Download Risperidone Induced Neuroleptic Malignant Syndrome: A case

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