Clozapine, Neuroleptic Malignant Syndrome, and Pancerebellar Syndrome

THOMAS M. BROWN, M.D.

euroleptic malignant syndrome (NMS) has been recognized as a complication of antipsychotic drug therapy since Delay and Deniker wrote about it in 1968, and the earliest case of NMS can probably be traced as far back as 1959.1,2 The classic ndings in NMS are the quartet of fever, autonomic instability, altered mental status, and skeletal muscle rigidity. The incidence of NMS has been debated for decades, with a low gure of 0.07% sometimes offered, but the debated incidence has generally ranged from 0.1% to 2.5%. Pope and coauthors reviewed 500 patient records, and they found that 1.4% of patients developed denite or probable NMS. This correlated well with a gure of 0.5% to 1.0% calculated for the development of NMS in a population of several hundred patients observed by Delay and coauthors.35 Factors that have been reported to predispose to NMS include dehydration, mood disorder, youth, being male, severe agitation, low serum iron concentrations, intramuscular route of antipsychotic administration, higher dosages of antipsychotic medication, and probably mental retardation or prior structural brain injury.68 Although generally regarded as a rare complication of antipsychotic drug therapy, such percentages strongly suggest that underrecognition of this disorder may play a role in the apparent infrequence of NMS. First reported in conjunction with the use of lithium by Pope and coauthors, clozapine-associated NMS has subsequently been reported in conjunction with other nonneuroleptic medications, and with clozapine alone.912 Complicating the potential problem of underrecognition of NMS when it presents as fever, autonomic instability, altered mental status, and skeletal muscle rigidity, is the problem of determining whether NMS is present when one of the ndings is absent. This is important in the case of
Received January 22, 1998; accepted April 28, 1999. From the Department of Psychiatry and Neurology, Tulane University Medical Center, 900 Powells Point, Gautier, MS 39553; e-mail: drugeffects@ibm.net. Address correspondence and reprint requests to Dr. Brown at the same address. Copyright 1999 The Academy of Psychosomatic Medicine.

clozapine, for which both typical cases of NMS involving all four ndings, and atypical cases, in which rigidity is lacking, have been reported.8,1316 Of note, NMS in the absence of rigidity has been reported for traditional neuroleptics.17 The following is a case of NMS without rigidity that developed after the initiation of clozapine in a patient with multiple predisposing factors, and concluded with residual brain injury consistent with a pancerebellar syndrome.

Case Report

BDC was a 17-year-old, institutionalized, black male with a history of cognitive disability and agitation who was started on clozapine in an attempt to manage his behavior. High doses of traditional neuroleptics were tried without successful reduction in episodic agitation. These neuroleptics included chlorpromazine, haloperidol, thioridazine, thiothixene, and triuoperazine. Severe akathisia complicated some of these drug trials; inconsistent effects on agitation were observed at other times. Ultimately, it was decided to give BDC a trial of clozapine. At this time, his medications were haloperidol (30 mg po tid), trihexyphenidyl (2 mg po qid), lithium carbonate (300 mg po qid), and chlorpromazine (50 mg po or im as needed) for agitation. A haloperidol taper was completed with 18 days. On the fteenth day of the haloperidol taper, clozapine (25 mg po qhs) was begun. Over the next 2 weeks, the clozapine was increased to 100 mg po bid. Sedation, enuresis, and orthostasis developed by the seventeenth day of clozapine therapy. BDC began to have multiple falls. On the 24th day of clozapine therapy, one fall concluded with tonic-clonic movements, which prompted an emergency room evaluation and discontinuation of clozapine. Two days after the seizure activity, an electroencephalogram (EEG) revealed bursts of slow waves and some spike forms . . . evidence of generalized encephalopathy. The consulting neurologist considered that the degree of slowing is unlikely to be due to Thorazine effect, with uncertain contributions from clozapine. A seizure due to clozapine-induced hypotension was suspected. A week after the clozapine was stopped, a repeat sleeping EEG was normal. The clozapine ultimately was held for 19 days, and then resumed at 100 mg po qhs. Psychosomatics 40:6, November-December 1999

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Lithium was continued throughout. Clozapine was increased 4 days later to 100 mg po bid. BDC gradually became lethargic again, and subsequently required Ensure as a feeding supplement. He was reported to vomit at least once. Fifteen days after the last dosage increase, the patient became unresponsive, with a temperature recorded at 102 F, and a pulse of 102 beats/minute. Muscle tone was noted to be normal, leading to the active exclusion of NMS from the differential diagnoses. BDC was transferred to a tertiary hospital for further evaluation. BDC required a 47-day hospitalization. His creatinine phosphokinase (CPK) peaked at 1,931 units/Liter on admission. Creatinine rose to 3.6 milligrams/deciliter, and blood urea nitrogen to 40 milligrams/deciliter in the rst week after admission. Fever to 104 F was noted, in a picket fence pattern. Fever was recorded for 11 days after admission. A magnetic resonance image of the brain was normal. The white blood cell count rose from 3.8 103 cells/microliter 8 days before admission, to 17.4 103 cells/microliter on Day 7 of admission, consistent with leukocytosis. Multiple blood and urine cultures were negative. Aspirin, a total of 1 gram of ceftriaxone, intravenous hydration, and enteral feeds were given. Bromocriptine and dantrolene were not used. BDC began to respond to commands after 3 days. He resumed communication within 3 weeks. Initially, though, he was mute, and did not speak when communicating. Throughout his hospitalization, BDC was noted to lack skeletal muscle rigidity. However, abnormalities of muscle tone and movement were noted. The consulting neurologist described BDCs muscle tone as accid. The nurses at the tertiary hospital observed that BDC had tremors of the arms when they are working with him. The neurologist found on occasion that BDC seemed to have athetosis, and on another occasion that BDC had hyperextended his neck and body in a manner that he found inconsistent with a seizure. Dysphagia was also noted. After discharge, BDC had severe truncal ataxia and difculty with head control . . . upper extremity movements had features of athetosis and hemiballismus as well as dystonia . . . [with] severe dysmetria and past pointing. BDC had difculty knowing where his limbs were in space. Eight years later, BDC has residual and severe hypotonia, dysarthria, truncal ataxia and limb ataxia, and balance problems. There is no evidence of athetosis, hemiballismus, dystonia, or difculty locating his extremities in space. Clozapine has never been resumed. However, BDC has occasionally received haloperidol without development of NMS.

Discussion BDC met all criteria typically offered for a diagnosis of NMS, except that he did not have severe skeletal muscle rigidity. Extrapyramidal ndings might have included tremor and athetosis noted early in BDCs course, as well as dysphagia and perhaps opisthonus.5 Other possible reasons for the absence of severe skeletal muscle rigidity may have included an overriding hypotonia as a result of cerePsychosomatics 40:6, November-December 1999

bellar injury: this would not have masked extrapyramidal ndings associated with movement, such as athetosis, but might have limited the ability to detect rigidity. However, it may be that the abnormal movements, interpreted as athetosis, tremor, and ballism were otherwise normal movements impaired by dyssynergia. It is also possible that clozapines distinct antagonism of serotonin 5HT2a receptors, as well as its more modest antagonism of muscarinic cholinergic receptors, may have masked the nding of rigidity.18 If profound dopamine D2 receptor blockade may be postulated as a possible cause of NMS, then it may be equally possible that some individuals will develop concomitant and profound muscarinic cholinergic receptor blockade. Such excessive receptor blockade might help to explain why clozapine when used alone may cause NMS.11 In BDCs case, the concomitant use of lithium may have been an important factor leading to the development of NMS. Lithium may play a facilitating role in the development of NMS through serotonergic mechanisms.19 The close temporal association of the development of NMS with the introduction of clozapine, and the fact that BDC had never experienced NMS during his treatment with multiple other antipsychotics, strongly link the development of NMS to BDCs use of clozapine.In addition to the atypical quality of BDCs case of NMS, the fact that BDC had lasting cerebellar injury is noteworthy. This is, in fact, the rst report of pancerebellar injury as a consequence of clozapine-induced NMS. Indeed, only one other case of lasting cerebellar injury due to NMS exists.20 If the cerebellar injury did in fact mask the extrapyramidal ndings, then it is possible that NMS with rigidity masked by hypotonia occurs more often than is generally realized.Finally, the issue of treatment must be discussed. Although BDC received vigorous hydration and an antipyretic, he never received electroconvulsive therapy (ECT) or a trial of bromocriptine. Understandably, ECT is sometimes difcult to orchestrate. However, a trial of bromocriptine is relatively easy to undertake. Bromocriptine might have proved helpful both in reducing the severity of BDCs acute illness and the extent of his residual brain injury, as well as helping to suggest whether a profound dopamine-receptor blockade consistent with a diagnosis of NMS was present. The risks of a trial of bromocriptine are relatively small compared to the complications of untreated NMS.21 These complications include death in roughly 20% to 30% of patients, primarily the untreated.22In retrospect, BDCs case underscores two crucial issues in relation to NMS. The rst is the possibility that an atypical form of NMS exists, in which skeletal muscle rigidity is not present. In cases in which the diagnosis
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of NMS is in doubt, the clinical criteria of Pope et al. represent an operationalized way to assess the possibility of the diagnosis.5 The second issue is that of treatment. If there are no strong contraindications to a trial of bromocriptine or of ECT, then the clinician must offer sound reasons for not attempting either of these treatmentseven if there is some doubt about the diagnosis of NMS in the absence of skeletal muscle rigidity.

References

1. Delay J, Deniker P: Drug-induced extrapyramidal syndromes, in Handbook of Neurology. Diseases of the Basal Ganglia, Vol 6, edited by Bruyn GW. Amsterdam, The Netherlands, North Holland Publishing Company, 1968, pp. 248266 2. Walker MFC: Simulation of tetanus by triuoperazine overdosage. Can Med Assoc J 1959; 81:109110 3. Addonizio G, Susman VL, Roth SD: Symptoms of neuroleptic malignant syndrome in 82 consecutive inpatients. Am J Psychiatry 1986; 143:15871590 4. Caroff SN: The neuroleptic malignant syndrome. J Clin Psychiatry 1980; 41:7983 5. Pope HG, Keck PE, McElroy SL: Frequency and presentation of neuroleptic malignant syndrome in a large psychiatric hospital. Am J Psychiatry 1986; 143:12271233 6. Boyd RD: Neuroleptic malignant syndrome and mental retardation: review and analysis of 29 cases. Am J Ment Retard 1993; 98:143 155 7. Kornhuber J, Weller M: Neuroleptic malignant syndrome. Curr Opin Neurol 1994; 7:353357 8. Amore M, Zazzeri N, Berardi D: Atypical neuroleptic malignant syndrome associated with clozapine treatment. Neuropsychobiology 1997; 35:197199 9. Pope HG, Cole JO, Choras PT, et al: Apparent neuroleptic malignant syndrome with clozapine and lithium. J Nerv Ment Dis 1986; 174:493495 10. Muller T, Becker T, Fritze J: Neuroleptic malignant syndrome after clozapine plus carbamazepine. Lancet 1988; ii:1500 11. Miller DD, Sharafuddin MJA, Kathol RG: A case of clozapineinduced neuroleptic malignant syndrome. J Clin Psychiatry 1991; 52:99101

12. Chatterton R, Cardy S, Schramm TM: Neuroleptic malignant syndrome and clozapine monotherapy. Aust N Z J Psychiatry 1996; 30:692693 13. Nopoulos P, Flaum M, Miller DD: Atypical neuroleptic malignant syndrome (NMS) with an atypical neuroleptic: clozapine-induced NMS without rigidity. Ann Clin Psychiatry 1990; 2:251253 14. Goates MG, Escobar JI: An apparent neuroleptic malignant syndrome without extrapyramidal symptoms upon initiation of clozapine therapy: report of a case and results of a clozapine rechallenge. J Clin Psychopharmacol 1992; 12:139140 15. Reddig S, Minnema AM, Tandon R: Neuroleptic malignant syndrome and clozapine. Ann Clin Psychiatry 1993; 5:2527 16. Sachdev P, Kruk J, Kneebone M, et al: Clozapine-induced neuroleptic malignant syndrome: review and report of new cases. J Clin Psychopharmacol 1995; 15:365371 17. Rosebush P, Stewart T: A prospective analysis of 24 episodes of neuroleptic malignant syndrome. Am J Psychiatry 1989; 146:717 725 18. Baldessarini RJ, Frankenburg FR: Clozapine: a novel antipsychotic agent. N Engl J Med 1991; 324:746754 19. Halman M, Goldbloom DS: Fluoxetine and neuroleptic malignant syndrome. Biol Psychiatry 1990; 28:518521 20. Slee AM, Kim TS, Liebling M, et al: Cerebellar degeneration in neuroleptic malignant syndrome: neuropathologic ndings and review of the literature concerning heat-related nervous system injury. J Neurol Neurosurg Psychiatry 1989; 52:387391 21. Brown TM, Stoudemire A: Antipsychotics, in Psychiatric Side Effects of Prescription and Over-the-Counter Medications. Washington, DC, American Psychiatric Press, 1998, pp. 333 22. Schneider SM: Neuroleptic malignant syndrome: controversies in treatment. Am J Emerg Med 1991; 9:360362

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