What is the approach to work up a patient with suspected Neuroleptic Malignant Syndrome (NMS)?

Workup of Neuroleptic Malignant Syndrome

The workup of suspected NMS requires immediate clinical diagnosis based on a point-based scoring system (≥76 points indicates probable NMS), combined with targeted laboratory testing to assess severity and exclude alternative diagnoses, while simultaneously initiating supportive care. 1

Clinical Assessment and Diagnostic Scoring

Use the following point-based diagnostic system to establish probable NMS (≥76 points required): 1

• Dopamine antagonist exposure or dopamine agonist withdrawal within 3 days: 20 points 1
• Hyperthermia (>100.4°F oral on ≥2 occasions): 18 points 1
• Rigidity (specifically lead pipe rigidity): 17 points 1
• Mental status alteration (ranging from alert mutism to agitation to stupor to coma): 13 points 1
• Creatine kinase elevation (≥4 times upper limit of normal): 10 points 1
• Sympathetic nervous system lability (tachycardia, blood pressure fluctuations): 10 points 1
• Hypermetabolism: 5 points 1
• Negative workup for infectious, toxic, metabolic, or neurologic causes: 7 points 1

Temporal Progression to Recognize

Mental status changes and rigidity are the initial manifestations in 82.3% of cases, typically appearing before hyperthermia and autonomic dysfunction. 2 Early recognition of tachycardia, blood pressure fluctuations, and diaphoresis is critical as these autonomic symptoms often precede other manifestations. 1

Essential Laboratory Testing

Obtain the following labs immediately to assess severity and guide management: 3

• Complete blood count (expect leukocytosis 15,000-30,000 cells/mm³) 1, 4
• Creatine kinase (typically ≥4 times upper limit of normal, indicates rhabdomyolysis severity) 1, 4
• Comprehensive metabolic panel (electrolytes, renal function, liver function—expect dehydration-related abnormalities and elevated transaminases) 1, 3, 4
• Arterial blood gases (assess for metabolic acidosis) 3
• Coagulation studies (screen for disseminated intravascular coagulation) 3

Differential Diagnosis to Exclude

You must actively rule out the following conditions to assign the 7 points for negative workup: 1

• Serotonin syndrome: Distinguished by hyperreflexia, clonus, and myoclonus (not lead pipe rigidity), plus recent serotonergic drug exposure 1, 4
• Malignant hyperthermia: Triggered by anesthetic agents in the operating room setting, not antipsychotics 1, 4
• CNS infections: Obtain lumbar puncture if meningitis or encephalitis suspected 1
• Anticholinergic toxicity: Typically presents with dry skin (not diaphoresis), mydriasis, and urinary retention 1
• Acute catatonia: May have overlapping features but lacks the severe autonomic instability and hyperthermia 1
• Toxic metabolic encephalopathies: Usually lack the severe rigidity and hyperthermia characteristic of NMS 4

Risk Factor Assessment

Document the following risk factors in your evaluation: 1

• Recent antipsychotic initiation, dose increase, or withdrawal of dopaminergic agents 1
• Coadministration of multiple psychotropic agents 1
• Dehydration, physical exhaustion, or agitation 1
• Use of long-acting depot antipsychotics 1
• Preexisting organic brain disease 1
• Male gender (2:1 male predominance) 1

Critical Pitfalls to Avoid

NMS presentations can be variable and attenuated, making recognition challenging. 1 Do not wait for all classic features to be present—early intervention is what reduced mortality from 76% in the 1960s to <10-15% currently. 1, 3, 4 The diagnosis is entirely clinical; there are no pathognomonic laboratory findings. 1 Symptoms may develop within days after starting or increasing antipsychotic medication. 1

Immediate Actions During Workup

While obtaining diagnostic workup, simultaneously initiate: 3

• Discontinue all antipsychotic medications immediately 3
• Begin aggressive IV fluid resuscitation for dehydration and elevated CK/rhabdomyolysis 3, 4
• Implement external cooling measures for hyperthermia 3, 4
• Administer benzodiazepines for agitation 3, 4
• Avoid physical restraints as they exacerbate isometric muscle contractions, worsening hyperthermia and lactic acidosis 3

Approximately 25% of NMS patients require ICU admission, so arrange for higher level of care early if the patient scores ≥76 points or has extreme hyperthermia (>41.1°C). 3