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 Overview of Heat Illness Heat illness encompasses a number of disorders ranging in severity from muscle cramps and heat exhaustion to heatstroke (which is a life-threatening emergency). Heat illness, although preventable... read more .)
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.
Neuroleptic malignant syndrome can also occur in patients withdrawing from levodopa or dopamine agonists.
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 Serotonin Syndrome Serotonin syndrome is a potentially life-threatening condition resulting from increased central nervous system serotonergic activity that is usually drug related. Symptoms may include mental... read more 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 Malignant Hyperthermia Malignant hyperthermia is a life-threatening elevation in body temperature usually resulting from a hypermetabolic response to concurrent use of a depolarizing muscle relaxant and a potent,... read more and withdrawal of intrathecal baclofen can cause findings similar to those of neuroleptic malignant syndrome, but they are usually easily differentiated by history.
Systemic infections, including sepsis Sepsis and Septic Shock Sepsis is a clinical syndrome of life-threatening organ dysfunction caused by a dysregulated response to infection. In septic shock, there is critical reduction in tissue perfusion; acute failure... read more , 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.
There are no confirmatory tests, but patients should have testing for complications, including serum electrolytes, blood urea nitrogen, creatinine, glucose, calcium, magnesium, and creatine kinase, urine myoglobin, and usually neuroimaging and cerebrospinal fluid analysis. Electroencephalography may be done to exclude nonconvulsive status epilepticus.
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 Key Points Neuroleptic malignant syndrome is characterized by altered mental status, muscle rigidity, hyperthermia, and autonomic hyperactivity that occur when certain neuroleptic drugs are used. Clinically... read more ). Severe hyperthermia is treated very aggressively, mainly with physical cooling (see Heatstroke: Treatment Treatment Heatstroke is hyperthermia accompanied by a systemic inflammatory response causing multiple organ dysfunction and often death. Symptoms include temperature > 40° C and altered mental status... read more ). Some patients may require tracheal intubation (see Airway Establishment and Control/Tracheal Intubation Tracheal Intubation Most patients requiring an artificial airway can be managed with tracheal intubation, which can be Orotracheal (tube inserted through the mouth) Nasotracheal (tube inserted through the nose)... read more ) and induced coma. Benzodiazepines, given IV in high doses, can be used to control agitation. Adjunctive drug therapy can be used, although efficacy has not been shown in clinical trials. Dantrolene 0.25 to 2 mg/kg IV every 6 to 12 hours to a maximum of 10 mg/kg/24 hours can be given for hyperthermia. Bromocriptine 2.5 mg every 6 to 8 hours or, alternatively, amantadine 100 to 200 mg every 12 hours can be given orally or via nasogastric tube to help restore some dopaminergic activity. This condition may not respond to even rapid and aggressive therapy, and mortality in treated cases is about 10 to 20%.
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.
Serotonin syndrome can often be differentiated from neuroleptic malignant syndrome by use of an SSRI or other serotonergic drug (and often developing within 24 hours of administration of its drug trigger) and hyperreflexia.
Stop the causative drug, initiate rapid cooling, and begin aggressive supportive care, usually in an ICU.
