What are the diagnostic criteria and treatment for neuroleptic malignant syndrome?

Diagnosis of Neuroleptic Malignant Syndrome

NMS is diagnosed clinically when a patient exposed to dopamine antagonists (or dopamine agonist withdrawal) presents with the characteristic tetrad of hyperthermia, rigidity, altered mental status, and autonomic instability, supported by elevated creatine kinase and exclusion of other causes. 1, 2

Diagnostic Criteria

The most recent international expert consensus uses a point-based system where ≥76 points indicates probable NMS 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: 17 points 1
• Mental status alteration: 13 points 1
• Creatine kinase elevation (≥4 times upper limit of normal): 10 points 1
• Sympathetic nervous system lability: 10 points 1
  • Defined as ≥2 of: BP elevated ≥25% baseline OR fluctuations (≥20 mmHg diastolic or ≥25 mmHg systolic within 24 hours), diaphoresis, or urinary incontinence 1
• Hypermetabolism: 5 points 1
  • Heart rate increase ≥25% above baseline AND respiratory rate ≥50% above baseline 1
• Negative workup for infectious, toxic, metabolic, or neurologic causes: 7 points 1

Clinical Presentation Pattern

Early recognition is critical—mortality has decreased from 76% in the 1960s to <10-15% with prompt management. 2, 3

Cardinal Features (in typical order of appearance):

1. Autonomic dysfunction appears first: tachycardia, blood pressure fluctuations, diaphoresis 2
2. Mental status changes: delirium ranging from alert mutism to agitation to stupor to coma 2
3. Muscular rigidity: lead pipe rigidity is most common, though akinesia, dyskinesia, or waxy flexibility may occur 2
4. Hyperthermia: fever progressing to dangerous hyperthermia 2
5. Additional symptoms: sialorrhea and dysphagia 2

Laboratory Findings:

• Leukocytosis (15,000-30,000 cells/mm³) 2
• Elevated creatine kinase (often markedly elevated) 2, 4
• Elevated liver enzymes 1, 2
• Electrolyte abnormalities consistent with dehydration 2
• Myoglobinuria (rhabdomyolysis) and potential acute renal failure 4

Critical Diagnostic Pitfalls

NMS can present with variable and attenuated symptoms, making recognition challenging. 2 The diagnosis is entirely clinical—there are no pathognomonic laboratory criteria. 2

Atypical presentations occur, particularly with newer antipsychotics: rigidity may be absent or minimal, as documented with olanzapine. 5 This supports a spectrum concept of NMS requiring more flexible diagnostic criteria than rigid DSM requirements. 5

Prodromal signs precede full syndrome: watch for worsening alterations in consciousness, which is the most important early warning sign. 6

Differential Diagnosis to Exclude

The workup must systematically rule out 1, 4:

• Serotonin syndrome (distinguished by hyperreflexia, clonus, and recent serotonergic drug exposure) 1
• Malignant hyperthermia (triggered by anesthetics, not antipsychotics) 1
• Anticholinergic toxicity 1
• CNS infections (meningitis, encephalitis) 1
• Heat stroke 4
• Central anticholinergic toxicity 4
• Acute catatonia 1

Risk Factors That Should Raise Suspicion

• Recent antipsychotic initiation or dose escalation (symptoms typically develop within days) 2
• Rapid loading rate of neuroleptics (more important than total dose or drug class) 6
• Male gender (2:1 male predominance) 2
• Coadministration of multiple psychotropic agents 2
• Dehydration, physical exhaustion 2
• Preexisting organic brain disease 2
• Long-acting depot antipsychotics 2
• Severe agitation or altered consciousness preceding syndrome onset 6

Treatment Approach

Immediate discontinuation of all antipsychotic medications is the first and most critical step, combined with aggressive supportive care. 3, 4

First-Line Management:

• Stop all neuroleptics immediately 3, 4
• Benzodiazepines for agitation (first-line agent) 1, 3
• External cooling measures for hyperthermia (cooling blankets) 1, 3
• IV fluids for dehydration and elevated creatine kinase/rhabdomyolysis 1, 3
• Avoid physical restraints (exacerbate isometric contractions, worsening hyperthermia and lactic acidosis) 3

Monitoring Requirements:

• Complete blood count, electrolytes, renal function, liver function, creatine kinase, arterial blood gases, coagulation studies 3
• Watch for complications: rhabdomyolysis, metabolic acidosis, renal failure, seizures, disseminated intravascular coagulation 3
• ICU admission required in approximately 25% of cases 3

Second-Line Pharmacologic Interventions (for severe cases):

• Bromocriptine (dopamine agonist to address dopamine deficiency) 3, 7, 8
• Dantrolene sodium (muscle relaxant to reduce rigidity and hyperthermia) 3, 7, 8
• Evidence for these agents is mixed—some studies show no difference in duration or complications compared to supportive care alone 6, while others report dramatic improvement 7

Advanced Interventions:

• Emergency sedation, neuromuscular paralysis, and intubation for extreme hyperthermia (>41.1°C) 3
• Hemodialysis if renal failure occurs (note: does not remove protein-bound antipsychotics) 1
• Electroconvulsive therapy as second-line treatment in refractory cases 9

Reintroduction of Antipsychotics Post-Recovery:

If antipsychotic treatment is required after NMS recovery, wait at least 2 weeks, use low-potency agents at minimal doses with gradual titration, and monitor closely for recurrence. 4, 6 Recurrences have been reported, so careful patient selection and monitoring are essential. 4