What is Neuroleptic Malignant Syndrome (NMS)?

What is Neuroleptic Malignant Syndrome (NMS)?

Neuroleptic Malignant Syndrome (NMS) is a life-threatening idiosyncratic reaction to antipsychotic medications characterized by four cardinal features: hyperthermia, severe muscle rigidity (typically "lead pipe" rigidity), altered mental status, and autonomic instability. 1, 2

Pathophysiology

NMS results from dopamine D2 receptor blockade in critical brain regions 1:

• Hypothalamic blockade increases the temperature set point and impairs heat-dissipating mechanisms, causing hyperthermia that can reach 41°C or higher 1
• Nigrostriatal pathway blockade produces severe muscle rigidity through extrapyramidal pathways 1
• Increased calcium release from the sarcoplasmic reticulum causes sustained muscle contractility, generating both rigidity and excessive heat production 1
• Muscle breakdown (rhabdomyolysis) from sustained contraction releases creatine kinase into the bloodstream, often reaching levels of 1,000-10,000 U/L 1

Clinical Presentation

Temporal Progression of Symptoms

Mental status changes or rigidity typically appear first (82.3% of cases), followed by hyperthermia, then autonomic dysfunction 3. The complete tetrad includes 1, 4:

Mental Status Changes:

• Ranges from alert mutism to delirium to stupor to coma 1, 4
• Delirium is the most common presentation 4

Muscle Rigidity:

• "Lead pipe" rigidity is the hallmark neurologic finding 1, 4
• May also present as akinesia, dyskinesia, or waxy flexibility 4
• Contributes to both hyperthermia and CK elevation through muscle breakdown 1

Hyperthermia:

• Temperatures reach 41°C or higher 1
• Results from both increased set point and heat generation from muscle rigidity 1

Autonomic Instability:

• Tachycardia and blood pressure fluctuations (often the earliest signs) 4
• Profuse diaphoresis 4
• Sialorrhea and dysphagia 4

Laboratory Findings

Essential diagnostic markers 1:

• Creatine kinase elevation (≥4 times upper limit of normal, often 1,000-10,000 U/L) is the single most important laboratory marker and receives 10 points in diagnostic scoring 1
• Leukocytosis (15,000-30,000 cells/mm³) commonly accompanies NMS 1, 4
• Elevated liver enzymes (AST, ALT) due to muscle breakdown and systemic stress 1
• Electrolyte abnormalities consistent with dehydration 1, 4
• Metabolic acidosis on arterial blood gas indicates severe disease and poor prognosis 1

Diagnostic Criteria

The American Academy of Pediatrics recommends a point-based system where ≥76 points indicates probable NMS 4:

• Dopamine antagonist exposure or dopamine agonist withdrawal within 3 days: 20 points 4
• Hyperthermia (>100.4°F oral on ≥2 occasions): 18 points 4
• Rigidity: 17 points 4
• Mental status alteration: 13 points 4
• Creatine kinase elevation (≥4 times upper limit): 10 points 4
• Sympathetic nervous system lability: 10 points 4
• Negative workup for other causes: 7 points 4
• Hypermetabolism: 5 points 4

Risk Factors

Pharmacological risks 4:

• Any antipsychotic medication (typical or atypical) can trigger NMS 5, 2
• Abrupt withdrawal of dopaminergic agents 4
• Multiple psychotropic agents used simultaneously 4
• Long-acting depot antipsychotics 4

Patient-related risks 4:

• Male gender (2:1 male predominance) 4
• Dehydration 4
• Physical exhaustion 4
• Preexisting organic brain disease 4

Differential Diagnosis

Critical distinctions to make 1, 4:

• Serotonin syndrome: Features hyperreflexia, myoclonus, and clonus (not lead-pipe rigidity), with recent serotonergic drug exposure; typically has lower CK levels than NMS 1, 4
• Malignant hyperthermia: Triggered by anesthetic agents in the operating room, not antipsychotics 1, 4
• Anticholinergic toxicity: Lacks severe rigidity and extreme CK elevation 4
• CNS infections: Meningitis or encephalitis should be excluded 4
• Acute catatonia: May present similarly but lacks the extreme hyperthermia and CK elevation 4

Prognosis

With early recognition and prompt management, mortality has decreased dramatically from 76% in the 1960s to less than 10-15% in recent years. 6, 1, 4 This improvement underscores that NMS diagnosis is a clinical emergency requiring immediate intervention 1, 2.

Common Pitfalls

• Do not wait for all laboratory results before initiating treatment—immediately discontinue the offending agent and begin supportive care as soon as NMS is suspected 1
• Do not confuse with serotonin syndrome—NMS shows much higher CK levels (often >1,000 U/L), more pronounced leukocytosis, and lead-pipe rigidity rather than hyperreflexia 1
• Avoid physical restraints—they exacerbate isometric muscle contractions, worsening hyperthermia and lactic acidosis, thereby increasing mortality 6
• Avoid anticholinergics—they may worsen autonomic instability 6