Patients have generally been exposed to a dopamine antagonist within 72 hours prior to symptom development. Hyperthermia (>100.4°F or >38.0°C on at least two occasions, measured orally), associated with profuse diaphoresis, is a distinguishing feature of neu- roleptic malignant syndrome, setting it apart from other neurological side effects of anti- psychotic medications. Extreme elevations in temperature, reflecting a breakdown in central thermoregulation, are more likely to support the diagnosis of neuroleptic malig- nant syndrome. Generalized rigidity, described as ”lead pipe” in its most severe form and usually unresponsive to antiparkinsonian agents, is a cardinal feature of the disorder and may be associated with other neurological symptoms (e.g., tremor, sialorrhea, akinesia, dystonia, trismus, myoclonus, dysarthria, dysphagia, rhabdomyolysis). Creatine kinase elevation of at least four times the upper limit of normal is commonly seen. Changes in mental status, characterized by delirium or altered consciousness ranging from stupor to coma, are often an early sign. Affected individuals may appear alert but dazed and unre- sponsive, consistent with catatonic stupor. Autonomic activation and instability—mani- fested by tachycardia (rate>25% above baseline), diaphoresis, blood pressure elevation 225 mmHg systolic change within 24 hours), urinary incontinence, and pallor—may be seen at any time but provide an early clue to the diagnosis. Tachypnea (rate >50°/o above baseline) is common, and respiratory distress—resulting from metabolic acidosis, hyper- metabolism, chest wall restriction, aspiration pneumonia, or pulmonary emboli—can oc- cur and lead to sudden respiratory arrest.
A workup, including laboratory investigation, to exclude other infectious, toxic, met- abolic, and neuropsychiatric etiologies or complications is essential (see the section ”Dif- ferential Diagnosis” later in this discussion). Although several laboratory abnormalities are associated with neuroleptic malignant syndrome, no single abnormality is specific to the diagnosis. Individuals with neuroleptic malignant syndrome may have leukocytosis, metabolic acidosis, hypoxia, decreased serum iron concentrations, and elevations in se- rum muscle enzymes and catecholamines. Findings from cerebrospinal ﬂuid analysis and neuroimaging studies are generally normal, whereas electroencephalography shows gen- eralized slowing. Autopsy findings in fatal cases have been nonspecific and variable, de- pending on complications.