AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

Even the newer atypical antipsychotics, which are not classified accurately as neuroleptics, can cause NMS. 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 NMS 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.

Pathophysiology

The most widely accepted mechanism by which antipsychotics cause NMS 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 NMS 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 NMS.

Direct muscle toxicity also has been proposed as a mechanism of NMS.

Frequency

United States

NMS is associated with the use of various antipsychotic medicines, most frequently the older antipsychotics, termed neuroleptics. Development of NMS 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. Data largely come from case control studies rather than prospective randomized trials.

International

The frequency of NMS 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. A retrospective study conducted in India showed an incidence of 0.14% (Chopra, 1999).

Mortality/Morbidity

Mortality from NMS 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 NMS 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 NMS 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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Criteria for the diagnosis of NMS 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 NMS, 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 NMS includes the following:
• • Diaphoresis
  • Dysphagia
  • Tremor
  • Incontinence
  • Delirium, mutism 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 NMS 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). 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.
• Lethal catatonia (LC) is a similar condition that might be confused with NMS. LC occurs in people with schizophrenia or during manic episodes. Neuroleptics might either improve or worsen the symptoms of LC. Distinguishing LC from NMS can be difficult, although a detailed history might reveal episodes of catatonia while a patient is not taking neuroleptics. LC also tends to have a prodrome of excitement and agitation prior to the onset of rigidity, while NMS tends to begin with rigidity.
• Antipsychotics can cause a variety of reactions that can be confused with NMS. 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 NMS. 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 NMS 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.
• Medication-induced movement disorders not otherwise specified can be very similar to NMS 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. MH 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 NMS occurs more frequently in patients susceptible to MH.
• 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 NMS include central nervous system infections, status epilepticus, stroke, brain trauma, neoplasms, acute intermittent porphyria, and tetanus.
• Laboratory abnormalities observed in NMS have broad differential diagnoses and only specific points are presented in this chapter (see Lab Studies). Elevated creatinine kinase (CK) can be observed with intramuscular injections and the use of restraints. Leukocytosis occurs with central nervous system infections.

Physical

NMS tends to start with muscular rigidity and progress to hyperthermia with autonomic instability and a fluctuating level of consciousness. Compared to disease in adults, NMS 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 NMS.
• Extrapyramidal symptoms include so-called lead pipe rigidity; dysphagia; a short, shuffling gait; resting tremor; dystonia; and dyskinesia.
• Tremor and excessive or purposeless motor activity can reflect psychomotor agitation.
• Delirium, mutism, incontinence, lethargy, stupor, or coma can reflect changes in the level of consciousness.
• Other features include pallor, rash, and dyspnea.

Causes

All classes of antipsychotics have been associated with NMS, including low-potency neuroleptics, high-potency neuroleptics, and the newer (or atypical) antipsychotics. NMS 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. In the United States, only 2 long-acting forms are available at present—fluphenazine decanoate or enanthate and haloperidol decanoate.
• 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 NMS 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. NMS has been reported in postpartum women.
• Genetic factors also might play a role. Case reports have been published on NMS occurring in identical twins as well as in a mother and 2 of her daughters.
• Patients who have experienced episodes of NMS previously are at risk for recurrences. The risk of recurrence is strongly related to the elapsed time between an episode of NMS and restarting antipsychotics.
• • If patients are rechallenged with antipsychotics within 2 weeks of an episode of NMS, 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 NMS 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 NMS.
• 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)
  • Methylphenidate
• A summary of the well supported risk factors for NMS includes the following:
• • High-potency neuroleptic use
  • High-dose neuroleptic use
  • Rapid increase in neuroleptic dose
  • Depot injectable neuroleptic use
  • Prior episodes of NMS
  • Age younger than 40 years
  • Male sex
• A summary of the potential risk factors for NMS includes the following:
• Dehydration
• Agitation
• Exhaustion
• Malnutrition
• Organic brain syndromes
• Nonschizophrenic mental illness
• Lithium use
• Past history of ECT
• Warm and humid environments
• Inconsistent use of neuroleptics
• Postpartum period

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Manic-depressive illness
Lethal catatonia
Neuroleptic-induced acute dystonia
Neuroleptic-induced acute akathisia
Neuroleptic-induced tardive dyskinesia
Neuroleptic-induced parkinsonism
Serotonin syndrome
Malignant hyperthermia
Heat stroke
Central nervous system infections
Status epilepticus
Stroke
Brain trauma
Neoplasms
Acute intermittent porphyria
Tetanus

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• The rigidity and hyperthermia found in NMS contribute to muscle damage and necrosis. Elevated blood CK, aminotransferases (aspartate aminotransferase [AST], alanine aminotransferase [ALT]), and lactate dehydrogenase (LDH) reflect damage and necrosis, which can progress quickly to rhabdomyolysis with hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia. Elevated blood levels of myoglobin and myoglobinuria can be observed and ultimately can lead to renal failure.
• More general laboratory features include leukocytosis, thrombocytosis, and evidence of dehydration. Cerebrospinal fluid protein might be elevated. Serum iron concentration might be decreased.
• Investigate other causes for fever based on the clinical scenario.
• Investigate symptoms and signs of urinary tract, respiratory, and CNS infections.
• A summary of the laboratory abnormalities associated with NMS includes the following:
• • Increased LDH
  • Increased CK
  • Increased AST
  • Increased ALT
  • Increased alkaline phosphatase
  • Hyperuricemia
  • Hyperphosphatemia
  • Myoglobinemia
  • Leukocytosis
  • Thrombocytosis
  • Proteinuria
  • Decreased serum iron
  • Increased cerebrospinal fluid (CSF) protein
  • Hypocalcemia
  • Myoglobinuria

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The most important intervention is to discontinue all antipsychotics. In most cases, symptoms will resolve in 1-2 weeks. NMS precipitated by long-acting depot injections of antipsychotics can last as long as a month. During the course of NMS, use supportive care aggressively. The value of other interventions, such as dantrolene, amantadine, bromocriptine, and ECT, is uncertain.

• Supportive measures are aimed at preventing further complications and maintaining organ function.
• • Patients should receive circulatory and ventilatory support as needed.
  • Cooling blankets and antipyretics can be used to control temperature.
  • Aggressive fluid resuscitation and alkalization of urine can help prevent acute renal failure and enhance excretion of muscle breakdown products.
• ECT has been proposed as a treatment based on its effectiveness in acute lethal catatonia. Some data suggest that ECT is effective for NMS, but serious treatment-related complications have occurred (see Complications). Specifically, NMS patients have developed cardiac arrest and ventricular fibrillation after ECT.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Specific drug therapies, such as dantrolene, amantadine, bromocriptine, and ECT, have an uncertain role in the treatment of NMS. While they generally are felt to be helpful, they have been found to be deleterious in some studies.

Drug Category: Skeletal muscle relaxants

Modulate contractions of muscle cells.

Drug Category: Dopaminergic agents

In order for a dopamine agonist to offer clinical benefit, it must stimulate D2 receptors. The role of other dopamine receptor subtypes currently is unclear.

Drug Category: Benzodiazepines

Used in a small number of patients unresponsive to above measures. In most cases, a continuous IV infusion of diazepam or lorazepam has been utilized.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Complications

• Complications include dehydration from poor oral intake, acute renal failure from rhabdomyolysis, and deep vein thrombosis and pulmonary embolism from rigidity and immobilization.
• Avoiding antipsychotics can cause complications related to uncontrolled psychosis. Most patients taking antipsychotic medicines are being treated for a severe and persistent psychiatric disorder; a high likelihood exists that a patient will relapse while off antipsychotics.
• A summary of the potential complications of NMS includes the following:
• • Rhabdomyolysis
  • Renal failure
  • Cardiac arrest
  • Infection
  • Aspiration
  • Respiratory failure
  • Seizure
  • Pulmonary embolism
  • Hepatic failure
  • Uncontrolled psychoses

Prognosis

• Most series suggest that the mortality rate is 10-20%. When reporting bias is factored in, the true rate of mortality from NMS might be much lower. Mortality rates generally are higher in patients who develop severe muscle necrosis and resulting rhabdomyolysis.
• Patients who have previously experienced episodes of NMS are at risk for recurrences. The risk of NMS recurrence is strongly related to the elapsed time between an episode of NMS and restarting antipsychotics.
• • If patients are rechallenged with antipsychotics within 2 weeks of an episode of NMS, 63% will have a recurrence. If more than 2 weeks has elapsed, only 30% will have a recurrence.
  • Eighty-seven percent of patients who develop NMS will be able to tolerate another antipsychotic at some point in the future, which is very important because most patients taking neuroleptics require them to maintain a reasonable functional status. Current practice is to switch to a different class of antipsychotic when reintroducing these medications. Often, one of the newer atypical antipsychotics is chosen because current evidence suggests a lower incidence of NMS with these agents.

Patient Education

• Educational approaches can help patients and their relatives to understand what has happened to the patient, why the NMS has developed in the past, and what possibility of the recurrence of NMS if the patient is rechallenged with a different class of antipsychotics. This may help patients and their relatives to decide about giving consent to restart antipsychotics. They have to be aware of the early signs of developing NMS such as rigidity, hyperthermia, and changes of consciousness to bring attention of the medical staff to the possible redevelopment of NMS.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• When a patient develops NMS, especially when the result is fatal, physicians can be sued.
• Predicting who will develop NMS essentially is impossible given the current state of medical technology. Knowing that men younger than 40 years and those who previously have had NMS are at somewhat higher risk might help in risk stratification.
• Informed consent is particularly important before initiating treatment in these populations. Unfortunately, therapy with neuroleptics often is begun when patients are least likely to hear and interpret information accurately for informed consent, which presents a difficult area medicolegally because NMS is a rare but serious complication of neuroleptic therapy.
• The safest course is to provide patients and their families with as much information as they can absorb and follow up with additional information. This can be difficult to achieve in an often less-than-ideal setting.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: May 17, 2006