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Risperidone Induced Neuroleptic Malignant Syndrome: A case report and review of the literature. Authors: First Author Roopali Sharma, Pharm.D Assistant Professor Arnold & Marie Schwartz College of Pharmacy, Adjunctive clinical instructor of department of medicine State University of New York at Brooklyn Brooklyn, NY Second Author Brian Trappler, M.D. Assistant Clinical Professor of Psychiatry State University of New York at Brooklyn Brooklyn, NY Third Author Yiu Kee NG, M.D. Clinical Assistant Instructor State University of NY at Brooklyn Brooklyn, NY Fourth Author Cavin Leeman, M.D. Professor of Clinical Psychiatry State University of NY at Brooklyn Brooklyn, NY Corresponding author: Roopali Sharma, Pharm.D. Address for reprints: Health Science center at Brooklyn 445 Lenox Rd., Box 36 Brooklyn, NY 11203 Phone: (718) 270-1527 Fax: (718) 270-3360 ABSTRACT OBJECTIVE: To describe a patient with neuroleptic malignant syndrome (NMS) induced by risperidone, an atypical antipsychotic and to review the available literature related to risperidone associated NMS. DATA SOURCE: Case report information was obtained from the resident physician and medical records. MEDLINE and Index Medicus were searched to obtain literature published between 1960 and 1995. DATA SYNTHESIS: We report an adolescent boy who developed NMS after treatment with risperidone. Risperidone therapy was started after unsuccessful treatment and development of extrapyramidal side effects with haloperidol. The patient demonstrated the classic tetrad of fever, generalized skeletal muscle rigidity, altered mental status, and autonomic dysfunction. Risperidone was discontinued and the patient recovered after a prolonged hospital course with supportive management. CONCLUSIONS: Clinicians are cautioned about the possibility of NMS with risperidone. Risperidone Induced Neuroleptic Malignant Syndrome: A case report and review of the Literature. Neuroleptic malignant syndrome (NMS) is a serious and potentially fatal complication of neuroleptic drug therapy, first described by Delay et al.1 in 1960 during early clinical trials of haloperidol. The existence of this syndrome was confirmed by other clinicians, and by 1986 more than 150 cases had been reported.2 Estimates of the incidence of NMS attributed to neuroleptics have ranged from 0.5% to 2.4%.3 The true incidence is probably in the higher range due to under reporting and unrecognized cases. Failure to treat and recognize NMS results in death in up to 20% of patients.4 The classic presentation of NMS consists of a tetrad of fever, generalized skeletal muscle rigidity, altered mental status, and autonomic dysfunction.5 (Table I.) The most accepted theory for the pathogenesis of this syndrome is depletion of dopamine both centrally and peripherally.6 Virtually, all classes of D2 dopamine receptor antagonists have been associated with NMS.7 We describe a 15 yr-old Hispanic boy who developed NMS after treatment with risperidone, an atypical neuroleptic drug. To our knowledge this is the 10th reported case of NMS secondary to risperidone treatment, the first case in an adolescent, and the second in which NMS developed after re-exposure to a single dose of risperidone. CASE REPORT A 15 year-old Hispanic boy was hospitalized with expansive mood, flight of ideas, restlessness, irritability, insomnia, and grandiose delusions. He had no psychiatric problems, or tobacco, alcohol, or drug abuse. Treatment was begun with haloperidol 4 mg/d, lithium carbonate 600 mg/d, and benzotropine 2 mg/d. Over the following week lithium was increased to 1200 mg/d, (Serum lithium concentration 0.9 meq/L) haloperidol to 8 mg/d and benzotropine to 4 mg/d. On day number 17 haloperidol was increased to 15 mg/d. The patient remained refractory to treatment and subsequently developed extrapyramidal side effects (EPS), drooling, dystonia, and bradykinesia, despite being treated with benzotropine. On day 24 valproic acid (500 mg/d) was added to the patient's regimen. On day 30, haloperidol was stopped because of persistent akinesia and drooling, amantadine 200 mg/d was then started. The EPS abated promptly and 1 day later the benztropine was discontinued. Four days later, when the plasma concentration of valproic acid was therapeutic (serum concentration 75 mg/L), lithium carbonate was discontinued. On day 37, the patient was prescribed risperidone 2 mg/d for worsening psychotic symptoms. The dosage of risperidone was increased to 4 mg/d, over 72 hours, with a dramatic resolution of all affective and psychotic symptoms. Risperidone was discontinued on day 41 because the patient developed dramatic EPS with bradykinesia, rigidity, and drooling, in-spite of the co-administration of amantadine. Valproic acid was continued and after an 8-day neuroleptic-free period, the patient recovered from all EPS; however, he exhibited reemergence of psychotic thinking with paranoid delusions. As a result, risperidone was resumed at a lower dose (1 mg/d) on day 49. The next day, after receiving a single dose, the patient developed fever (T. max 1010F), tachycardia (120 b/min), tachypnea (22 breaths/min), unstable blood pressure (ranging from 170/90 to 150/70). He was diaphoretic, tremulous, and incontinent of urine. He exhibited muscular rigidity, severe dystonia, bradykinesia, and clouding of consciousness evolving into stupor. Laboratory evaluation revealed a white blood count of 16,000/mm3. Blood urea nitrogen was 15 mg/dl and serum creatinine 0.8 mg/dl. Serum electrolytes and liver function tests were within normal limits. The maximum creatinine phosphokinase (CPK) was 415 IU/l. Arterial blood gas analysis revealed a pH of 7.44, pO2 of 116, pCO2 of 38 on room air. Computed tomography of the head, electroencephalogram, and magnetic resonance imaging were normal, as were blood cultures, chest x-ray, and electrocardiogram. The patient was diagnosed with NMS and transferred to the Pediatric Intensive Care Unit. Risperidone and valproic acid were discontinued, bromocriptine 15 mg/d was started, and amantadine 200 mg/d was continued. Over the next 10 days the patient's rigidity, akinesia and dystonia resolved, his blood pressure and heart rate returned to baseline. ( BP 115/70 mm Hg, HR 70 beats/min). He remained confused for another 2 weeks after returning to our inpatient psychiatric unit. During this period he remained free of psychiatric and manic symptoms; therefore, no attempt was made to reintroduce either neuroleptics or mood stabilizers. Prophylactic use of Valproic acid was suggested but this recommendation was rejected by the patient's family. Further treatment consisted of individual and group psychotherapy, recreational activity and physical therapy. He was discharged 4 weeks after returning from intensive care unit, free of psychiatric symptoms. DISCUSSION Our patient demonstrated the classic tetrad of NMS. His temperature ranged from 990F to 1010F. Autonomic instability was demonstrated by tachycardia, hypertension, tachypnea, diaphoresis, and incontinence of urine. Serious mental status changes consisted of delirium evolving into a stuporous state. Sepsis was ruled out by negative blood cultures, normal urinalysis and chest X-ray. NMS is considered to be an idiosyncratic reaction because it does not correlate with the dosage or blood concentration of the associated agent.6 It frequently occurs within 7 days after the initiation of neuroleptic treatment, or 2 to 4 weeks after the first dose of a depot neuroleptic, but it also may be seen after a single dose or after years of treatment. Eight days prior to the development of NMS our patient was taking risperidone (for 1 week) and valproic acid when he developed significant EPS. Risperidone was stopped but was resumed after 8 days because of psychotic relapse. After rechallenge with a single 1 mg, he manifested signs and symptoms of NMS. Valproic acid has been associated with NMS. Several reports have documented syndromes resembling NMS with valproic acid in combination with neuroleptic drugs. (personal communication, Robert Hoff, MD, associate medical director II, Professional Information and Product Safety, Abbott Laboratories, Abbott Park, IL, June 14, 1995.) A synergistic role also has been documented with lithium in combination with neuroleptics and their association with NMS.8 Table 2 lists the essential features of the 9 other reports (10 total cases) published to date.[9-17] There appears to be an even distribution between the sexes. The two patients described by Webster and Wijeratne9 and the one by Singer et al.14 were geriatric patients. The other seven cases were adults aged between 24 and 42 years. Three patients were diagnosed with underlying organic brain disease as a comorbid illness, one9 with vascular dementia and two16,17 with mental retardation. One patient had an axis I diagnosis of vascular dementia9 and all the other patients had an axis I diagnosis of Paranoid schizophrenia (n = 4), schizoaffective disorder (n = 3) , psychosis complicating mental retardation (n = 1), and undifferentiated schizophrenia (n = 1) . In the 10 cases reported there was one death, all the others recovered with cessation of the risperidone and by the use of established treatment for NMS. The clinical symptoms of risperidone induced NMS appeared to be classic in all 10 cases, with alteration in mental status, rigidity, fever, and autonomic dysregulation. In all cases except one, creatinine phosphokinase concentrationss were elevated. Clinical trials have demonstrated that risperidone, a serotonin-dopamine antagonist, is an effective antipsychotic agent that improves negative as well as positive symptoms of schizophrenia.18 At recommended doses the frequency of overall adverse effects and EPS is lower with risperidone than with the conventional antipsychotic agent haloperidol. It is important for clinicians to realize, however, that risperidone, as with the typical antipsychotics, can precipitate NMS, a potentially fatal complication. NMS can lead to various complications.6 The most common is rhabdomyolysis. Other reported findings are aspiration pneumonia, pulmonary emboli, myoglobinuria, renal failure, and disseminated intravascular coagulation. When death occurs, it usually results from cardiac or respiratory arrest. All patients, therefore, require close monitoring of temperature, CPK, renal function, and cardiac function. Our patient did not develop any of these serious complications and recovered uneventfully. Treatment of NMS always includes cessation of the neuroleptic medication.6 Supportive care is the mainstay of treatment, including fluid and electrolyte replacement, reduction of temperature and support of cardiac, respiratory and renal functions. Pharmacotherapy may include bromocriptine, dantrolene, and amantadine. The rationale for this treatment is to reverse the centrally mediated dopamine blockade and reverse the skeletal muscle spasm. Anticholinergic agents such as benztropine are not helpful in NMS. Our patient received bromocriptine, amantadine, nasogastric tube feeding and intravenous fluid replacement. Affective disorders in children and adolescents can be complicated by psychotic symptoms.19 As a consequence, neuroleptics, both typical and atypical, may become a part of the management of adolescents suffering from a primary affective disorder. Risperidone, like clozapine, is an atypical neuroleptic drug that has gained increased popularity because of its antipsychotic properties with relative sparing of EP side effects.20 However Cozza et al.21 reported that risperidone may cause greater sensitivity to EPS in an adolescent population at doses usually well tolerated in the adults. Although ours is the first published case of risperidone induced NMS in an adolescent, clinicians working with this population should be aware of its potentially life threatening consequences. REFERENCES 1. Delay J, Pichot P, Lemperiere T, Elissalde B, Peigne F. Un neuroleptique majeur nonphenothiazine et non-reserpinique, l'haloperidol, dans le traitement des psychoses. Ann Med Psychol 1960;118:145-152. 2. Caroff SN , Mann SC, Lazarus A, Sullivan K, MacFadden W. Neuroleptic malignant syndrome Diagnostic issues. Psychiatr Ann 1991;21:130-147. 3. Pope HG, Keck PE, McElroy SL. Frequency and presentation of neuroleptic maalignant syndrome in a large psychiatric hospital. Am J Psychiatry, 1986:143:1227-1233. 4. Freidman JH, Davis R, Wagner R. Brief report - neuroleptic malignant syndrome. The result of a 6 month prospective study of incidence in a state psychiatric hospital. Clin Neuropharmacology 1988;52:578- -86. 5. Crurrera RJ, Chang SS, Romero JA. A comparison of diagnostic criteria for neuroleptic malignant syndrome. J. Clin Psychiatry 1992;53:56-62. 6. Ebadi M, Pfeiffer RF, Murrin LC. Pathogenesis and treatment of neuroleptic malignant syndrome. Gen Pharmacol 1992;21:367-86. 7. Legras A, Hurel D, Dabrowski G, Grenet D, Gravrleau P, Loirat P. Protracted neuroleptic malignant syndrome complicating long-acting neuroleptic administration. Am J Med 1988;86:875-8. 8. Koehler PJ, Mirandolle JF. Neuroleptic malignant-like syndrome and Lithium. Lancet 1988; 22:1499-500. 9. Webster P, Wijeratne C. Risperidone-induced neuroleptic malignant syndrome. Lancet 1994;344:1228-9. 10. Lee H, Ryan J, Mullett G, Lawlor BA. Neuroleptic malignant syndrome associated with the use of risperidone, an atypical antipsychotic agent. Hum Psychopharmacol 1994;9:303-305. 11. Raitasuo V, Vataja R, Elomaa E. Risperidone-induced neuroleptic malignant syndrome in young patient. Lancet 1994;344(8938):1705. 12. Tomsic J, Chatt PL, Chandarana P. Neuroleptic malignant syndrome caused by risperidone. (Abstract) Poster at the 25th Annual Professional Practice Conference of the Canadian Society of Hospital Pharmacists. 1994 [N103141/1] 13. Najara JE, Enikeev I. Risperidone and neuroleptic malignant syndrome, A case report. J Clin Psych, in press, 1995. 14. Singer S., Richards C, Boland RJ. Two cases of risperidone-induced neuropleptic malignant syndrome. Am J Psychiatry 1995; 15(8):1234. 15. Murray S and Haller E. Risperidone and NMS? Psychiatric Services 1995;46(9):951. 16. Dave, M. Two cases of risperidone-induced neuropleptic malignant syndrome. Am J Psychiatry 1995;152(8):1233-1234. 17. Levin G, Lazowick A, Powell H. J Clin. Psychopharmacology 1996; 16(2). (In Press). 18. Chouinard G, Jones B, Remington G. A Canadian multi-center placebo controlled study of fixed doses of risperidone and haloperidol with treatment of chronic schizophrenic patients. J Clin Psychopharmacology 1993;13:25-40. 19. Joshi PT, Capozzoli JA, Coyle JT. The John Hopkins Depression Scale. Narrative data and validation in child psychiatry patient. J Am Acad of Child Adol Psychiatry 1990;29(2):283-288. 20. Busatto GF, Pilowsky LS, Costa DC, Burrell M. Dopamine D2 receptor blockade in vivo with the novel antipsychotics risperidone, remoxipride an 1233I-IBMZ single photon emission tomopraphy (SPET) study. Psychopharmacology 1995;22:42-46. 21. Cozza SJ, Edison DL. Risperidone in Adolescents. J. Am. Acad. Child Adolesc. Psychiatry 1994;33:8 ________________________________________________________________________ Table I: Common clinical and laboratory features of neuroleptic malignant syndrome. ________________________________________________________________________ CLINICAL FEATURES General Fever Skeletal " Lead pipe" rigidity, Tremor, Movement disorder Autonomic Blood pressure abnormalities, Tachycardia, Tachypnea diaphoresis, Incontinence Mental Status Changes Clouding of consciousness, Mutism, Delirium, LABORATORY Increased CPK Increased ALT, AST Increased BUN and Serum Creatinine Increased White blood cell count Increased LDH ________________________________________________________________________ NAME A DIAGNOSIS G E Webster & Wijeratne Webster & Wijeratne 82 Schizoid personality M disorder 81 Vascular dementia F Lee 24 Paranoid M Schizophrenia Najara & Enikeev 42 Schizo-affective F Raitasuo 31 Chronic M undifferentiated schizophrenia 25 Schizo-affective F Murray & Huller Levin, 26 Mild mental Lazowick & M retardation with Powell psychosis disorder Dave, M 35 Mild mental F retardation and schizo-affective disorder Singer, 70 Paranoid Richards & M Schizophrenia Boland Tomsic 39 Paranoid F Schizophrenia Sharma, 15 Schizoaffective Trappler, M Ng, Leeman DO DU SE RA TIO N 1 5D mg 2 12 mg hrs OUT SYMPTOMS CO ME 3 4 mg mo nth s 6 10 mg D Rec Lethargy, rigidity, unresponsive, over õ Temp,õ HR, confusion, CPK = 118 IU ed Died Unstable BP, EPS, urinary incontinence, pale, sweaty, and õ temp, CPK = 1100 IU/L Rec õ temp, õHR, urinary incontinence, EPS, CPK over = 1200 IU/L ed 14 4 Rec õ temp, õ HR, unstable BP, EPS, sweaty, mg wee over confused, CPK = 2129 ks ed 6 24 Rec EPS, õ HR, õ temp, mutism, incontinence, mg day over unstable BP, diaphoresis, õ RR, CPK = 690 ed IU/L 6 15 Rec EPS, Incontinence, sweaty, vomiting, anuria, mg day over CPK = 92300 IU ed 6 6 Rec Confusion, rigidity, mental status changes, mg day over and autonomic dysregulation, õ BP, õ HR ed CPK = 810 IU/L 6 36 Rec Lethargy, rigidity, drooling, incontinence, mg day over fever, lower extremity weakness, CPK = s ed 19,710 IU/L 6 4 Rec õ Temp, EPS, lethargy, õ HR, tremors, rigidity, mg day over diaphoresis, autonomic dysregulation, s ed CPK = 825 IU/L Rec EPS, autonomic instability, õ HR, unstable over BP, ed CPK = 1153 IU/L 1-4 7 D Rec EPS, unstable BP, Diaphoresis, tremors, mg over incontinence, rigidity, increase in HR, ed Leukocytosis, CPK = 415 IU/l Table 2. Neuroleptic malignant Syndrome Induced by Risperidone; Summary of the cases reported* · Abbreviations: BP = Blood pressure, CPK = Creatinine Phosphokinase, EPS = Extrapyramidal side - effects, HR = Heart rate, Temp = Temperature, RR = Respiratory rate, M = Male, F = Female