Neuroleptic Malignant Syndrome

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Chapter 82 Neuroleptic Malignant Syndrome

Jennifer M. Hall, DO , James L. Jacobson, MD

1 What is neuroleptic malignant syndrome (NMS)?

NMS is a rare, potentially fatal, idiosyncratic complication of antipsychotic medications. The usual presentation consists of four primary features:

image Hyperthermia

image Extreme generalized muscular rigidity

image Autonomic instability

image Altered mental status

These features generally appear 24 to 72 hours after the administration of an antipsychotic; however, NMS can also occur with chronic use. Altered mental status is the first presenting symptom in 80% of NMS cases. Mean recovery time after antipsychotic discontinuation is 7 to 10 days but may be prolonged when long-acting depot antipsychotics are implicated. For other common features of NMS, see Box 82-1.

Box 82-1 Signs and Symptoms of Neuroleptic Malignant Syndrome

Primary Features

Hyperthermia

Altered mental status

Autonomic instability

Extreme generalized rigidity (often called lead pipe rigidity)

Other Common Features

Laboratory evidence of muscle injury (elevated creatine kinase muscle fraction)

Tremor

Mutism

Leukocytosis

Labile hypertension (less often hypotension)

Tachycardia

Tachypnea

Dysphagia

Diaphoresis

Sialorrhea

Incontinence

2 How common is NMS?

Recent data suggest that the incidence of NMS in patients treated with antipsychotics ranges between 0.01% and 0.02%. Previous estimates were as high as 3%; however, because of increased awareness, judicious antipsychotic use, and rapid recognition and treatment the incidence of NMS has declined.

3 What is the mortality rate for NMS?

Despite the declining incidence of NMS, it remains a significant source of morbidity and mortality among patients receiving antipsychotics. The original description of NMS in 1968 estimated a mortality rate as high as 75%, which subsequently declined to 20% to 30% in the 1980s. More recently, the U.S. Agency for Healthcare Research and Quality reports that, of an estimated 2000 cases diagnosed annually in hospitals, mortality rates approximate 10%. Cause of death in NMS is usually a result of cardiac or respiratory arrest (cardiac failure, infarction, arrhythmia, aspiration pneumonia, or pulmonary emboli), myoglobinuric renal failure, or disseminated intravascular coagulation.

4 What is the pathogenesis of NMS?

Although the pathophysiology of NMS is poorly understood, dopamine receptor antagonism in the basal ganglia, hypothalamus, and postganglionic sympathetic neurons is hypothesized to be the primary culprit. Given the complexity of NMS, it is also hypothesized that other neurotransmitter systems involving γ-aminobutyric acid (GABA), serotonin, and glutamate have a contributing role in initiation and progression of NMS.

5 What are the diagnostic criteria for NMS?

The diagnosis of NMS is a clinical diagnosis of exclusion in which the administration of an antipsychotic medication has occurred (usually 24-72 hours) before the onset of the syndrome.

Research criteria in the American Psychiatric Association’s Diagnostic and Statistical Manual, fourth edition (DSM-IV-TR), include the following:

A. The development of severe muscle rigidity and elevated temperature associated with the use of neuroleptic medication.

B. Two or more of the following: diaphoresis, dysphagia, tremor, incontinence, changes in level of consciousness ranging from confusion to coma, mutism, tachycardia, elevated or labile blood pressure, leukocytosis, and laboratory evidence of muscle injury.

C. The symptoms in criteria A and B are not due to another substance or a neurologic or other general medical condition.

D. The symptoms in criteria A and B are not better accounted for by a mental disorder.

6 What is the differential diagnosis of NMS?

NMS is a clinical diagnosis of exclusion; therefore central, systemic, and toxic causes of hyperthermia, rigidity, rhabdomyolysis, and altered mental status must be excluded. See Box 82-2.

Box 82-2 Differential Diagnosis of Neuroleptic Malignant Syndrome

Infectious

Meningitis or encephalitis

Postinfectious encephalomyelitis syndrome

Brain abscess

Sepsis

Psychiatric or Neurologic

Idiopathic malignant catatonia

Agitated delirium

Benign extrapyramidal side effects

Nonconvulsive status epilepticus

Structural lesions, particularly involving the midbrain

Toxic or Pharmacologic

Anticholinergic delirium

Salicyl poisoning

MH (inhalational anesthetics, succinylcholine)

Serotonin syndrome (monoamine oxidase inhibitors, triptans, linezolid)

Substances of abuse (amphetamines, hallucinogens)

Withdrawal from dopamine agonists, baclofen, sedative-hypnotics, and alcohol

Endocrine

Thyrotoxicosis

Pheochromocytoma

Environmental

Heat stroke

7 Are there specific laboratory findings for NMS?

No laboratory findings are pathognomonic for NMS, but findings may support or confirm the diagnosis of NMS while excluding other systemic illnesses. Common laboratory abnormalities include the following:

image Elevated serum creatine kinase level of 1000 to 100,000 International Units/L

image Leukocytosis (10,000-40,000/mm3)

image Elevated lactate dehydrogenase, alkaline phosphatase, and liver transaminase levels

image Electrolyte disturbances: hypernatremia, hyponatremia, hyperkalemia, hypocalcemia, hypomagnesemia, and hypophosphatemia

image Metabolic acidosis

image Myoglobinuric acute renal failure: proteinuria, elevated blood urea nitrogen and creatinine levels

image Low serum iron concentration

8 Are special diagnostic tests or imaging studies useful?

Cerebrospinal fluid values are usually normal, but nonspecific elevations in protein have been reported in 37% of cases. Electroencephalogram may show diffuse slowing without focal abnormalities. Magnetic resonance imaging and computed tomography results are typically normal, but cerebral edema has been reported in the setting of severe metabolic imbalances.

9 Which agents have been implicated in the development of NMS?

First- and second-generation antipsychotic medications have been reported to cause NMS:

image First-generation antipsychotics include chlorpromazine, fluphenazine, haloperidol, paliperidone, perphenazine, and thioridazine.

image Second-generation antipsychotics include aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone.

NMS also has been reported with antiemetic medications such as domperidone, droperidol, metoclopramide, prochlorperazine, promethazine, and trimethobenzamide, as a result of their dopamine antagonism. Abrupt withdrawal of dopaminergic medications (amantadine or L-dopa) and GABA-ergic medications has been reported to precipitate an NMS-like reaction.

10 What are risk factors for development of NMS?

Several clinical, systemic, and metabolic risk factors have been associated with NMS. Suggested risk factors include history of NMS, baseline electrolyte disturbances, preexisting abnormalities in CNS dopamine activity or receptor function, iron deficiency, acute medical or neurologic illness, dehydration, primary diagnosis of an affective disorder (particularly bipolar disorder and psychotic depression), comorbid substance use disorder, acute catatonia, psychomotor agitation, use of restraints, delirium, dementia, concurrent use of other psychotropic medications, high doses of antipsychotics, rapid dose escalation, and parenteral administration or depot formulations of antipsychotics.

Recent evidence also suggests genetic vulnerability as a potential risk factor for the development of NMS. Age and sex alone are not considered independent risk factors; however, younger male patients may be more likely to receive higher doses of antipsychotics to control combative behavioral symptoms, which results in their overrepresentation in NMS case studies. Although the variables listed above correlate with the risk of NMS, they are not practical in predicting the development of NMS.

11 Does NMS have a genetic predisposition?

Some evidence has suggested a familial predisposition in the development of NMS. The human dopamine D2 receptors gene (DRD2) contains a TaqI A restriction fragment polymorphism containing A1 and A2 alleles. Subjects with one or two A1 alleles have lower dopamine D2 receptor density and also have diminished dopaminergic activity and glucose metabolism in brain regions abundant with dopamine receptors. Previous studies have shown that the proportion of subjects with the A1/A1 or A1/A2 genotype was significantly higher in patients with NMS than in those without NMS. This polymorphism is not regarded as a specific marker as 60% of patients without NMS also have the A1 allele.

12 What is the suggested management for NMS?

Early recognition and diagnosis of NMS is crucial to provide appropriate and prompt treatment. The mainstay of management is to:

image Stop the offending agent and other psychotropic agents.

image Provide the necessary supportive care.

Volume resuscitation should be aggressive as most patients are severely dehydrated in the acute phase of the illness. Serial monitoring and correction of electrolyte and metabolic abnormalities are critical, and using alkalinized fluids or bicarbonate loading may be helpful in preventing renal failure. Hyperthermia should be addressed by using physiologic cooling measures because peak and duration of temperature elevation are predictive of morbidity and mortality. Markedly elevated blood pressures should be lowered pharmacologically, and heparin or low-molecular-weight heparin should be administered to prevent deep venous thrombosis. Patients should be closely monitored in the intensive care unit for complications including cardiorespiratory failure, acute renal failure, aspiration pneumonia, and coagulopathies that may require prompt intervention or additional supportive measures.

13 What pharmacologic treatments are useful?

In most cases, cessation of antipsychotic medications and supportive medical management are sufficient to reverse the symptoms of NMS. Several empirical off-label treatment approaches can be used in a case-by-case basis:

image Recent clinical reports suggest that benzodiazepines (oral or parenteral) may ameliorate symptoms of agitation or catatonia and hasten recovery of NMS. A trial of lorazepam 1 to 2 mg parenterally is a reasonable first-line intervention for patients with acute NMS.

image Dopamine agonists, such as amantadine and bromocriptine, have been reported to reverse Parkinsonian symptoms, hasten recovery, and decrease mortality rates when used alone or in combination with other pharmacologic agents. Amantadine is generally initiated at 200 to 400 mg/day orally in divided doses. Bromocriptine can be started at 2.5 mg two to three times a day orally with a maximum daily dose of 45 mg. Be advised that bromocriptine can worsen psychosis and hypotension, as well as precipitate vomiting, and must be used with caution. Abrupt discontinuation of bromocriptine can also precipitate rebound symptoms.

image Dantrolene may be useful in cases of extreme hyperthermia, rigidity, and hypermetabolism. Typical dosing is 1 to 2.5 mg/kg intravenously initially and may be increased to 1 mg/kg every 6 hours. Side effects include respiratory impairment and hepatic toxicity.

image Electroconvulsive therapy (ECT) has been shown to be effective when NMS symptoms are refractory to supportive care and pharmacologic treatment. The typical ECT course was six to 10 bilateral treatments with initial response expected in the first few treatments. During ECT succinylcholine should be avoided in patients with rhabdomyolysis to prevent acute hyperkalemia and cardiovascular complications.

14 Will NMS recur with subsequent use of neuroleptic medications?

The likelihood of development of NMS after restarting antipsychotic medications once the original episode of NMS has resolved is approximately 30%. To reduce risk of recurrence allow at least 2 weeks of recovery before restarting any antipsychotic medications. It is best to choose a low-dose or low-potency antipsychotic and titrate gradually while closely monitoring for subtle signs or symptoms of NMS.

15 Is there any way to prevent NMS?

No. When clinically indicated, reducing antipsychotic dose, avoiding parenteral or depot antipsychotic formulation, avoiding rapid dose escalation, and minimizing other risk factors (e.g., dehydration) may decrease the overall risk for development of NMS. Given that catatonia may be a strong risk factor for the development of NMS, antipsychotics should be avoided in patients with catatonia, if possible, for whom benzodiazepines may be effective treatment.

16 Are there alternatives to antipsychotic medications for acutely psychotic patients?

A number of alternative treatment options exist for acutely psychotic patients. Benzodiazepines may help reduce agitation in a hyperactive psychotic patient and may potentially lower the absolute dose of antipsychotic needed to manage symptoms. When the primary diagnosis is an affective disorder, aggressive treatment with mood stabilizers or antidepressants is indicated. However, if psychotic symptoms are present in the context of an affective disorder, antipsychotic medications are usually necessary. ECT is also a viable nonpharmacologic alternative for treatment of manic psychosis, depressive psychosis, and catatonia.

17 Are there alternatives to antipsychotic medications for patients with chronic psychotic illnesses?

In chronic psychotic disorders (e.g., schizophrenia, schizoaffective disorder, delusional disorder) there may be no alternative treatment to antipsychotic medications that adequately manages symptoms. Hence, if NMS has occurred caution is advised on rechallenging with a different class of antipsychotics. Special attention must be paid to second-generation antipsychotics and treatment of reversible risk factors. Efforts must also be made to minimize polypharmacy when clinically indicated.

18 Are malignant hyperthermia (MH) and NMS related?

MH and NMS have similar clinical presentations but different pathophysiologies. MH develops after exposure to inhalation anesthetics, such as halothane, and depolarizing muscle relaxants, such as succinylcholine. MH is characterized by diffuse muscle rigidity, fever, hypermetabolism, elevated serum creatine kinase level, hyperkalemia, tachycardia, hypoxemia, metabolic acidosis, and myoglobinuria. MH is caused by a genetic defect in a sarcoplasmic reticulum calcium channel protein, which results in excessive calcium release into skeletal muscle after exposure to triggering medications. Susceptibility to MH is diagnosed by the muscle contracture test. In susceptible people, excessive contractions occur in muscle strips exposed to varying concentrations of halothane and caffeine. Family studies and muscle contracture testing indicate that patients with one of the disorders do not appear to be at increased risk for the other.

19 What is serotonin syndrome?

Serotonin syndrome is a rare but potentially fatal syndrome characterized by the triad of altered mental status, autonomic dysfunction, and neuromuscular abnormalities, which is thought to result from central and peripheral hyperserotonergic activity. The similarity between serotonin syndrome and NMS often leads to misdiagnosis. Serotonin syndrome can develop after the addition of a serotonergic medication (e.g., monoamine oxidase inhibitor, tricyclic antidepressant, selective serotonin reuptake inhibitor) to a regimen that already includes serotonin-enhancing drugs or after overdoses of serotonergic drugs. The presentation is heterogeneous, but common clinical features include confusion, agitation, restlessness, myoclonus, hyperreflexia, diaphoresis, tachycardia, blood pressure fluctuation, shivering, tremor, diarrhea, incoordination, and fever.

20 How is serotonin syndrome differentiated from NMS?

Serotonin syndrome follows a history of exposure to serotonergic medications, not antipsychotic medications. Compared with NMS, the observed tremor and myoclonus in serotonin syndrome are more prominent than muscle rigidity. Fever is present less often and the laboratory abnormalities seen in NMS (e.g., elevated creatine phosphokinase level) are usually absent in serotonin syndrome. Discontinuation of serotonergic medications and supportive measures are most important during treatment of serotonin syndrome. As with NMS, the role of pharmacologic treatment in serotonin syndrome is unclear. Lorazepam, propranolol, and cyproheptadine may be effective in symptomatic management.

Acknowledgments

The authors gratefully acknowledge the contribution of Ryan Peirson, MD, and Erin Fellner, MD, for revisions to a previous edition.

Key Points Neuroleptic Malignant Syndromeimage

1. NMS can develop with exposure to any antipsychotic medication—acute or chronic use.

2. When considering the differential diagnosis, the physician should pay particular attention to recent changes in doses and psychotropic polypharmacy.

3. Other agents, such as antiemetic agents, can also cause NMS.

4. Treatment is primarily supportive.

5. In most cases, the most important factors that distinguish NMS from serotonin syndrome are hyperthermia and rigidity.

Bibliography

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