Neuroleptic Malignant Syndrome

Many antipsychotics and antiemetics can be causative (see table Drugs That Can Cause Neuroleptic Malignant Syndrome). The factor common to all drug causes is a decrease in dopaminergic transmission; however, the reaction is not allergic but rather idiosyncratic. Etiology and mechanism are unknown. Risk factors appear to include high drug doses, rapid dose increases, parenteral administration, and switching from one potentially causative drug to another.

Symptoms of neuroleptic malignant syndrome begin most often during the first 2 weeks of treatment with neuroleptic drugs but may occur earlier or after many years.

The 4 characteristic symptoms usually develop over a few days and often in the following order:

• Altered mental status: Usually the earliest manifestation is a change in mental status, often an agitated delirium, and may progress to lethargy or unresponsiveness (reflecting encephalopathy).

• Motor abnormalities: Patients may have generalized, severe muscle rigidity (sometimes with simultaneous tremor, leading to cogwheel rigidity) or, less often, dystonias, chorea, or other abnormalities. Reflex responses tend to be decreased.

• Hyperthermia: Temperature is usually > 38° C and often > 40° C.

• Autonomic hyperactivity: Autonomic activity is increased, tending to cause tachycardia, arrhythmias, tachypnea, and labile hypertension.

• Clinical evaluation

• Exclusion of other disorders and complications

Neuroleptic malignant syndrome should be suspected based on clinical findings. Early manifestations can be missed because mental status changes may be overlooked or dismissed in patients with psychosis.

Other disorders can cause similar findings. For example:

• Serotonin syndrome tends to cause rigidity, hyperthermia, and autonomic hyperactivity, but it is usually caused by selective serotonin reuptake inhibitors (SSRIs) or other serotonergic drugs, and patients typically have hyperreflexia and sometimes myoclonus. Also, temperature elevations and muscle rigidity are usually less severe than in neuroleptic malignant syndrome, onset may be rapid (eg, < 24 hours), and nausea and diarrhea may precede serotonin syndrome.

• Malignant hyperthermia

• Nonconvulsive status epilepticus can cause altered mental status, rigidity, and hyperthermia. Electroencephalography should be obtained to exclude status epilepticus.

• Systemic infections, including sepsis, pneumonia, and central nervous system infection, can cause altered mental status, hyperthermia, and tachypnea and tachycardia, but generalized motor abnormalities are not expected. Also, in neuroleptic malignant syndrome, unlike most infections, altered mental status and motor abnormalities tend to precede hyperthermia.

• Rapid cooling, control of agitation, and other aggressive supportive measures

In patients with neuroleptic malignant syndrome, the causative drug is stopped and complications are treated supportively, usually in an intensive care unit (ICU) (1). Severe hyperthermia is treated aggressively, mainly with physical cooling (see Heatstroke: Treatment). Some patients may require tracheal intubation (see Airway Establishment and Control/Tracheal Intubation