CASE REPORT
RICHARD A. BERNSTEIN, M.D.
Malignant neuroleptic syndrome: An atypical case Hyperthermia is a relatively rare but important sideeffect of the neuroleptic agents. Three types have been described: (I) the mild temperature elevations seen early in treatment with a variety of anti psychotics, (2) drug-related heat stroke, and (3) the so-called malignant neuroleptic syndrome, a serious idiosyncratic reaction that occurs without respect to the ambient temperature. I .) The present paper confines itself to the third type. A case report detailing the course ofa patient with recurrent hyperthermia is presented and discussed. Included in the discussion are some clinical guidelines for the recognition of the syndrome, a review of the suspected pathophysiology, and a consideration of other hyperthermias with which the syndrome might be confused. Case report A 36-year-old woman was admitted to the hospital for treatment of an acute psychosis characterized by labile affect, pressured speech, and flights of ideas. Despite a long previous outpatient record and a strong family history of mental illness, she had never before been hospitalized. Active medical problems on admission included mild hypertension, moderate obesity, and osteoarthritis.
Dr. Bernstein is assistant professor ofpsychiatry at the Universitr of Vermont Colle[{e of Medicine and director of the inpatient service at the Medical Center Hospital of Vermont. Reprint requests to him at Medical Alumni Building, Burlington, VT 05401.
840
Treatment began with 150 mg of chlorpromazine, given orally and repeated every six hours over four days, with some symptom remission. A syncopal episode attributed to the chlorpromazine led to the substitution of trifluoperazine. A total of 30 mg of this drug was given orally over the next two days with an additional single oral dose of 200 mg of chlorpromazine on hospital day 7 when the patient became agitated. Shortly thereafter, she experienced an episode of severe autonomic dysregulation, manifested by tachycardia, flushing, profuse diaphoresis, tachypnea, urinary incontinence, and hypotension with rebound hypertension. A thorough medical evaluation was started but it produced nothing definitive. On the eighth hospital day the woman was observed to be moving stiffly. Bilateral cogwheeling was found on examination. Benztropine, 2 mg, was given intramuscularly and continued as a 1-mg oral dose twice daily from day 9 to 13. Haloperidol, 3 mg orally twice daily, was given as the sole neuroleptic 2 from day 11 to 13. During this period the patient went from a state of passive hopelessness with fear of impending death to a highly agitated manic state. The patient again experienced an episode of autonomic instability on hospital day 13. In addition to the symptoms mentioned above, she developed a rectal temperature in excess of the 42 C limit of the thermometer. Her blood pressure fell precipitously, and a diagnosis of acute anterior myocardial infarction with pulmonary edema was made. She was transferred to the coronary care unit, where vigorous treatment was required to maintain her blood pressure and lower her temperature. The psychiatric status of the patient improved with her medical condition in the coronary care unit. She was maintained comfortably on small doses of diazepam and flu raze-
PSYCHOSOMATICS
Case report
pam. Shortly after her return to the psychiatric floor, however, she deteriorated. The mania returned, accompanied by confusion and marked loosening of associations. Lithium carbonate was started on hospital day 33 and was increased to a daily dose of 1800 mg. From day 34 to 37 the patient received a total of 400 mg of chlorpromazine orally. This was discontinued following the development of a rectal temperature of 38.2 C. Significant improvement was noted as lithium therapy continued. Sixteen days after starting the salt, the patient went home on pass. She returned in a disoriented manic state. At this point, molindone hydrochloride was added to the regimen and slowly increased to 60 mg daily. After 110 days in the hospital, the patient was discharged on lithium and 20 mg of molindone daily. Re-admission was required in less than three weeks. Again the patient responded well to lithium and molindone. When she was fully stabilized, she and her family gave permission for a drug challenge. The molindone was stopped but the lithium was continued. Haloperidol, 5 mg orally four times daily, was given for three days uneventfully. On the fourth day, 2 mg daily of benztropine was started for cogwheeling. The autonomic symptoms appeared again and the temperature rose to 38.4 C rectally. A decision was made not to rechallenge with chlorpromazine. Lithium and molindone were restarted and the patient was readied for discharge.
Discussion The patient developed hyperthermia on three separate occasions. Two episodes were closely associated with the administration of haloperidol and benztropine and one with chlorpromazine. Lithium was also being administered during the second and third episode. During the first two events she was severely agitated and therefore physiologically stressed. At the time of the challenge, she was stabilized emotionally and presumably at baseline physiologically. This point is significant, since physical exhaustion and dehydration have been postulated as necessary substrates for the development of the malignant neuroleptic syndrome. 4 All three episodes were heralded by marked autonomic dysregulation, which became worse and then persisted through the febrile course. Itoh and associates 4 made similar observations. Thus, autonomic instability may be regarded as a premonitory sign of hyperpyrexia and appropriate action can be taken. At no time was ambient temperature a factor; hospitalization occurred in the winter and early spring. The occurrence of a severe myocardial infarction greatly complicated an already complex course. At 36 years of age, menstruating, nonsmoking, and without a DECEMBER 1979 • VOL 20 • NO 12
strong family history, the patient was at relatively low risk. The sequence of events, and absence of other important cause, weigh the evidence heavily toward hyperpyrexia as a significant etiologic factor in the infarction. This is further supported by the fact that hypercoagulability of the blood, as well as other changes that facilitate thrombus formation, occurs with increased temperature. s In addition, the original description of the malignant neuroleptic syndrome (MNS) makes reference to "signs in the lung. such as congestions or infarcts,"3 which, like the patient's pulmonary edema, added stress to an already compromised myocardium. The mechanism of cardiac injury notwithstanding. the management of an agitated manic patient two weeks post infarct, for whom a further bout of hyperthermia could be fatal, was demanding. MNS has been reported with most of the major tranquilizers. 6 The sedative-hypnotics were ineffective. The anesthesia risk for electroconvulsive therapy was thought too great. Lithium was started when it was determined that the patient could handle the salt hemodynamically. Molindone was selected because MNS has not been reported with its use and, of the newer neuroleptics, it appears to have fewer autonomic side-effects. 6 It is noteworthy that MNS developed on relatively small doses of medication given by the oral route. This is in sharp contrast to the large doses of haloperidol given intramuscularly7 and chlorpromazine 8 as reported recently. The combination of lithium and haloperidol has been blamed for high fever and brain damage. 9 However, the small amounts of haloperidol and the occurrence of hyperpyrexia in the absence of this drug combination in the present case imply a different mechanism. A diagnosis ofdrug-induced hyperthermia was made when other causes were excluded. Presumptive evidence came from the temporal sequence of events. Infectious etiology was ruled out by negative cultures of blood. urine, sputum, and CSF. Metabolic tests including thyroid function, urinary 5-HIAA and vanillylmandelic acid were normal, as were screening tests for collagen vascular disease. A neurologic evaluation including lumbar puncture, skull x-rays, EEG, and CT scan was normal. The differentiation of MNS from other drug-caused hyperthermias is important. This is especially true of the central anticholinergic syndrome, which may be caused by the same agents. Here, the peripheral signs of atropine poisoning are present and the temperature is 84S
Case report
usually not as elevated. Physostigmine salicylate, indicated in treating the anticholinergic toxicity, is not beneficial in MNS. Immediate temperature reduction by all standard methods in addition to stopping any suspected drugs is the treatment. Whether MNS can be distinguished neurochemically from the "acute lethal catatonia" first described by Stauder in 1934 is open to question. 1O The two conditions can be almost identical clinically. Significant, however, is the fact that Stauder's observations antedated the "phenothiazine era," virtually eliminating the neuroleptics as causal agents. Another, perhaps related, entity is malignant hyperthermia. This inherited neuromuscular disorder is characterized by the predisposition in affected individuals to react to general anesthetic agents with very high fever and muscular rigidity'" Possibly all three syndromes share a neurochemical substrate. The pathophysiology of MNS has not been fully elucidated. Two mechanisms have been postulated, one central, the other peripheral. Centrally the neuroleptics may cause hyperthermia by inhibiting the thermoregulatory capacity of the hypothalamus. b This might be related to the ability of these drugs to block monoamines.'2 Peripherally the neuroleptics inhibit sweating, with subsequent reduction of cutaneous heat loss. 13 This atropinic effect is probably enhanced by using two antipsychotics simultaneously'4 or by using an antipsychotic with an antiparkinsonian agent having anticholinergic properties of its own. In the present case the patient developed her highest fever on haloperidol with
846
benztropine, but also became febrile when receiving chlorpromazine alone. Finally, the role of organic brain disease as a precondition for MNS has been suggested. 1O To date the patient is free of demonstrable organic pathology. However, suspicion has been raised recently by some new data, and further investigation is under way. 0
REFERENCES 1. Belfer ML, Shader RI: Autonomic effects, in Shader R, DiMascio A (eds): Psychotropic Drug Side Effects: Clinical and Theoretical Perspectives. Baltimore, Williams & Wilkins, 1970, pp 116-123. 2. Zelman S, Guillan R: Heat stroke in phenothiazine·treated patients: A report of three fatalities. Am J Psychiatry 126:1787-1790, 1970. 3. Delay J, Deniker P: Drug·induced extrapyramidal syndromes, in Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology, vol 6, Diseases of the Basal Ganglia. New York, American Elsevier, 1968, pp 248-266. 4. Itoh H, Ohtsuka N, Ogita K, et al: Malignant neuroleptic syndrome-its present status in Japan and clinical problems. Folia Psychiafr Neurol 31:565-576,1977. 5. Liebschutz DC, Boutros AR, Printen KJ: Metabolic responses to hyper· pyrexia. Surg Gynecol Obstet139:403-405, 1974. 6. van der Kolk BA, Shader RI, Greenblatt OJ: Autonomic effects of psychotropic drugs, in Lipton MA, DiMascio A, Killam KF (eds): Psychopharmacology: A Generation of Progress. New York, Raven Press, 1978. 7. Greenblatt OJ, Gross PL, Harris J, et al: Fatal hyperthermia following haloperidol therapy of Sedative-hypnotic withdrawal. J Clin Psychiatry 39:57-59, 1978. 8 Forester 0: Fatal drug-induced heat stroke. J Amer Coli Emer Physicians 7:243-244,1978. 9. Cohen WJ, Cohen NH: Lithium carbonate, haloperidol, and irreversible brain damage. JAMA 230:1283-1287,1974. 10. Meltzer HY: Rigidity, hyperpyrexia and coma following fluphenazine enanthate. Psychopharmacofogia 29:337-346,1973. 11. Britt BA, Anaes 0, Kalow W: Malignant hyperthermia: A statistical review. Can Anaesth Soc J 17:293-315, 1970 12. Lomax P: Drugs and body temperature, in Pfeiffer S (ed): International Review Neurobiol. New York, Academic Press, 1970, vol 12, pp 1-44. 13. Mahrer PR, Bergman PS, Estren S: Atropine-like poisoning due to tranquilizing agents. Am J Psychiatry 115:337-339,1958. 14. Westlake RJ, Rastegar A: Hyperpyrexia from drug combinations. JAMA 225:1250,1973.
PSYCHOSOMATICS
RICHARD A. BERNSTEIN, M.D.
Malignant neuroleptic syndrome: An atypical case Hyperthermia is a relatively rare but important sideeffect of the neuroleptic agents. Three types have been described: (I) the mild temperature elevations seen early in treatment with a variety of anti psychotics, (2) drug-related heat stroke, and (3) the so-called malignant neuroleptic syndrome, a serious idiosyncratic reaction that occurs without respect to the ambient temperature. I .) The present paper confines itself to the third type. A case report detailing the course ofa patient with recurrent hyperthermia is presented and discussed. Included in the discussion are some clinical guidelines for the recognition of the syndrome, a review of the suspected pathophysiology, and a consideration of other hyperthermias with which the syndrome might be confused. Case report A 36-year-old woman was admitted to the hospital for treatment of an acute psychosis characterized by labile affect, pressured speech, and flights of ideas. Despite a long previous outpatient record and a strong family history of mental illness, she had never before been hospitalized. Active medical problems on admission included mild hypertension, moderate obesity, and osteoarthritis.
Dr. Bernstein is assistant professor ofpsychiatry at the Universitr of Vermont Colle[{e of Medicine and director of the inpatient service at the Medical Center Hospital of Vermont. Reprint requests to him at Medical Alumni Building, Burlington, VT 05401.
840
Treatment began with 150 mg of chlorpromazine, given orally and repeated every six hours over four days, with some symptom remission. A syncopal episode attributed to the chlorpromazine led to the substitution of trifluoperazine. A total of 30 mg of this drug was given orally over the next two days with an additional single oral dose of 200 mg of chlorpromazine on hospital day 7 when the patient became agitated. Shortly thereafter, she experienced an episode of severe autonomic dysregulation, manifested by tachycardia, flushing, profuse diaphoresis, tachypnea, urinary incontinence, and hypotension with rebound hypertension. A thorough medical evaluation was started but it produced nothing definitive. On the eighth hospital day the woman was observed to be moving stiffly. Bilateral cogwheeling was found on examination. Benztropine, 2 mg, was given intramuscularly and continued as a 1-mg oral dose twice daily from day 9 to 13. Haloperidol, 3 mg orally twice daily, was given as the sole neuroleptic 2 from day 11 to 13. During this period the patient went from a state of passive hopelessness with fear of impending death to a highly agitated manic state. The patient again experienced an episode of autonomic instability on hospital day 13. In addition to the symptoms mentioned above, she developed a rectal temperature in excess of the 42 C limit of the thermometer. Her blood pressure fell precipitously, and a diagnosis of acute anterior myocardial infarction with pulmonary edema was made. She was transferred to the coronary care unit, where vigorous treatment was required to maintain her blood pressure and lower her temperature. The psychiatric status of the patient improved with her medical condition in the coronary care unit. She was maintained comfortably on small doses of diazepam and flu raze-
PSYCHOSOMATICS
Case report
pam. Shortly after her return to the psychiatric floor, however, she deteriorated. The mania returned, accompanied by confusion and marked loosening of associations. Lithium carbonate was started on hospital day 33 and was increased to a daily dose of 1800 mg. From day 34 to 37 the patient received a total of 400 mg of chlorpromazine orally. This was discontinued following the development of a rectal temperature of 38.2 C. Significant improvement was noted as lithium therapy continued. Sixteen days after starting the salt, the patient went home on pass. She returned in a disoriented manic state. At this point, molindone hydrochloride was added to the regimen and slowly increased to 60 mg daily. After 110 days in the hospital, the patient was discharged on lithium and 20 mg of molindone daily. Re-admission was required in less than three weeks. Again the patient responded well to lithium and molindone. When she was fully stabilized, she and her family gave permission for a drug challenge. The molindone was stopped but the lithium was continued. Haloperidol, 5 mg orally four times daily, was given for three days uneventfully. On the fourth day, 2 mg daily of benztropine was started for cogwheeling. The autonomic symptoms appeared again and the temperature rose to 38.4 C rectally. A decision was made not to rechallenge with chlorpromazine. Lithium and molindone were restarted and the patient was readied for discharge.
Discussion The patient developed hyperthermia on three separate occasions. Two episodes were closely associated with the administration of haloperidol and benztropine and one with chlorpromazine. Lithium was also being administered during the second and third episode. During the first two events she was severely agitated and therefore physiologically stressed. At the time of the challenge, she was stabilized emotionally and presumably at baseline physiologically. This point is significant, since physical exhaustion and dehydration have been postulated as necessary substrates for the development of the malignant neuroleptic syndrome. 4 All three episodes were heralded by marked autonomic dysregulation, which became worse and then persisted through the febrile course. Itoh and associates 4 made similar observations. Thus, autonomic instability may be regarded as a premonitory sign of hyperpyrexia and appropriate action can be taken. At no time was ambient temperature a factor; hospitalization occurred in the winter and early spring. The occurrence of a severe myocardial infarction greatly complicated an already complex course. At 36 years of age, menstruating, nonsmoking, and without a DECEMBER 1979 • VOL 20 • NO 12
strong family history, the patient was at relatively low risk. The sequence of events, and absence of other important cause, weigh the evidence heavily toward hyperpyrexia as a significant etiologic factor in the infarction. This is further supported by the fact that hypercoagulability of the blood, as well as other changes that facilitate thrombus formation, occurs with increased temperature. s In addition, the original description of the malignant neuroleptic syndrome (MNS) makes reference to "signs in the lung. such as congestions or infarcts,"3 which, like the patient's pulmonary edema, added stress to an already compromised myocardium. The mechanism of cardiac injury notwithstanding. the management of an agitated manic patient two weeks post infarct, for whom a further bout of hyperthermia could be fatal, was demanding. MNS has been reported with most of the major tranquilizers. 6 The sedative-hypnotics were ineffective. The anesthesia risk for electroconvulsive therapy was thought too great. Lithium was started when it was determined that the patient could handle the salt hemodynamically. Molindone was selected because MNS has not been reported with its use and, of the newer neuroleptics, it appears to have fewer autonomic side-effects. 6 It is noteworthy that MNS developed on relatively small doses of medication given by the oral route. This is in sharp contrast to the large doses of haloperidol given intramuscularly7 and chlorpromazine 8 as reported recently. The combination of lithium and haloperidol has been blamed for high fever and brain damage. 9 However, the small amounts of haloperidol and the occurrence of hyperpyrexia in the absence of this drug combination in the present case imply a different mechanism. A diagnosis ofdrug-induced hyperthermia was made when other causes were excluded. Presumptive evidence came from the temporal sequence of events. Infectious etiology was ruled out by negative cultures of blood. urine, sputum, and CSF. Metabolic tests including thyroid function, urinary 5-HIAA and vanillylmandelic acid were normal, as were screening tests for collagen vascular disease. A neurologic evaluation including lumbar puncture, skull x-rays, EEG, and CT scan was normal. The differentiation of MNS from other drug-caused hyperthermias is important. This is especially true of the central anticholinergic syndrome, which may be caused by the same agents. Here, the peripheral signs of atropine poisoning are present and the temperature is 84S
Case report
usually not as elevated. Physostigmine salicylate, indicated in treating the anticholinergic toxicity, is not beneficial in MNS. Immediate temperature reduction by all standard methods in addition to stopping any suspected drugs is the treatment. Whether MNS can be distinguished neurochemically from the "acute lethal catatonia" first described by Stauder in 1934 is open to question. 1O The two conditions can be almost identical clinically. Significant, however, is the fact that Stauder's observations antedated the "phenothiazine era," virtually eliminating the neuroleptics as causal agents. Another, perhaps related, entity is malignant hyperthermia. This inherited neuromuscular disorder is characterized by the predisposition in affected individuals to react to general anesthetic agents with very high fever and muscular rigidity'" Possibly all three syndromes share a neurochemical substrate. The pathophysiology of MNS has not been fully elucidated. Two mechanisms have been postulated, one central, the other peripheral. Centrally the neuroleptics may cause hyperthermia by inhibiting the thermoregulatory capacity of the hypothalamus. b This might be related to the ability of these drugs to block monoamines.'2 Peripherally the neuroleptics inhibit sweating, with subsequent reduction of cutaneous heat loss. 13 This atropinic effect is probably enhanced by using two antipsychotics simultaneously'4 or by using an antipsychotic with an antiparkinsonian agent having anticholinergic properties of its own. In the present case the patient developed her highest fever on haloperidol with
846
benztropine, but also became febrile when receiving chlorpromazine alone. Finally, the role of organic brain disease as a precondition for MNS has been suggested. 1O To date the patient is free of demonstrable organic pathology. However, suspicion has been raised recently by some new data, and further investigation is under way. 0
REFERENCES 1. Belfer ML, Shader RI: Autonomic effects, in Shader R, DiMascio A (eds): Psychotropic Drug Side Effects: Clinical and Theoretical Perspectives. Baltimore, Williams & Wilkins, 1970, pp 116-123. 2. Zelman S, Guillan R: Heat stroke in phenothiazine·treated patients: A report of three fatalities. Am J Psychiatry 126:1787-1790, 1970. 3. Delay J, Deniker P: Drug·induced extrapyramidal syndromes, in Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology, vol 6, Diseases of the Basal Ganglia. New York, American Elsevier, 1968, pp 248-266. 4. Itoh H, Ohtsuka N, Ogita K, et al: Malignant neuroleptic syndrome-its present status in Japan and clinical problems. Folia Psychiafr Neurol 31:565-576,1977. 5. Liebschutz DC, Boutros AR, Printen KJ: Metabolic responses to hyper· pyrexia. Surg Gynecol Obstet139:403-405, 1974. 6. van der Kolk BA, Shader RI, Greenblatt OJ: Autonomic effects of psychotropic drugs, in Lipton MA, DiMascio A, Killam KF (eds): Psychopharmacology: A Generation of Progress. New York, Raven Press, 1978. 7. Greenblatt OJ, Gross PL, Harris J, et al: Fatal hyperthermia following haloperidol therapy of Sedative-hypnotic withdrawal. J Clin Psychiatry 39:57-59, 1978. 8 Forester 0: Fatal drug-induced heat stroke. J Amer Coli Emer Physicians 7:243-244,1978. 9. Cohen WJ, Cohen NH: Lithium carbonate, haloperidol, and irreversible brain damage. JAMA 230:1283-1287,1974. 10. Meltzer HY: Rigidity, hyperpyrexia and coma following fluphenazine enanthate. Psychopharmacofogia 29:337-346,1973. 11. Britt BA, Anaes 0, Kalow W: Malignant hyperthermia: A statistical review. Can Anaesth Soc J 17:293-315, 1970 12. Lomax P: Drugs and body temperature, in Pfeiffer S (ed): International Review Neurobiol. New York, Academic Press, 1970, vol 12, pp 1-44. 13. Mahrer PR, Bergman PS, Estren S: Atropine-like poisoning due to tranquilizing agents. Am J Psychiatry 115:337-339,1958. 14. Westlake RJ, Rastegar A: Hyperpyrexia from drug combinations. JAMA 225:1250,1973.
PSYCHOSOMATICS
