown to cause NMS.8 The NMS in our patientdeveloped soon after the neuroleptic dose wasincreased, a previously reported pattern.2

Neuroleptic drugs predispose to hyperpyrexia bytheir anticholinergic properties, which block sweatingand heat dissipation, and by their antidopaminergicproperties, which interfere with hypothalamic

thermoregulation.>" When an abrupt catastrophicdisorder associated with hyperpyrexia occurs in apatient taking neuroleptics, the clinician must distin-guish heat stroke from NMS. Neuroleptic-inducedheat stroke can be differentiated from NMS by theabsence of extrapyramidal signs, absence ofdiaphoresis, and a history of physical exercise orexposure to high ambient temperature.2 A permanentcerebellar syndrome has been reported in a patientwith neuroleptic-induced heat stroke,9 but a patho-logical correlate was not described.Most patients who develop NMS survive without

complications. Reported fatalities have usuallyoccurred in the acute stages, within hours or days.2Our patient had an unusually long (4j month) survivalfollowing NMS, resulting in unique and dramaticpathologic alterations in the brain. This caserepresents the longest survival of heat-induced CNSinjury to be studied at postmortem examination. In the

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Table Cerebellar degeneration in hyperpyrexia

*Nwnbers of Purkinje cellAuthor(s) Aetiology cases Clinical signs degeneration

Current case NMS I Not Elicited +Yaqub et al'2 Heat stroke 1 Pancerebellar syndrome (atrophy on CT) NAYaqub et al'3 Heat stroke 1 Cerebe1Iar ataxia +Delgado et al" Heat stroke 1 Lower motor neuron and anhidrosis +Saksena et al5 Heat stroke I Pancerebellar syndrome NALefkowitz et aP Heat stroke 1 Pancerebellar syndrome NAPal and Chobra'6 Heat stroke 41 NA +Mehta and Baker'7 Heat stroke I Cerebellar, upper and lower motor neuron NAShibolet et al" Heat stroke 4 NA +Silverman and Wilson25 Thyroidectomy I Pancerebellar syndrome NAGore and Isaacson24 Fever therapy 17 NA +Malamud et al" Heat stroke 125 NA +Freeman and Dumoffl Heat stroke 2 Pancerebellar syndrome +Schwab2' Heat stroke (Animals) NA NA +Stewart22 Heat stroke I Pancerebellar syndrome NAWeisenberg23 Heat stroke I Cerebellar ataxia, aphasia, and motor NA

NA: Not Available.Numbers of cases showing clinical and/or pathologic cerebellar damage.

present case neuronal loss was marked in thecerebellum but not found in the cerebral cortex, basalganglia, or hippocampus indicating selective vulner-ability of cerebellar neurons to heat-induced injury.

It is clear from the previous studies that cerebellardeficits, either transient or permanently disabling, arecharacteristic of heat-induced CNS injury, whetherdue to heat stroke,9 12-23 fever therapy,24 or postsurgical(thyroidectomy) complications.25 To our knowledge,no cerebellar complications have been previouslyreported in patients surviving NMS or MH. Thedetails of the relevant literature including pathologicstudies of heat-induced CNS changes are summarisedin the table.

In neuropathological studies of hyperpyrexia,'61924the most common CNS abnormalities were oedema,congestion, and haemorrhages, particularly in th~evicinity of third and fourth ventricles, and in the whitematter. It was felt that these non-specific alterationswere related to terminal shock or circulatory collapsethat accompanied hyperpyrexia, since the severity anddistribution of these lesions were similar to thechanges in shock not associated with hyperpyrexia.The parenchymal injury due to hyperpyrexia per se

was most striking and constant in the cerebellum. Inthose cases where death occurred after more than aweek, the Purkinje cells were almost entirely lost, andthe neurons of the deep cerebellar nuclei were alsoinjured. With shorter survivals, however, the Purkinjecell changes were more subtle, consisting of neuronalswelling, pyknosis, or focal drop out. Interestingly, thecerebral cortex and basal ganglia were less frequentlyand only focally involved. This is in contrast tohypoxic CNS injury, in which selective vulnerability isshared among neurons in different regions of the brainincluding cerebral cortex, hippocampal Sommer's

sector, cerebellum, and basal ganglia.26The physical and biochemical properties that are the

basis of this selective vulnerability of cerebellarneurons to heat-induced injuries are not completelyknown. It has been shown, however, that preferentialdegeneration of cerebellar neurons can be induced byheat stress in animals.2' It has also been shown thatcertain cells, such as established cancer cell lines, differin their expression of heat shock protein during heatstress2" implying that response to heat stress is to someextent a function ofcell type. Recent in situ hybridisa-tion studies of heat shock protein expression in thebrains of rabbits have demonstrated heat shock geneinduction in the cerebellar neurons, in the absence ofsimilar changes in neurons ofother parts ofthe brain.28This would further indicate that cerebellar neurons areunique in their response to heat stress.

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