Incidence of NMS is estimated at 0.1% to 2%. There is a preponderance of young men with NMS, but this may be because of the increased frequency of schizophrenia and affective disorders in this group and the subsequent increased use of neuroleptics. Other risk factors may include neuroleptic-induced catatonia, dehydration or malnutrition as a precipitating cause, and a history of elevated serum creatinine kinase (CK) during psychotic episodes not in association with NMS.

The motor symptoms consist most commonly of parkinsonian-type symptoms such as “lead-pipe” rigidity, but other symptoms include a tremor superimposed on the rigidity (“cogwheel rigidity”), akinesia, bradykinesia, and dystonia (e.g., blepharospasm, opisthotonus, oculogyric crises, trismus, and orobuccal dyskinesia). The altered mental status ranges from delirium to stupor or even coma. A fever is seen in almost all cases (unlike malignant hyperthermia) and is usually greater than 38°C and often greater than 41°C. Arrhythmias, blood pressure fluctuations, and respiratory abnormalities constitute the main, potentially life-threatening autonomic features of NMS. Rare clinical manifestations include seizures, ataxia, and nystagmus. NMS usually evolves over 24 to 72 hours. Occasionally there can be a slower progression over days, but in the case of depot neuroleptics (e.g., intramuscular form of fluphenazine), progression over a couple of weeks has been reported. The clinical course lasts 7 to 10 days, with a longer time if the inciting agent was depot neuroleptics, because of slower
clearance. Laboratory abnormalities found in association with NMS are leukocytosis in the range of 10 to 40,000 cells/αL and elevated serum creatinine kinase (CK) in the range of 200 to several thousand IU/L.

Cases of NMS with prominent medical complications and fatalities are widely described. Some of the causes for the morbidity and mortality of NMS relate to its secondary complications. Because of the associated rhabdomyolysis, severe dehydration and prerenal acute renal failure can occur. This is predictive of mortality, with aggressive hydration absolutely necessary (urine alkalinization is controversial). Because of rigidity and consequent immobility, as well as activation of the coagulation cascade to metabolic conditions created by the rhabdomyolysis, venous thromboembolism has been reported. Pulmonary embolism has been reported to cause almost one quarter of fatalities. In severe cases, aspiration pneumonia, respiratory failure, cardiac arrhythmias, and dysautonomia have been reported.