NEUROLEPTIC MALIGNANT SYNDROME : A REPORT OF 2 CASES

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1 Chiang Mai Med bull 2005;44(2): Case report NEUROLEPTIC MALIGNANT SYNDROME : A REPORT OF 2 CASES Oranee Sanmaneechai, M.D., Surachai Likasitwattanakul, M.D. Department of Pediatrics, Faculty of Medicine, Chiang Mai University Abstract Neuroleptic malignant syndrome (NMS) is an iatrogenic and potentially fatal complication of neuroleptic medications. It is characterized by fever, altered mental status, muscle rigidity, and autonomic instability. Since these symptoms are non-specific, a high index of suspicious should be made especially in any patients with a history of neuroleptic treatment. The authors report two cases of adolescent girls who developed NMS after the use of neuroleptic medications and stress on prompt recognition and treatment in this condition. Chiang Mai Med Bull 2005;44(2): Keywords: Neuroleptic malignant syndrome, children Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal complication of neuroleptic medications. 1 Its cardinal features are sudden onset of hyperthermia, muscle rigidity, alteration of mental status, and autonomic dysfunction. (1-2) The estimated incidence of NMS in those individuals exposed to neuroleptic medications ranges from 0.07 to 1.4%. (3) NMS has been reported in all age groups and both sexes, but predominantly in young and middle-aged adults. (2,4) Since mortality in this syndrome is as high as 25%, especially when under-recognized, prompt recognition and early treatment are crucial. (5) The authors report 2 adolescent girls who developed NMS after the use of neuroleptic medications. Case report Case 1 A 13-year-old girl, who was blind from retinopathy of prematurity, was admitted to a provincial hospital one month before referral with brief psychotic disorder. A one-week trial of haloperidol at 3 mg /day and artane at 4 mg/day was given without clinical improvement. She was then placed on thioridazine at 150 mg/day and fluoxitin at 10 mg/day. Two weeks after this combination, her consciousness fluctuated between agitation and a decreased level of consciousness. Fever at a peak of 38.5 C and muscle stiffness of the body and limbs were observed. Chlorpromazine, propanolol and diazepam were given Address requests for reprints: Surachai Likasitwattanakul, M.D. Department of Pediatric, Faculty of Medicine, Mahidol University, Bangkok 10330, Thailand. sisli@mahidol.ac.th Received 11 August 2004, and in revised form 1 Decmeber 2004

2 74 Likasitwattanakul S. without clinical improvement, she was then referred to Chiang Mai University Hospital. On admission, her body temperature was 37 C, respiratory rate 36 breaths/min, blood pressure 136/92 mmhg, and pulse rate 100 beats/min. She was restless and verbally unresponsive. Neurological examination revealed generalized hypertonia, lead-pipe rigidity and hyperreflexia. Laboratory findings showed a leukocytosis of 12,000 cells/mm (3) with 74% neutrophils, and serum creatine kinase (CK) of 335 IU/L (normal 0-195). Cerebrospinal fluid examination, and renal and liver function tests were normal. NMS was diagnosed. During the next 24 hours, fluctuation of respiratory rate (20-36 breaths/ min), pulse rate ( beats/min) and blood pressure ( mmhg systolic and mmhg diastolic) were observed. All medications were discontinued, and bromocriptine at 10 mg/day and diphenhydramine at 100 mg/day were started. Her consciousness gradually improved on the third hospital day and the extrapyramidal symptoms improved after one week of treatment. The serum CK decreased to 44 IU/L after two weeks of treatment. Case 2 A previously healthy 12-year-old girl was transferred to our hospital with fever and altered mental status. One day before, she was admitted to a local hospital with hyperventilation syndrome that occurred after having an argument with her mother. After multiple doses of intravenous diazepam for agitation and recurrent hyperventilation syndrome episodes, intramuscular haloperidol at 10 mg was given. Within 2 hours after the injection, her consciousness fluctuated between agitation and no response to verbal command. Fever, muscle rigidity, and lead-pipe rigidity were observed. She was then transferred to Chiang Mai University Hospital. On admission, her body temperature was 38.8 C, pulse 130 beats/min, blood pressure 116/64 mmhg, and respiratory rate 22 breaths/min. Neurological examination revealed resting tremor, generalized hypertonia and lead-pipe rigidity. Laboratory findings showed a leukocytosis of 14,800 cells/mm 3 with 78% neutrophils, and serum CK of 407 IU/L. Other laboratory results, including CSF analysis, renal and liver function tests and electrolyte were normal. Urine heme was positive. Fluctuations of pulse rate were observed during the first 24 hours ( beats/minute). On the basis of these findings, NMS was diagnosed. Soon after admission she developed respiratory failure and needed respiratory support. Bromocriptine at 7.5 mg/day and diphenhydramine at 100 mg/day were administered via nasogastric tube. Intravenous lorazepam was given intermittently for severe agitation. Supportive treatment included intravenous fluid, and alkalinization of the urine to prevent renal failure from myoglobinuria. She developed generalized tonic seizure during admission and was controlled with phenobarbital. Serum CK was initially increased to 1,219 IU/L on day 5 after admission and decreased to 424 on day 10. Her consciousness gradually improved and she was extubated after 5 days of mechanical ventilation. Persistence of extrapyramidal symptoms including oro-facial dystonia and limb rigidity were observed after a 3-week hospital stay. She was discharged from hospital, with bromocriptine and artane prescribed for extrapyramidal symptoms and phenobarbital for seizure control. Rigidity as well as dystonia of oro-facial muscles and limbs improved

3 Neuroleptic maliganant syndrome 75 gradually and no seizures were noted after being discharged. All medications were discontinued within 4 months. Discussion These two cases had all the cardinal features of NMS after receiving conventional neuroleptic drugs. In the first patient, symptoms of NMS occurred within 2 weeks after neuroleptic medication. Since the patient s mental status deteriorated, which could have been caused by worsening of the brief psychotic episode, additional neuroleptic drugs were used. This might have contributed to the full clinical picture of NMS in this patient. In the second patient, symptoms of NMS occurred rather rapidly after an intramuscular injection of haloperidol, which can be seen in up to 16% of patients with NMS. (6) This patient developed several complications from NMS such as rhabdomyolysis, hemoglobinuria and respiratory failure. With supportive care and use of bromocriptine, both patients survived without complications. NMS is a rare, idiosyncratic reaction to neuroleptic medications. (1) The most common drugs that cause NMS are conventional neuroleptic medications (haloperidol, chlorpromazine). (1,2,4) However, atypical neuroleptic medications such as risperidone and olanzapine may also cause this syndrome. (7) The risk of developing NMS among neuroleptic medication users ranges from %. (3) Several cases have been reported from Thailand, however, this condition is still under recognized. (8-10) Factors that increase the risk of NMS are those among patients with psychomotor agitation, higher dose and rapid rate of dosage increase, and parenteral injections. (11) Of the patients who develop NMS, 16% develop NMS features within 24 hours after exposure to neuroleptic medications, 66% by 1 week, and 96% within 30 days. (6) Four prominent clinical features of NMS are hyperthermia, motor symptoms, altered mental status and autonomic instability. (2) Hyperthermia is found in 98% of patients and their temperature peak ranges from 38 C to over 41 C. The most common motor symptoms include lead-pipe rigidity. Other less common features are tremor, bradykinesia, or akinesia that characterize parkinsonian phenotype. Altered mental status ranges from clouding of consciousness to stupor or coma. Autonomic instability manifests by tachycardia, fluctuation of blood pressure and respiratory irregularities. The two most important laboratory findings in NMS are leukocytosis and increased serum CK level. (2,4) Nonspecific leukocytosis with or without left shift ranges from 15,000-30,000/mm. (3) Elevated CK level, which results from muscle injury, ranges from 2,000-15,000 IU/L, but may be lower than 600 IU/L in a few patients. (1) However, the clinical features and severity as well as laboratory findings in NMS vary from patient to patient. Many diagnostic criteria for NMS such as the Diagnostic and Statistical Manual of Mental Disorders, 4 th edition (DSM IV) (3) (Table 1) and Levenson s criteria. (1) (Table 2) are proposed to facilitate the diagnosis of this condition. Differential diagnoses of NMS include central nervous system infection, metabolic encephalopathy, malignant hyperthermia, and serotonin syndrome (SS). (12) Both patients had normal renal and liver function tests, and CSF examination and that excluded CNS infection

4 76 Likasitwattanakul S. and metabolic disturbances. No history of halogenated inhalation anesthetic agent use excluded malignant hyperthermia. SS shares many clinical features with NMS. SS should be a differential diagnosis in the first patient, since she received a combination of antipsychotic drugs a and selective serotonin reuptake inhibitor (SSRI). However, a lack of clinical features for myoclonus, pupillary dilatation and bowel hyperactivity favored a diagnosis of NMS in this patient. In addition, typically, SS develops very quickly, with 75% of patients developing the syndrome during the first 24 hours after initiating or increasing the dosage of an SSRI agent. Although the pathogenesis of NMS is not completely understood, it is believed that the condition is a result of altered central dopamine neurotransmission. (1-2) Medications that block central dopaminergic receptors, such as neuroleptic drugs, are the most common causes of NMS. In addition, sudden discontinuation of dopaminergic drugs could cause NMS, as seen in patients with pakinsonism. (4) Prompt recognition and discontinuation of the offending drugs are a crucial part of management. (5) Symptomatic treatment includes adequate intravenous fluids, antipyretics, correction of metabolic disturbances, and adequate renal and cardiopulmonary support and monitoring. (12) Fever reduction is very important, since it may cause hyperthermia and multiple organs injury. No controlled trial study is available for the use of pharmacologic treatment in this condition. Nevertheless, the most common drugs used in this syndrome are dantrolene and bromocriptine. Dantrolene is a muscle relaxant, which is used for controlling spasticity and hyperthermia. Unfortunately, this medication is not available in Thailand. Table 1. Criteria for diagnosis of NMS (DSM IV) (3) A. The development of severe muscle rigidity and elevated temperature associated with the use of antipsychotic medication. B. Two or more of the following: - Diaphoresis - Elevated blood pressure - Tachycardia - Incontinence - Dysphagia - Mutism - Tremor - Changes in the level of consciousness ranging from confusion to coma - Leukocytosis - Laboratory evidence of muscle injury (e.g. elevated CK). C. The symptoms in criteria A and B are not due to another substance (e.g. phencyclidine), or neurologic or other medical condition (e.g. viral encephalitis). D. The symptoms in criteria A and B are no better accounted for by a mental disorder (e.g. mood disorder with catatonic features). From: Diagnostic and Statistical Manual of Mental Disorders, fourth edition. Washington, DC: American Psychiatry Association; 1994 Table 2. Levenson s clinical criteria for diagnosis of NMS (1) Major manifestations - Fever - Rigidity - Elevated creatinine phosphokinase concentration Minor manifestations - Abnormal arterial pressure - Altered consciousness - Diaphoresis - Leukocytosis The presence of all three major or two major and four minor criteria suggests a high probability of the presence of NMS, if supported by clinical history (e.g. not indicative of malignant hyperthermia).

5 Neuroleptic maliganant syndrome 77 Bromocriptine is a dopaminergic agonist and presumably actis by reversing dopaminergic receptor blockage caused by neuroleptic medications. The initial dose should be 2.5 to 5 mg t.i.d. with an increment of 2.5 mg t.i.d. every 24 hours. Doses of up to 60 mg per day have been used. (12) Side effects of this medication include hypotension, nausea and worsening of psychotic symptoms. Medications should be continued for at least 10 days and up to 2-3 weeks when depot neuroleptics are used after the resolution of the symptoms. (12) Treatment with these medications has shown to improve outcome and shorten the course of NMS. (5,14) Other medications used in NMS are amantadine, levodopa, and benzodiazepine. (2,12) Both beneficial and harm-ful effects from anticholinergic drugs in NMS have been reported. (13) Electroconvulsive treatment has been shown as effective in the treatment of NMS, especially in severe cases that are refractory to medications, when it is difficult to rule out lethal catatonia, or when the underlying conditions are psychotic depression or catatonia. (14) Treatment with ECT is relatively safe and the response may be apparent during early treatment. Symptoms of NMS usually subside 5-10 days after cessation of the medication, but 2-3 times longer with long-acting depot injections. (12) A complication from NMS is rhabdomyolysis, which may cause acute renal failure. It is the most common cause of death in patients with NMS. (5) Respiratory failure may occur from aspiration, pulmonary emboli, septic shock, or decreased chest wall movement from muscle rigidity. (1) Other complications are cardiac failure, arrhythmia, pulmona-ry embolism, and disseminated intravascular coagulation. Death from this syndrome may be as high as 25%, especially when it is unrecognized. 5 Decreased mortality rate may reflect early awareness of this syndrome rather than early treatment. Recurrence of NMS by rechallenging these patients with neuroleptic medications may be as high as 30%. (2) Using less potent drugs at the lowest clinically effective dose, and the time reintroduction starting at least 2 weeks after complete resolution of NMS, can reduce the risk of recurrent NMS. (12) Conclusion Neuroleptic malignant syndrome is a potentially life threatening condition caused by an idiosyncratic reaction to neuroleptic agents. A high index of suspicion is needed to recognize this syndrome, especially in any febrile patients with a history of neuroleptic treatment. Early recognition, discontinuation the offending medications, supportive care and appropriate use of pharmacologic treatment may lead to effective management and decreased morbidity. References 1. Levenson JL. Neuroleptic malignant syndrome. Am J Psychiatry 1985;142: Caroff SN, Mann SC. Neuroleptic malignant syndrome. Med Clin North Am 1993;77: American Psychiatric Association. Diagnostic and statistical manual of mental disorders. Washington DC: American Psychiatric Press, 1994: Guze BH, Baxter LR, Jr. Current concepts. Neuroleptic malignant syndrome. N Engl J Med 1985;313: Shalev A, Hermesh H, Munitz H. Mortality from neuroleptic malignant syndrome. J Clin Psychiatry 1989;50:18-25.

6 78 Likasitwattanakul S. 6. Caroff SN, Mann SC. Neuroleptic malignant syndrome. Psychopharmacol Bull 1988;24: Ananth J, Parameswaran S, Gunatilake S, Burgoyne K, Sidhom T. Neuroleptic malignant syndrome and atypical antipsychotic drugs. J Clin Psychiatry 2004; 65: Kanchanapongkul J. Neuroleptic malignant syndrome: a report of a case and review of the literature. J Med Assoc Thai 1991; 74: Poungvarin N, Prayoonwiwat N, Viriyavejakul A. Neruoleptic malignant syndrome: A case report and review of the literature. Siriraj Hosp Gaz 1993; 74: Kankirawatana P, Raksadawan N. Neuroleptic malignant syndrome. Siriraj Hosp Gaz 1995; 47: Keck PE, Jr., Pope HG, Jr., Cohen BM, McElroy SL, Nierenberg AA. Risk factors for neuroleptic malignant syndrome. A casecontrol study. Arch Gen Psychiatry 1989; 46: Richard IH. Acute, drug-induced, lifethreatening neurological syndromes. The Neurologist 1998; 4: Smego RA, Jr., Durack DT. The neuroleptic malignant syndrome. Arch Intern Med 1982; 142: Trollor JN, Sachdev PS. Electroconvulsive treatment of neuroleptic malignant syndrome: a review and report of cases. Aust N Z J Psychiatry 1999;33: กล มอาการน วโรเลพต ค มาล กแนนท : รายงานผ ป วย 2 ราย อรณ แสนมณ ช ย, พ.บ., ส รช ย ล ขส ทธ ว ฒนก ล, พ.บ. ภาคว ชาก มารเวชศาสตร คณะแพทยศาสตร มหาว ทยาล ยเช ยงใหม บทค ดย อ กล มอาการน วโรเลพต ค มาล กแนนท เป นภาวะแทรกซ อนจากการใช ยาท พบได น อยมาก ผ รายงานได รายงานผ ป วยเด ก 2 รายท ม อาการไข ม ระด บสต ส มปช ญญะเปล ยนแปลง ม อาการ เกร งของกล ามเน อ และม ความผ ดปกต ของระบบประสาทเสร ภายหล งได ยาประเภทยากล อม ประสาทหล ก ผ ป วยท งสองรายได การร กษาด วยยาโบรโมคร พท นและการร กษาแบบประค บ- ประคองซ งได ผลด เน องจากผ ป วยท ม ภาวะแทรกซ อนชน ดน อาจจะเส ยช ว ตได ผ รายงานจ งเน น ถ งการท แพทย ใช ยาประเภทน ควรม ความร และสามารถว น จฉ ยภาวะน ได ต งแต เน นๆ ซ งอาจจะ ท าให ผ ป วยรอดช ว ตจากภาวะแทรกซ อนน ได เช ยงใหม เวชสาร 2548;44(2): ค าส าค ญ: กล มอาการน วโรเลพต ค