Neuroleptic malignant syndrome is characterized by altered mental status, muscle rigidity, hyperthermia, and autonomic hyperactivity that occur when certain neuroleptic drugs are used. Clinically, neuroleptic malignant syndrome resembles malignant hyperthermia. Diagnosis is clinical. Treatment is aggressive supportive care.
Among patients taking neuroleptic drugs, about 0.02 to 3% develop neuroleptic malignant syndrome. Patients of all ages can be affected.
(See also Overview of Heat Illness.)
Etiology of 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.
Drugs That Can Cause Neuroleptic Malignant Syndrome
Class | Drugs |
|---|---|
Antipsychotics, traditional | Mesoridazine |
Antipsychotics, newer | |
Antiemetics | Domperidone |
Symptoms and Signs of Neuroleptic Malignant Syndrome
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.
Diagnosis of Neuroleptic Malignant Syndrome
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.
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.
Treatment of Neuroleptic Malignant Syndrome
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
Treatment reference
1. Schönfeldt-Lecuona, C, Kuhlwilm L, Cronemeyer M, et al: Treatment of the neuroleptic malignant syndrome in international therapy guidelines: a comparative analysis. Pharmacopsychiatry 53(2):51-59, 2020 doi: 10.1055/a-1046-1044
Key Points
Neuroleptic malignant syndrome develops infrequently in patients taking neuroleptic or other drugs that decrease dopaminergic transmission.
Suspect the disorder if patients develop altered mental status, muscle rigidity or involuntary movements, hyperthermia, and autonomic hyperactivity.
Stop the causative drug, initiate rapid cooling, and begin aggressive supportive care, usually in an ICU.
