Key Facts

NMS is a rare but potentially fatal adverse reaction to dopamine-blocking drugs. It is an idiosyncratic (not dose-dependent) reaction but is more common with high-potency agents and rapid dose escalation.

Epidemiology

Incidence approximately 0.01-0.02% of patients treated with antipsychotics. More common with first-generation (typical) antipsychotics but can occur with any dopamine-blocking agent. M:F ~2:1. Can occur at any point during treatment but most common in first 2 weeks.

Aetiology

• Any dopamine-blocking drug: Antipsychotics (haloperidol highest risk), metoclopramide, prochlorperazine
• Dopamine agonist withdrawal: Abrupt cessation of levodopa or dopamine agonists in Parkinson's disease
• Risk factors: High-potency typical antipsychotics, rapid dose escalation, IM route, dehydration, agitation, physical exhaustion, iron deficiency

Pathophysiology

• Central D2 receptor blockade in hypothalamus → impaired thermoregulation → hyperthermia
• D2 blockade in basal ganglia → rigidity
• D2 blockade in autonomic centres → autonomic instability
• Peripheral skeletal muscle effects → sustained contraction → rhabdomyolysis → raised CK, myoglobinuria → AKI
• Exact mechanism of susceptibility remains unclear — may involve genetic variation in D2 receptors

Cardinal Features

1. Hyperthermia: Temperature often >38°C, can exceed 40°C
2. Lead-pipe rigidity: Generalised, severe (differs from cogwheel of parkinsonism)
3. Autonomic instability: Tachycardia, labile BP, diaphoresis, tachypnoea, urinary incontinence
4. Altered consciousness: Confusion, agitation, progressing to stupor or coma

Laboratory Findings

• CK: Markedly elevated (often 1,000-100,000+ IU/L)
• WCC: Leucocytosis (15,000-30,000)
• LFTs: Raised transaminases
• U&Es: AKI (from rhabdomyolysis)
• Myoglobinuria: Dark urine
• Metabolic acidosis: From tissue damage

Red Flags

• Rapidly rising temperature on antipsychotic — assume NMS until proven otherwise
• Renal failure developing — aggressive fluid resuscitation needed
• DIC — rare but can occur in severe cases

Bedside

• Temperature: Core temperature monitoring
• Observations: Continuous HR, BP, RR, SpO2, NEWS2
• ECG: Arrhythmia screening

Bloods

• CK: Markedly elevated — serial monitoring
• FBC: Leucocytosis
• U&Es: AKI assessment (creatinine, K⁺)
• LFTs: Hepatic injury
• Coagulation: DIC screen
• ABG/VBG: Metabolic acidosis, lactate
• Myoglobin: In urine — risk of renal tubular obstruction

Imaging

• CXR: If aspiration suspected
• CT head: If altered consciousness to exclude intracranial pathology

Immediate (Medical Emergency)

1. STOP the causative antipsychotic immediately
2. Supportive care: HDU/ICU admission
3. Cooling: Active cooling — ice packs, cooling blankets, evaporative cooling
4. IV fluids: Aggressive hydration to prevent renal failure from rhabdomyolysis (target UO >1 mL/kg/hr)
5. VTE prophylaxis: High risk due to immobility and dehydration

Pharmacological

• Dantrolene: 1-2.5mg/kg IV bolus, then 1mg/kg IV QDS; muscle relaxant — reduces rigidity and heat production
• Bromocriptine: 2.5-10mg TDS PO/NG; dopamine agonist — restores dopaminergic tone
• Lorazepam: 1-2mg IV for agitation and catatonic features
• Sodium bicarbonate: If metabolic acidosis or to alkalinise urine (prevents myoglobin precipitation in kidneys)

Post-Recovery

• Wait at least 2 weeks before cautiously restarting an antipsychotic (if clinically necessary)
• Choose a different, lower-potency antipsychotic (e.g., quetiapine, aripiprazole)
• Start at the lowest dose and titrate slowly
• Close monitoring for NMS recurrence (~30% rechallenge risk)

Referral Criteria

• ICU/HDU admission for all confirmed NMS
• Nephrology if AKI develops
• Psychiatry for medication management post-recovery

• Mortality: ~5-10% with modern management; higher if delayed diagnosis
• Recovery: Most patients recover fully within 1-2 weeks after drug withdrawal
• Complications: AKI (~30%), respiratory failure (~20%), DIC (~10%), cardiac arrest
• Rechallenge: ~30% risk of recurrence if antipsychotic reinstituted — use different agent, low dose, slow titration
• Residual effects: Uncommon; some may have persistent cognitive or motor deficits in severe cases

NMS vs Serotonin Syndrome