Description

• Neuroleptic malignant syndrome (NMS) is a life-threatening condition that may develop during treatment with neuroleptic medications; 2/3 of cases develop within the first 2 weeks of initiating therapy but can happen at any time during therapy.
• Nonneuroleptic medications with antidopaminergic activity have also been implicated to a lesser degree.
• Characterized by muscular rigidity due to dopamine antagonism in the nigrostriatal pathway
• Signs and symptoms include hyperthermia from antagonism of hypothalamic thermoregulation (more likely in the setting of benzodiazepine withdrawal); autonomic instability, cognitive changes, and elevations of serum creatine phosphokinase (CPK) are other hallmarks.
• Can be indistinguishable from other causes of drug-induced hyperthermia (e.g., malignant hyperthermia, serotonin syndrome, lethal catatonia, anticholinergic toxins, or sympathomimetic poisoning); detailed history is essential to differentiate between these other conditions.

Epidemiology

Incidence

• Variably reported as 0.01–3%
• 2,000 new cases annually in the United States
• Predominant sex: male > female
• Predominant age: <40 years

Prevalence
0.15% +/− 0.05% among patients receiving neuroleptics (1)

Etiology and Pathophysiology

• Exact mechanism: unknown
• Most likely due to central dopaminergic blockade of nigrostriatal, hypothalamic, mesocortical/limbic pathways
• Sympathoadrenal hyperactivity and defects in neuronal calcium regulatory proteins may also contribute.
• Most commonly seen with typical antipsychotics: phenothiazines (e.g., fluphenazine), butyrophenones (e.g., haloperidol), and thiothixene (1)[C]
• May also be seen with atypical antipsychotics (e.g., clozapine, risperidone, olanzapine) (1)[C]
• Nonneuroleptic agents with antidopaminergic activity (e.g., metoclopramide, promethazine, and droperidol) have also been implicated.
• Rare cases have occurred with usage of medications not known to have any central antidopaminergic activity (e.g., lithium, phenelzine, and desipramine).
• Also associated with withdrawal from dopamine agonists in Parkinson disease, CNS shunt failure, and functional hemispherectomy

Genetics

• Some studies show a genetic predisposition to NMS.
• Polymorphisms: loss of DEL allele in 141C Ins/Del of the dopamine D₂ receptor gene and Ser9Gly in the dopamine D₃ receptor gene

Risk Factors

• High-potency neuroleptic medications; newly administered medication or a rapid increase in the dose of an existing agent
• Intramuscular or depot administration of medications
• Concurrent use of multiple neuroleptic agents
• Administration of neuroleptics with other drugs known to cause NMS, such as lithium
• Previous episodes of NMS
• Exposure to heat
• Dehydration/malnutrition
• Presence of an underlying structural/functional brain disorder (tumor, encephalitis, delirium/dementia)
• Postpartum women may be at an increased risk for developing NMS.