Chris lieseke 2009-06-26 07:49:55
NEUROLEPTIC MALIGNANT SYNDROME
Stanley N. Caroff, M.D., Professor of Psychiatry
Stephan C. Mann, M.D., Associate Professor of Psychiatry
E. Cabrina Campbell, M.D., Assistant Professor of Psychiatry
Department of Psychiatry, University of Pennsylvania School of Medicine and the Department of
Veterans Affairs Medical Center, Philadelphia, Pennsylvania
Published in Adverse Drug Reaction Bulletin, August 2001, No. 209, pgs 799-802, copyright 2001
Lippincott Williams & Wilkins.
Since the initial description of neuroleptic malignant syndrome (NMS) forty years ago, a wealth of
clinical data has accumulated on the manifestations, course, treatment and pathogenesis of this
uncommon but serious and potentially lethal drug reaction. Nevertheless, vigilance must be
maintained, as this disorder remains obscure to most practicing physicians. Herein, the authors
provide a clinical overview of NMS to enhance patient safety and reduce physician liability whenever
neuroleptics are administered.
Neuroleptic malignant syndrome (NMS) was first described by Delay et al during early trials of
haloperidol.1 Although subsequently studied in France and Japan, NMS remained obscure until 1980
when increasing recognition resulted in hundreds of published case reports, primarily in the
psychiatric literature.2 The abundance of clinical observations supported a more precise definition
of NMS, clarified risk factors and treatment strategies, renewed interest in related hypermetabolic
disorders, and shed light on its pathogenesis. Nevertheless, the clinical manifestations of NMS
remain obscure to most practicing physicians. This is alarming, given that NMS remains potentially
life threatening if unrecognized, and underscores the need for increased awareness of the diagnosis
and management of this serious drug reaction.
Although NMS is uncommon, the widespread use of neuroleptic drugs suggests that the absolute number
of cases is not insignificant. Estimates of the incidence of NMS have varied depending on the
population at risk, prescribing practices and methods of assessment. If data from published studies
of NMS in patients treated with neuroleptics are combined, the incidence of NMS averages 0.2
percent.3 Importantly, several authors were able to demonstrate that conservative use of
neuroleptics, attention to risk factors and early recognition of incipient cases could successfully
reduce the incidence of NMS.
In an attempt to identify potential risk factors, several small controlled studies have been
conducted.3,4 In terms of patient variables, NMS has been reported in both sexes and all age groups.
Although elevated environmental heat and humidity have been proposed as contributing factors in a
few cases, NMS generally occurs independent of ambient conditions. NMS is not specific to any
neuropsychiatric diagnosis. It has been reported in patients treated with neuroleptics for diverse
psychiatric illnesses, as well as in medical patients who receive neuroleptics as antiemetics or
sedatives. However, several authors have proposed a greater risk for NMS in patients with certain
psychiatric disorders, pre-existing catatonia,5 and other disorders affecting deep brain
structures.6 Additional evidence suggests that exhaustion, agitation , and dehydration may
predispose patients to the development of NMS.3,4
Pharmacologic variables have also been studied. It appears that about 17 percent of NMS patients
experienced a similar episode during prior treatment with neuroleptics, suggesting a trait
susceptibility to the disorder. Virtually all classes of drugs that induce dopamine-2 receptor
blockade have been associated with NMS. This includes all typical neuroleptics used in antipsychotic
therapy. Although the newer, atypical antipsychotics have also been associated with NMS in published
case reports, the relative risk of NMS with these new drugs compared to the typical antipsychotics
Apart from antipsychotics, NMS cases, including some that were fatal, have been reported in
association with other drugs used in medicine that have neuroleptic properties. These include
antiemetics (prochlorperazine), pro-peristaltic agents (metoclopramide), anesthetics (droperidol),
and sedatives (promethazine).
Data on dosage indicate that NMS is not a result of overdosage with neuroleptics, and usually occurs
within the therapeutic range.3 Within that range, however, several studies have suggested that
patients who develop NMS are more likely to have received higher doses, more rapid titration and
more parenteral injections of neuroleptics compared to controls. Data are inconclusive as to whether
adjunctive or concomitant medications, e.g., antiparkinsonian drugs or lithium, increase or decrease
the risk of NMS.
Although evidence suggests that these clinical and pharmacologic variables may correlate with the
risk of NMS, the disorder is too infrequent and idiosyncratic for these findings to be used as
reliable risk factors that outweigh the benefits of neuroleptic therapy when indicated in a given
In addition to the development of reliable risk factors, it would be useful to identify early signs
of NMS that could be used to abort the progression of the syndrome. Although NMS has a variable
onset and sometimes evolves rapidly, rigidity and altered mental status usually occur early,
followed by autonomic changes and hyperthermia.8 In over 80% of cases, rigidity or mental status
changes herald the onset of the syndrome.8 Specific early signs include obtundation, catatonia,
tachycardia, tachypnea, labile blood pressure, dysarthria, dysphagia, diaphoresis, sialorrhea,
incontinence, rigidity, myoclonus, tremors, low grade fevers or serum creatine kinase elevations.
Clinicians should be prepared to diagnose NMS early and to document the rationale for continuation
or cessation of neuroleptic therapy. However, these early signs are not specific for NMS, do not
necessarily progress to NMS, and do not invariably precede the syndrome.3
Diagnostic criteria are listed in Table 1. Patients with NMS have drug-induced hyperthermia, usually
associated with profuse sweating. Extreme temperature elevations constitute a medical emergency and
predispose to complications, including irreversible brain damage, if not reduced immediately.
Generalized rigidity, described as “lead-pipe”, is a core feature of NMS, and is usually associated
with myonecrosis. Cogwheeling, myoclonus and coarse tremors are often described along with other
extrapyramidal signs. Mental status changes include clouding of consciousness ranging from stupor to
coma, delirium, and the development of catatonia. The classic NMS patient appears awake but dazed,
stuporous and mute. Autonomic activation and instability are common, manifested by tachycardia,
oscillations in blood pressure, and tachypnea.
Although several laboratory abnormalities have been reported in NMS, none are specific or
pathognomonic for the diagnosis. Rather, a thorough laboratory evaluation is essential in excluding
other causes of hyperthermia and detecting medical complications. Serum creatine kinase is
frequently elevated and occasionally reaches extraordinary levels reflecting massive rhabdomyolysis.
Although elevations in serum creatine kinase are not specific to NMS, determination of the enzyme
concentration remains important as a measure of severity of rhabdomyolysis and the risk of
myoglobinuric renal failure. Other frequently described laboratory abnormalities include metabolic
acidosis, hypoxia, low serum iron, elevations in serum catecholamines, electrolyte abnormalities and
Nonfocal generalized slowing on electroencephalography, consistent with encephalopathy, has been
reported in over half of NMS cases. In contrast, brain imaging studies, cerebrospinal fluid
examination and sepsis evaluation are negative in NMS, and allow for the exclusion of other causes
of fever and neurologic deterioration.
Clinical Course of Illness
NMS is a result of complex neurochemical changes induced by neuroleptics during the initial stages
of treatment. In a review by Caroff and Mann,9 16 percent of patients developed NMS within 24 hours
of initiating neuroleptic treatment, 66 percent by one week, and virtually all cases occurred within
the first 30 days. Conversely, once neuroleptics were discontinued, NMS was self-limited barring
complications. Following discontinuation of oral neuroleptics, the mean recovery time has been
estimated at 7 to 10 days.3,9 About 63 percent recover within one week, and nearly all within 30
However, the course of NMS may be prolonged in some cases. For example, patients receiving
long-acting depot neuroleptics may remain ill nearly twice as long.3,9 In addition, occasional
patients may develop a residual catatonic-parkinsonian state that can persist for weeks to months if
left untreated after the acute hyperthermic symptoms of NMS subside.10 Although dopamine agonists
and benzodiazepines have been advocated for treatment of this residual state, electroconvulsive
therapy (ECT) appears to be more rapidly effective with reduced mortality.10
Although increased familiarity with the diagnosis and early intervention have contributed to a
decline in the mortality rate, not all patients recover from NMS. Death may result from sudden and
unexpected cardiopulmonary arrest, aspiration pneumonia, pulmonary emboli, myoglobinuric renal
failure, or disseminated intravascular coagulation. Findings at autopsy are usually non-specific and
variable, depending on complications.
Persistent clinical sequelae of NMS are rare in recovered patients. However, cases of amnestic
syndromes, extrapyramidal and cerebellar disorders, peripheral neuropathy, myopathy and contractures
have been reported.3
The differential diagnosis of NMS is challenging and encompasses a broad range of disorders
presenting with fever, necessitating a thorough medical and neurologic evaluation (Table 2). Despite
careful investigation, the cause of the syndrome in some patients may remain elusive or reflect
Other disorders that can simulate NMS include primary disorders of the brain and systemic disorders
that secondarily affect brain function. Among the former are infectious encephalitis, structural
lesions, and rare cases of status epilepticus.3, 6, 11
Advanced stages of psychotic disorders associated with catatonia (lethal catatonia) can progress to
exhaustion, stupor, hyperthermia and death.12, 13 Although the incidence of lethal catatonia may
have decreased, it still occurs and can be indistinguishable from NMS. In fact, NMS has been
conceptualized has a drug-induced iatrogenic form of lethal catatonia.12, 13 In either NMS or lethal
catatonia, neuroleptics should be discontinued; in most NMS cases, symptoms should subside within
two weeks, whereas in lethal catatonia, neuroleptics appear to be ineffective and even detrimental.
In contrast, ECT appears to be the treatment of choice in lethal catatonia, and is often effective
Patients with neuroleptic-induced parkinsonism may develop intercurrent fevers caused by infections
or dehydration and be mistaken for cases of NMS. Hyperthermia may be observed in patients with
thyrotoxicosis and pheochromocytoma, which can be distinguished from NMS by the absence of rigidity.
Systemic lupus erythematosus or other autoimmune diseases may present with fever and neurologic
signs. Heatstroke may develop during hot weather, and be confused with NMS. Although rigidity is
unusual in heatstroke, the prior administration of neuroleptics in such patients may both increase
the risk of heatstroke and further obscure the correct diagnosis.
Many toxins and drugs have been associated with hyperthermia and must be considered in the
differential diagnosis. Volatile anesthetics and succinylcholine are associated with malignant
hyperthermia during surgery, which can be confused with NMS if neuroleptics are administered.15
Although NMS has been reported before and after surgery, it appears unlikely to develop
intra-operatively in contrast to malignant hyperthermia.15
Withdrawal of levodopa, or other dopamine agonists, in patients with Parkinson’s disease or other
disorders, has resulted in hyperthermic syndromes indistinguishable from NMS, reflecting the same
mechanisms of acute dopaminergic deficiency. Illegal stimulants and hallucinogens have been
associated with hyperthermia, seizures, rigidity, rhabdomyolysis and death. Antiparkinsonian and
other anticholinergic drugs can result in atropinic toxicity manifested by fever without rigidity.
Withdrawal states, such as delirium tremens, can also be difficult to distinguish from NMS, when
neuroleptics have been administered.
Finally, serotonin syndrome is frequently considered in the differential of NMS, and has been
increasingly reported in association with selective serotonergic agents introduced for the treatment
of depression and migraine headaches.16 Although in its most severe form, associated with monoamine
oxidase inhibitors, serotonin syndrome presents as an NMS-like hypermetabolic state, it usually
presents with milder and more transient symptoms indicative of an agitated delirium.16
The basic management of NMS remains risk reduction, early diagnosis, cessation of neuroleptic
medications, and institution of intensive medical and nursing care.14, 17 There is less evidence
concerning the comparative efficacy of specific pharmacologic agents and ECT in the treatment of
NMS. This results from the fact that NMS is a self-limited disorder in most cases if diagnosed
properly, regardless of specific therapies, and is due also to the scarcity of controlled clinical
treatment trials. Nevertheless, there are rational theories and anecdotal clinical data to support
consideration of pharmacotherapy and ECT (Table 3).
Based on available evidence, we recommend that specific treatment of NMS should be individualized
and based empirically on the character, duration, and severity of clinical signs and symptoms.14,17
In some cases, supportive care alone with close monitoring for progression of symptoms or
complications is probably sufficient until recovery occurs. Benzodiazepines are useful in reversing
catatonia, easy to administer, and could be tried initially in most cases. Trials of bromocriptine,
amantadine, or other dopamine agonists may be a reasonable next step in patients with moderate
symptoms of NMS. Dantrolene appears to be beneficial primarily in cases of NMS involving significant
rigidity and hyperthermia. It has been beneficial in rapidly reducing extreme temperature elevations
in many cases. These medications are effective during the first few days of treatment of NMS and are
unlikely to show a delayed response.14, 17
In contrast, ECT remains effective even late in the course, often after other interventions have
failed. ECT may be preferred if idiopathic lethal catatonia cannot be excluded, if NMS symptoms are
refractory to other measures, in patients with prominent catatonic features, and in patients who
develop a residual catatonic state or remain psychotic after NMS has resolved.10, 14, 17
Among patients who recover from NMS, there may be a 30 percent risk of recurrent episodes following
subsequent neuroleptic rechallenge.3 However, the majority of patients who require neuroleptic
therapy can be safely treated, provided precautions are taken. Reports of previous episodes should
be checked for accuracy, indications for neuroleptics clearly documented, alternative medications
considered, informed consent obtained from patients and families, risk factors reduced, at least two
weeks allowed to elapse following recovery before rechallenge, low doses of low potency or atypical
neuroleptics titrated gradually after a test dose, and patients carefully monitored for incipient
signs of NMS.
There are several lines of evidence that provide strong support for an acute reduction in dopamine
activity in the brain as the basic mechanism underlying NMS.3, 18 All neuroleptics that have been
implicated share the property of dopamine-2 receptor blockade. Evidence from clinical studies
correlates the risk of NMS with dose, potency, rate and route of administration of dopamine
antagonists. Dopamine agonists are an effective treatment for NMS. Patients with Parkinson’s disease
or others withdrawn from dopamine agonists have developed NMS-like syndromes. Patients with lesions
interrupting dopamine pathways have developed hyperthermia. Studies of metabolites of
neurotransmitters in cerebrospinal fluid obtained from patients with NMS reveal pre-existing central
dopamine hypoactivity as a possible trait marker for NMS.18 Studies of functional correlates of
basal ganglia-thalamocortical circuits provide a framework within which individual NMS symptoms may
be localized to perturbations in specific dopamine pathways.18 Finally, changes in dopamine pathways
in response to stress may be implicated as an additional state-related cofactor in the pathogenesis
Neuroleptics are highly effective and safe medications that have achieved widespread use in medicine
and psychiatry. However, they have been associated with NMS in about 0.2 percent of patients.
Considerable progress has been achieved in recognizing, managing, and understanding this drug
reaction since it was first described over 40 years ago. Development of innovative neuroleptics,
conservative prescribing guidelines, reduction of proposed risk factors and education of staff can
result in a reduced incidence of this disorder. Awareness of the diagnosis, cessation of
medications, early medical intervention, and consideration of specific remedies can reduce morbidity
and mortality when NMS occurs. It is therefore essential for all physicians and nurses to become
familiar with the diagnosis and management of this unusual but fascinating drug reaction.
1. Delay J, Pichot P, Lemperiere T, Elissade B, Peigne F. Un neuroleptique majeur non-phenothiazine
et non reserpinique, l’haloperidol, dans le traitement des psychoses. Annales Medico-Psychologique
2. Caroff SN. The neuroleptic malignant syndrome. Journal of Clinical Psychiatry 1980; 41: 79-83.
3. Caroff SN, Mann SC. Neuroleptic malignant syndrome. Medical Clinics of North America 1993; 77:
4. Berardi D, Amore M, Keck PE Jr, Troia M, Dell’Atti M. Clinical and pharmacologic risk factors for
neuroleptic malignant syndrome: a case control study. Biological Psychiatry 1998; 44: 748-754.
5. White DAC, Robins AH. Catatonia: harbinger of the neuroleptic malignant syndrome. British Journal
of Psychiatry 1991; 158: 419-421.
6. Caroff SN, Mann SC, McCarthy M, Naser J, Rynn M, Morrison M. Acute infectious encephalitis
complicated by neuroleptic malignant syndrome. Journal of Clinical Psycholpharmacology 1998; 18:
7. Caroff SN, Mann SC, Campbell EC. Atypical antipsychotics and neuroleptic malignant syndrome.
Psychiatric Annals 2000; 30: 314-321.
8 Velamoor VR, Norman RM, Caroff SN, Mann SC, Sullivan KA, Antelo RE. Progression of symptoms in
neuroleptic malignant syndrome. Journal of Nervous and Mental Disease 1994; 182: 168-173.
9. Caroff SN, Mann SC. Neuroleptic malignant syndrome. Psychopharmacology Bulletin 1988; 24: 25-29.
10. Caroff SN, Mann SC, Keck PE Jr, Francis A. Residual catatonic state following neuroleptic
malignant syndrome. Journal of Clinical Psychopharmacology 2000; 20: 257-259.
11. Caroff SN, Mann SC, Gliatto MF, Sullivan KA, Campbell EC. Psychiatric manifestations of acute
viral encephalitis. Psychiatric Annals 2001; 31: 193-204.
12. Mann SC, Caroff SN, Bleier HR, Welz WKR, Kling MA, Hayashida M. Lethal catatonia. 1986; 143:
13. Fricchione G, Mann SC, Caroff SN. Catatonia, lethal catatonia and neuroleptic malignant
syndrome. Psychiatric Annals 2000; 30: 347-355.
14. Davis JM, Caroff SN, Mann SC. Treatment of neuroleptic malignant syndrome. Psychiatric Annals
2000; 30: 325-331.
15. Caroff SN, Rosenberg H, Mann, campbell EC, Gliatto MF, Sullivan KA. Neuroleptic malignant
syndrome in the perioperative setting. American Journal of Anesthesiology 2001; 28: 387-393.
16. Keck PE Jr, Arnold LM. The serotonin syndrome. Psychiatric Annals 2000; 30: 333-343.
17. Caroff SN, Mann SC, Keck PE Jr. Specific treatment of the neuroleptic malignant syndrome.
Biological Psychiatry 1998; 44: 378-381.
18. Mann SC, Caroff SN, Fricchione G, Campbell EC. Central dopamine hypoactivity and the
pathogenesis of the neuroleptic malignant syndrome. Psychiatric Annals 2000; 30: 363-374.
Table 1 Diagnostic criteria for definite NMS
Administration of neuroleptics
Hyperthermia (> 38 C)
Five of the following; mental status change, tremor, tachycardia, incontinence, labile blood
pressure, metabolic acidosis, tachypnea/hypoxia, CPK elevation, diaphoresis/sialorrhea leukocytosis
Exclusion of other central and systemic causes of hyperthermia