eMedicine Specialties > Psychiatry > Emergency

Neuroleptic Malignant Syndrome

Author: Joseph Tonkonogy, MD, PhD, Clinical Professor of Psychiatry and Neurology, University of Massachusetts Medical School; Consulting Staff, Departments of Psychiatry and Neurology, University of Massachusetts Medical Center
Coauthor(s): Darius P Sholevar, MD, Fellow, Cardiovascular Disease, Albert Einstein Medical Center
Contributor Information and Disclosures

Updated: May 7, 2009

Introduction

Background

Neuroleptic malignant syndrome (NMS) refers to the combination of hyperthermia, rigidity, and autonomic dysregulation that can occur as a serious complication of the use of antipsychotic drugs. Delay first used the term in 1960, after observing patients treated with high-potency antipsychotics.¹

Even the newer atypical antipsychotics, which are not classified accurately as neuroleptics, can cause neuroleptic malignant syndrome. Over the past 30 years, the syndrome has been associated with a variety of drugs that lead to decreased dopamine receptor activation.

While some clear risk factors for neuroleptic malignant syndrome are present, the low incidence of this syndrome and the consequent difficulty in studying it in a controlled, prospective manner make clinical features, predisposing conditions, treatment, and prognosis difficult to define.

Following is a case vignette of a patient with neuroleptic malignant syndrome that developed several days after the start of treatment with the atypical antipsychotic olanzapine.

A 66-year-old white male was hospitalized for increasingly aggressive behavior. He had no prior psychiatric admissions. On the day of admission after he sustained a fall, a CT scan of the brain revealed a subarachnoid hemorrhage at the right superior sulcus and a possible hemorrhagic contusion at the left frontal lobe. Over the course of hospitalization, the patient had a series of CT scans showing resolution of the hemorrhage. He was started on olanzapine for intermittent agitation. Olanzapine was titrated to 7.5 mg daily.

Ten days later the patient became abruptly somnolent with body temperature reaching 39.7 º C and severe muscle rigidity in both upper and lower extremities. He had severe diaphoresis and fluctuation of blood pressure and pulse. Laboratory data revealed elevation of white blood cells to 14800 K/L, creatine phosphokinase to 2800 U/L (normal <174 U/L), and mild elevation of serum alanine and aspartate aminotransferase. MRI of the brain, CSF studies, and chest radiograph were unremarkable. A presumptive diagnosis of neuroleptic malignant syndrome was made. Olanzapine was immediately discontinued and supportive care was initiated.

Intravenous lorazepam was given as needed every 4 hours for behavioral agitation along with a fixed 0.5 mg intravenous push twice daily. The patient received a total of 8.5 mg of lorazepam in the first 24 hours and 3 mg the next day. Fever and muscular rigidity resolved in 24 hours. All other manifestations of neuroleptic malignant syndrome resolved in 9 days.

Pathophysiology

The most widely accepted mechanism by which antipsychotics cause neuroleptic malignant syndrome is that of dopamine D2 receptor antagonism. In this widely accepted model, central D2 receptor blockade in the hypothalamus, nigrostriatal pathways, and spinal cord leads to increased muscle rigidity and tremor via extrapyramidal pathways. Hypothalamic D2 receptor blockade results in an elevated temperature set point and impairment of heat-dissipating mechanisms. Peripherally, antipsychotics lead to increased calcium release from the sarcoplasmic reticulum, resulting in increased contractility, which can contribute to hyperthermia, rigidity, and muscle cell breakdown.

Beyond these direct effects, D2 receptor blockade might cause neuroleptic malignant syndrome by removing tonic inhibition from the sympathetic nervous system. The resulting sympathoadrenal hyperactivity and dysregulation leads to autonomic dysfunction. This model suggests that patients with baseline high levels of sympathoadrenal activity might be at increased risk. While this has not been proven in controlled studies, several such states have been proposed as risk factors for neuroleptic malignant syndrome.²

Direct muscle toxicity also has been proposed as a mechanism of neuroleptic malignant syndrome.

Frequency

United States

Neuroleptic malignant syndrome is associated with the use of various antipsychotic medicines, most frequently the older antipsychotics, termed neuroleptics. Development of neuroleptic malignant syndrome appears to be independent of the conditions that these medicines treat.

The syndrome can occur after any duration of treatment, although two thirds of cases occur within the first week. The frequency has been variably reported as 0.07–2.2% of patients taking neuroleptics.³ Data largely come from case control studies rather than prospective randomized trials.

International

The frequency of neuroleptic malignant syndrome internationally parallels the use of antipsychotics, especially neuroleptics, in a given region. No data suggest geographic or racial variation. The one large randomized trial conducted in China showed an incidence of 0.12% in patients taking neuroleptics.⁴ A retrospective study conducted in India showed an incidence of 0.14%.⁵

Mortality/Morbidity

Mortality from neuroleptic malignant syndrome is very difficult to quantify due both to the case report designs of most of the literature and to the inconsistency of the diagnostic parameters used.

• In some series, mortality rates as high as 76% have been reported. Most series suggest, however, that the mortality rate is 10-20%. When reporting bias is factored in, the true rate of mortality from neuroleptic malignant syndrome might be much lower.
• Studies have also found that the mortality rate has been decreasing over the past 2 decades. Mortality is generally higher in patients who develop severe muscle necrosis and resulting rhabdomyolysis.

Race

No data suggest geographic or racial variation.

Sex

Incidence is higher in males.

Age

• Incidence is higher in persons younger than 40 years. Differential incidence simply might reflect a population that has a high rate of antipsychotic usage.
• Some small case series looking at neuroleptic malignant syndrome in elderly patients suggest that onset might occur after a longer duration of antipsychotic use.
• Studies in children suggest that clinical presentation might be somewhat different.

Clinical

History

• Criteria for the diagnosis of neuroleptic malignant syndrome are based on clinical features. Cardinal features are the development of severe muscular rigidity, hyperthermia, autonomic instability, and changes in the level of consciousness associated with the use of an antipsychotic medication, most often a neuroleptic.
• In addition to hyperthermia and rigidity, at least 2 other clinical features of neuroleptic malignant syndrome, including leukocytosis and laboratory evidence of muscle injury, should be present.
• The key to diagnosis is that symptoms occur only after exposure to antipsychotics. Symptoms should improve after the antipsychotic is stopped. No new focal neurological deficits should develop, although cases of neurological sequelae have been reported rarely.
• A summary of the clinical features of neuroleptic malignant syndrome includes the following:
  • Diaphoresis
  • Dysphagia
  • Tremor
  • Incontinence
  • Delirium progressing to lethargy, stupor, coma
• Labile blood pressure
• Pallor
• Dyspnea
• Psychomotor agitation
• Rigidity
• Hyperthermia
• Tachycardia
• Shuffling gait
• For accurate diagnosis, rule out reaction to another medication or medical condition that might be a more likely cause of the symptoms than use of an antipsychotic.
• Various other medications cause conditions that are indistinguishable from neuroleptic malignant syndrome and likely involve similar chemical structure and the same pathophysiology. All of these agents, including metoclopramide, prochlorperazine, promethazine, and droperidol, cause decreased dopamine receptor activation.
• A similar syndrome also has been associated with the rapid removal of medications with dopaminergic properties (eg, in patients treated for Parkinson disease).⁶ Medications in these classes often are used to treat Parkinson disease and include levodopa, bromocriptine, and amantadine. Dopaminergic drugs should be started as soon as possible to prevent rhabdomyolysis and renal failure.⁷
• Lethal catatonia (LC) is a similar condition that might be confused with neuroleptic malignant syndrome. Lethal catatonia occurs in people with schizophrenia or during manic episodes. Neuroleptics might either improve or worsen the symptoms of lethal catatonia. Distinguishing lethal catatonia from neuroleptic malignant syndrome can be difficult, although a detailed history might reveal episodes of catatonia while a patient is not taking neuroleptics. Lethal catatonia also tends to have a prodrome of excitement and agitation prior to the onset of rigidity, while neuroleptic malignant syndrome tends to begin with rigidity.⁸
• Antipsychotics can cause a variety of reactions that can be confused with neuroleptic malignant syndrome. These reactions often occur with increasing medication dosages. Neuroleptic-induced acute dystonia is an abnormal contraction or spasm of a group of skeletal muscles, often involving the head or neck. Neuroleptic-induced acute akathisia is motor restlessness, particularly involving the legs. Neuroleptic-induced tardive dyskinesia involves involuntary, rhythmic movements starting with mouth movements. Neuroleptic-induced parkinsonism, or pseudoparkinsonism, presents with the classic triad of tremor, muscular rigidity, and akinesia. Despite the term neuroleptic-induced, these conditions also can be caused, although less frequently, by many of the newer, nontraditional antipsychotic medications as well. In future editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM), the terminology might be changed to include nonneuroleptic antipsychotics.
• The serotonin syndrome is very similar to neuroleptic malignant syndrome. The triad of (1) altered mental status, (2) autonomic dysfunction, and (3) neuromuscular abnormalities that occurs on exposure to serotonergic agents characterizes the serotonin syndrome. Selective serotonin reuptake inhibitors (SSRIs) are the most frequently used medications in this class. The proposed mechanism is excessive 5-hydroxytryptamine (5-HT or serotonin) stimulation. Given the increasing use of the SSRIs, the serotonin syndrome might become increasingly prevalent. The serotonin syndrome can be distinguished from neuroleptic malignant syndrome in most cases by a detailed history of medication use with particular attention to recent dosage changes and the absence of severe rigidity. Treatment of this condition includes removal of the offending drug and supportive management, though 5-HT1A antagonists might have a role in the future.^9,10
• Medication-induced movement disorders not otherwise specified can be very similar to neuroleptic malignant syndrome but occur on exposure to other psychotropic medications. Malignant hyperthermia (MH) occurs after administration of halogenated inhalational anesthetics, such as halothane, and depolarizing muscle relaxants, such as succinylcholine, to genetically susceptible individuals. An underlying defect is an autosomal dominant mutation in the ryanodine receptor, which leads to excessive calcium release from the sarcoplasmic reticulum in skeletal muscle when one of the above agents is administered. A multifactorial pattern of inheritance also has been postulated. Malignant hyperthermia can be distinguished readily by history. Treatment is based on supportive care, use of dantrolene to decrease calcium release, and avoidance of precipitating medications. No evidence shows that neuroleptic malignant syndrome occurs more frequently in patients susceptible to malignant hyperthermia.
• Heat stroke can cause a similar picture, but patients have dry skin and flaccidity in addition to hyperthermia and hypotension.
• General medical conditions that might mimic neuroleptic malignant syndrome include central nervous system infections, status epilepticus, stroke, brain trauma, neoplasms, acute intermittent porphyria, and tetanus.
• Laboratory abnormalities observed in neuroleptic malignant syndrome have broad differential diagnoses and only specific points are presented in this chapter (see Lab Studies). Elevated creatine kinase (CK) can be observed with intramuscular injections and the use of restraints. Leukocytosis occurs with central nervous system infections.

Physical

Neuroleptic malignant syndrome tends to start with muscular rigidity and progress to hyperthermia with autonomic instability and a fluctuating level of consciousness. Compared to disease in adults, neuroleptic malignant syndrome in children and adolescents tends to present with more dystonia and less tremor.

• Symptoms of autonomic dysregulation include high fever, diaphoresis, tachypnea, tachycardia, and increased or labile blood pressure. In rare cases, a reversible cardiomyopathy mimicking cardiac infarction may develop the autonomic involvement in the course of neuroleptic malignant syndrome.¹¹
• Extrapyramidal symptoms include so-called lead pipe rigidity; dysphagia; a short, shuffling gait; resting tremor; dystonia; and dyskinesia.
• Excessive or purposeless motor activity and tremor can reflect psychomotor agitation.
• Delirium is characterized by the following:
  • Loss of awareness
  • Detachment from both the inside and outside worlds
  • Loss of orientation in time and space
  • Reduced ability to sustain the attention that wanders around and can not be directed at will
  • Speech that is often mumbled and incoherent
  • Development of illusions and hallucinations, especially visual
  • Level of consciousness fluctuates but may eventually decrease to the stages of lethargy, stupor, or coma
• Other features include pallor, rash, and dyspnea.

Causes

All classes of antipsychotics have been associated with neuroleptic malignant syndrome, including low-potency neuroleptics, high-potency neuroleptics, and the newer (or atypical) antipsychotics. Neuroleptic malignant syndrome has been reported most frequently in patients taking haloperidol and chlorpromazine.

• The clearest risk factors relate to the time course of therapy. Strongly associated factors are the use of high doses of antipsychotics (particularly the high-potency neuroleptics), rapid antipsychotic dosage increases, and the use of depot, the long-acting injectable forms of antipsychotics.¹² In the United States, only 3 long-acting forms are available at present—fluphenazine decanoate or enanthate, haloperidol decanoate, and risperdal consta.
• Other factors related to a patient's pharmacotherapy might be relevant, although their role has not been proven in controlled studies. Inconsistent use of neuroleptics and the use of other psychotropic medications, particularly lithium, have been suggested as risk factors. Prior treatment with electroconvulsive therapy (ECT) also has been proposed to have a role.
• Environmental and psychological factors that might predispose to neuroleptic malignant syndrome are hot and humid conditions, agitation, dehydration, and exhaustion.
• A number of demographic features have been implicated, many of which simply might reflect populations that have a high rate of neuroleptic usage. These include male sex and age younger than 40 years. Neuroleptic malignant syndrome has been reported in postpartum women.
• Genetic factors also might play a role. Case reports have been published on neuroleptic malignant syndrome occurring in identical twins as well as in a mother and 2 of her daughters¹³ .
• Patients who have experienced episodes of neuroleptic malignant syndrome previously are at risk for recurrences. The risk of recurrence is strongly related to the elapsed time between an episode of neuroleptic malignant syndrome and restarting antipsychotics.
  • If patients are rechallenged with antipsychotics within 2 weeks of an episode of neuroleptic malignant syndrome, 63% will have a recurrence. If more than 2 weeks have elapsed, only 30% will have a recurrence.
  • Eighty-seven percent of patients who develop neuroleptic malignant syndrome will be able to tolerate an antipsychotic at some point in the future. Given the present understanding of this syndrome, on reintroducing an antipsychotic, switch to a different antipsychotic class and, if possible, use an atypical antipsychotic because these might be less likely than traditional neuroleptics to cause neuroleptic malignant syndrome.
• A summary of medications that may induce movement disorders includes the following:
  • MAOIs
  • MAOIs combined with tricyclic antidepressants
  • MAOIs combined with serotonergic agents
  • MAOIs combined with meperidine
  • Lithium at toxic levels
  • Anticholinergics
  • Amphetamines
  • Fenfluramine
  • Cocaine
  • Phencyclidine
  • 3,4-Methylenedioxymethamphetamine (MDMA; ecstasy, XTC)
  • Methylphenidate¹⁴
• A summary of the well supported risk factors for neuroleptic malignant syndrome includes the following:
  • High-potency neuroleptic use
  • High-dose neuroleptic use
  • Rapid increase in neuroleptic dose
  • Depot injectable neuroleptic use
  • Prior episodes of neuroleptic malignant syndrome
  • Age younger than 40 years
  • Male sex
• A summary of the potential risk factors for neuroleptic malignant syndrome includes the following:
  • Dehydration¹⁵
  • Agitation¹⁵
  • Exhaustion
  • Malnutrition
  • Organic brain syndromes
  • Nonschizophrenic mental illness
  • Lithium use
  • Past history of electroconvulsive therapy
  • Warm and humid environments
  • Inconsistent use of neuroleptics
  • Postpartum period¹⁶

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