Recommendations

Key Recommendations

The diagnosis is made in the presence of the tetrad of altered mental status, muscle rigidity, autonomic dysfunction, and hyperthermia. A high index of suspicion leads clinicians to stop antipsychotic medications and institute supportive measures simultaneously with diagnostic evaluation, given the critical nature of this syndrome. This means that less severe cases (partial NMS, mild NMS) may be seen more often than the traditional severe and life-threatening presentations. This also makes the diagnosis more challenging, as many other conditions present with some or all of the features of NMS.

NMS remains a diagnosis of exclusion. A careful assessment, including physical exam and comprehensive tests, is required to exclude other potential causes.[3][12]

History and physical exam

NMS is more likely to develop following initiation of antipsychotic therapy or an increase in the dose.[1][5][28][39][40][41][42][43] All antipsychotic medications have been associated with NMS, presumably through their antagonism of dopamine D2 receptors.[24] Almost all patients develop symptoms within 30 days, with 16% developing symptoms within 24 hours after drug initiation and 66% within 1 week.[1][35]

A prior episode of NMS is generally believed to significantly increase risk for subsequent episodes.

Often it can be difficult to differentiate an acute extrapyramidal reaction from NMS, especially if the prior episode is poorly described in the medical records.[3][9][37][41][44]

It is useful to ask about a history of delirium, dementia, brain trauma, Wilson disease, or Parkinson disease because they appear to be associated with an increased risk for NMS in the context of antipsychotic use or abrupt withdrawal of dopaminergic drugs.[18][28][29]

Key clinical features to make a diagnosis include:

  • Altered mental status: characterized by confusion, delirium, or stupor.

  • Muscle rigidity: patients can develop muscle rigidity de novo, or worsening of preexisting muscle rigidity. It can be difficult to distinguish these two entities. Generalized rigidity (described as "lead pipe" in its most severe form and usually unresponsive to antiparkinsonian agents) is a cardinal feature. It may be associated with tremor, akinesia, dystonia, trismus, myoclonus, dysarthria, and dysphagia. Patients may have sialorrhea and rhabdomyolysis.[35]

  • Hyperthermia: may occur simultaneously with diaphoresis or flushing, indicating a disruption of normal thermoregulatory coordination.

  • Autonomic disturbances: may include labile hypertension, tachycardia, tachypnea, urinary incontinence, and diaphoresis.

Tests

Laboratory investigations are essential to exclude other disorders or complications.

  • CBC: helpful to rule out sepsis, in conjunction with other clinical parameters.

  • Serum creatine kinase (CK) levels: patients with NMS may have significant increases in serum CK indicating muscle injury, with the risk of myoglobinuric acute kidney injury. Subsequent tests should be performed, often daily, until symptoms and laboratory abnormalities resolve.

  • Basic metabolic panel (BUN, creatinine): to evaluate the presence of complications such as acute kidney injury, and hydration status.

  • Myoglobin levels and urinalysis: myoglobinuria is a poor prognostic sign.

  • Urine/blood cultures and chest x-ray may be obtained to rule out sepsis and pneumonia.

  • CT/MRI brain scan: to rule out brain infection, mass, or bleed.[12]

  • Electroencephalogram: may be needed to rule out status epilepticus.

  • Toxicology screen: to exclude drug abuse/overdose/withdrawal.

  • Lumbar puncture: to rule out meningitis/encephalitis in patients with high fever, altered mental status, and rigidity.

More specific tests are guided by clinical circumstances.[12][45]

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