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Neuroleptic malignant syndrome in adolescents: four probable cases in the Western Cape.

Neuroleptic malignant syndrome (NMS) represents a cluster of adverse effects of antipsychotic medications including: hypertonicity, autonomic instability, fever, and cognitive disturbance. (1) It is a rare but potentially life-threatening complication of neuroleptic (antipsychotic) drug therapy, with a mortality rate of 5-25% (2) and an incidence of 0.01-0.02% in adults. (3) The incidence rates in children and adolescents are uncertain. Precipitation of NMS may occur within hours of the first dose or after a period of maintenance treatment if there has been an increase in dose. All antipsychotics, including the newer atypical ones, have been associated with the development of NMS. Morbidity and mortality are predominantly the result of cardiopulmonary and renal complications. (4)

Presentations of NMS vary, and many diagnostic criteria have been proposed. (2,3) The DSM-1V-TR diagnostic criteria (3) require both core symptoms (fever, rigidity) and 2 or more additional symptoms (diaphoresis, dysphagia, tremor, incontinence, altered mental status, mutism, tachycardia, labile blood pressure, leukocytosis and evidence of muscle damage, e.g. raised creatine phosphokinase CK level). (3) Therefore, a raised CK level is not a mandatory diagnostic sign but one of many possible additional features. Diagnostic criteria used in adults are applied to children and adolescents and, with a few exceptions, NMS presents similarly in children and in adults. (1)

Table I presents data from 4 cases of probable NMS seen between February 2009 and March 2010; all were eventually referred to, and managed at, a rehabilitation unit for adolescents with psychosis at Lentegeur Hospital. They represent 3.6% of admissions over that time. While reference is made to a diagnosis of NMS, it is acknowledged that the evidence is circumstantial and, while fairly strong, is nevertheless presumptive.


The cases suggest that male gender and polypharmacy (including the use of 2 or more antipsychotics), a past history of EPSE/NMS and agitation are important possible risk factors for NMS. Although intellectual disability and affective disorders are considered to increase vulnerability to NMS, these cases occurred in adolescents with normal intellectual functioning and without an overwhelming association with affective disorder. Other features include large variations in CK levels and a favourable outcome. Other key risk factors for NMS include: use of physical restraint to control psychomotor agitation, recent commencement of an antipsychotic regime, use of intramuscular antipsychotics, and excessive psychomotor agitation resulting in higher levels of dehydration. (5) This raises the dilemma about appropriate, yet safe, use of antipsychotics in youths who need antipsychotics to control their behaviour, in particular those receiving high doses in short time periods. (5) Zuclopenthixol acetate (clopixol acuphase) is a common denominator in 3 cases (2, 3 and 4), and oral haloperidol was co-prescribed in 3 cases (1, 2 and 4). The Cochrane systematic review database found limited efficacy data for claims that zuclopenthixol acetate would rapidly calm or sedate aggressive patients with schizophrenia. (6) Therefore, the use of zuclopenthixol acetate in neuroleptic-naive adolescents with a first-presentation psychotic illness, and for the specific purpose of rapid tranquillisation, must be carefully considered.

Body temperature recording in this series was often taken haphazardly and in difficult circumstances such as marked agitation and restlessness, when it is unsafe to use the oral method. Temperature readings were obtained from the axilla. In one case the temperature was never recorded, one patient had no pyrexia, and 2 patients showed only a mild elevation. A core feature of NMS is pyrexia; therefore it could be argued that at least 2 patients did not conform to a 'true' NMS. However, the additional signs and symptoms noted in all the subjects were consistent with a probable diagnosis of NMS.

Important differential diagnoses in adolescents with probable NMS are malignant hyperthermia, heat stroke, anticholinergic delirium, serotonin syndrome, central nervous system infection and neuroleptic-induced dystonia. The latter occurs within 7 days of initiating drug treatment or following a rapid increase in the dose and is an involuntary contraction of muscle groups forcing certain parts of the body into abnormal, sometimes painful, postures. It is not associated with fluctuations in blood pressure, pyrexia, tachycardia or any other additional signs or symptoms seen with NMS.

Silva et al. (1) emphasise that, in children and adolescents, NMS presents in a form and course similar to adults. A fatal outcome is associated with age <12 years, although the number of fatal outcomes has dropped sharply in all age groups in recent years. A milder course of NMS associated with atypical antipsychotics, a greater resilience in children, earlier detection, prompt antipsychotic discontinuation and more aggressive management of NMS are additional moderating factors. (3) The latency period in these 4 cases refers to the time elapsed between the administration of an intramuscular antipsychotic and the diagnosis of possible NMS. Signs of NMS develop within 24 hours in 16% of patients initiating antipsychotic medication, 66% by 1 week and 90% within 30 days, and NMS is less likely to occur after 30 days. (9) Treatment of NMS includes referral to a medical unit, fever reduction, intravenous rehydration, dantrolene and bromocriptine, and sedation with benzodiazepines. Electroconvulsive therapy is an effective treatment option both for the NMS and the underlying psychiatric illness. (3) After resolution of NMS and normalisation of CK level, a 2-week waiting period is recommended before re-exposure to antipsychotics.

In 2 of the 4 cases, crystal methamphetamine, a street drug manufactured from ephedrine or pseudo-ephedrine that is smoked or injected and popularly known as 'tik' in the Western Cape, was one of the substances used prior to illness. Its use has accelerated in the Western Cape since 2003, particularly among the youth. This observation suggests a possible relationship between substance abuse and the development of NMS. Methamphetamine causes the release of dopamine and noradrenaline (and, to a lesser extent, serotonin) into the synaptic cleft and inhibits their reuptake. This creates very high intrasynaptic dopamine concentrations that probably accelerate or exacerbate the psychotic process. Chronic use of stimulants such as methamphetamine or cocaine may predispose the individual to NMS. (11) A hypothetical mechanism is that the initial dopamine stimulation induced by methamphetamine is followed by a depletion of neuronal dopamine reserves with continuing use of the agent. The resulting dopamine deficiency would be aggravated by the therapeutic administration of antipsychotics that further compound the hypodopaminergic state by their blockade of post-synaptic receptors. These events establish a setting of reduced dopamine activity, which is probably the aetiological basis for NMS.

Ethics approval

Ethics approval was given by the University of Cape Town Research and Ethics Committee, and the Tygerberg Hospital and Lentegeur Hospital authorities provided permission to extract data from patient folders. I thank Professor Ashley Robins for his assistance in the writing of this paper, and Professor Denise White for her encouragement.


(1.) Silva R, Dinohra M, Alpert M, Perlmutter R, Diaz J. Neuroleptic malignant syndrome in children and adolescents. J Am Acad Child Adolesc Psychiatry 1999;38(2):187-194.

(2.) Erermis S, Bildik T, Tamar M, Gockay A, Karasoy H, Sabri Ercan E. Zuclopenthixol-induced neuroleptic malignant syndrome in an adolescent girl. Clinical Toxicology 2007;45:277-280.

(3.) Croarkin P, Emslie G, Mayes T. Neuroleptic malignant syndrome associated with atypical antipsychotics in paediatric patients: a review of published cases. J Clin Psychiatry 2008;69(7):1157-1165.

(4.) Kahn H, Syed N, Sheerani M, Khealini B, Kamal A, Wasay M. Neuroleptic malignant syndrome: need for early diagnosis and therapy. Journal Ayub Med Coll Abbottabad 2006;18:1.

(5.) Viejo L, Morales V, Punal P, Perez J, Sancho R. Risk factors in neuroleptic malignant syndrome. A case control study. Acta Psychiatr Scand 2003;107:45-49.

(6.) Gibson R, Fenton M, Campbell C. Zuclopenthixol acetate for acute schizophrenia and similar serious mental illnesses. Cochrane Database of Systematic Review 2004:3: Art no CD 000525.

(7.) Cohen O, Leibovici L, Mor F, Wysenbeek A. Significance of elevated levels of serum creatine phosphokinase in febrile diseases: a prospective study. Reviews of Infectious Diseases 1991;13:237 242.

(8.) Meltzer H, Cola P, Parsa M. Marked elevations of serum creatine kinase activity associated with antipsychotic drug treatment. Neuropsychopharmacology 1996;15(4):395-404.

(9.) Mahendran R, Winslow M, Lim D. Recurrent neuroleptic malignant syndrome. Aust N Z J Psych 2000;34(4):699-700.

(10.) Batki S, Harris D. Quantitative drug levels in stimulant psychosis: relationship to symptoms severity, catecholamines and hyperkinesias. Am J Addict 2004;13:461-470.

(11.) MaCauly J, Ruiz P. Neuroleptic malignant syndrome: A complication of neuroleptics and cocaine abuse. Psychiatric Q 1991;62(4):299-309.

Accepted 14 October 2010.

Lentegeur Hospital, Mitchell's Plain, Cape Town, and the Department of Psychiatry, University of Cape Town Terri Henderson, MB ChB, FCPsych (SA)

Corresponding author: T Henderson (
Table I. Patient data related to 4 probable cases of NMS

                       Case 1                 Case 2

Age, gender            17, male               16, male

Diagnosis              Schizophrenia          Bipolar mood

First presentation     No, known              Yes
                       previous EPSE,
                       treated on clozapine

Intellectual           Normal                 Normal

History of substance   Negative               Crystal
abuse                                         methamphetamine,

Presenting history     Psychotic,             Psychotic

Agitation prior to     Yes                    Yes

Medication (incl.      Haloperidol 2.5 mg     Zuclopenthixol
route of               20h00, flupentixol     acetate 25 mg,
administration and     10 mg IMI x 2          haloperidol 1.5 mg
dose)                                         twice daily,
                                              diazepam 20 mg
                                              thrice daily

Latency period         5 days                 11 days

Highest recorded       36.7[degrees]C         37.5[degrees]C

Rigidity               Present                Present

BP fluctuation         No                     No

Tachycardia            120 bpm                120 bpm

Tremor                 NN                     NN

Dystonia               Yes                    NN

Diaphoresis            NN                     Yes

Incontinence           NN                     NN

Dysphagia              NN                     NN

WCC                    15.9 cells/            NN

CK (highest)           5 307 IU/l             783 IU/l

Na, liver enzymes,     Negative               Negative
EEG, CT scan, MRI,

Treatment              Antipsychotics were    Antipsychotics were
                       stopped. Treated       stopped. Treated
                       with diazepam.         with lorazepam.

Outcome                Full recovery from     Full recovery from
                       NMS. Discharged on     NMS. Discharged on
                       clozapine.             quetiapine.

                       Case 3                 Case 4

Age, gender            16, male               16, male

Diagnosis              Schizophreniform       Schizophrenia

First presentation     Yes                    No, known
                                              previous diagnosis
                                              of NMS

Intellectual           Normal                 Normal

History of substance   Negative               Crystal
abuse                                         methamphetamine,
                                              cannabis, alcohol

Presenting history     Psychotic              Psychotic,

Agitation prior to     No                     Yes

Medication (incl.      Zuclopenthixol         Zuclopenthixol
route of               acetate 50 mg IMI,     acetate 50 mg IMI x
administration and     risperidone 0.5 mg     2, haloperidol 5 mg
dose)                  twice daily            twice daily,
                                              lorazepam 4 mg
                                              thrice daily

Latency period         1 day                  4 days

Highest recorded       37.4[degrees]C         37.4[degrees]C

Rigidity               Present                Present

BP fluctuation         No                     Not recorded

Tachycardia            126 bpm                Not recorded

Tremor                 No                     No

Dystonia               No                     No

Diaphoresis            No                     No

Incontinence           Yes                    No

Dysphagia              NN                     Yes

WCC                    7.86 cells/            3.86 cells/
                       [mm.sup.3]             [mm.sup.3]

CK (highest)           10 000 IU/l            1 173 IU/l

Na, liver enzymes,     Negative               Negative
EEG, CT scan, MRI,

Treatment              Antipsychotics         Antipsychotics were
                       stopped. IVI           stopped.
                       rehydration and

Outcome                Full recovery from     Full recovery from
                       NMS. Discharged on     NMS. Discharged on
                       clozapine.             risperidone.

NN = nil noted; EPSE = extra-pyramidal side-effects.
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Title Annotation:Original Articles
Author:Henderson, Terri
Publication:South African Medical Journal
Article Type:Report
Geographic Code:6SOUT
Date:Jun 1, 2011
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