Neuroleptic malignant syndrome

Overview

A potentially fatal, idiosyncratic adverse reaction to dopamine D2-blocking agents - caused by abrupt/excessive D2 receptor blockade leading to the classic tetrad of features. Not dose-dependent and cannot be reliably predicted.

Causes

•First-generation antipsychotics (higher risk) - haloperidol, chlorpromazine

•Second-generation antipsychotics - clozapine, olanzapine, risperidone

•Antiemetics - metoclopramide, prochlorperazine

•Dopaminergic withdrawal - abrupt levodopa cessation in Parkinson's disease

•Depot formulations - symptoms may persist up to 21 days after discontinuation

Presentation

Develops over 24-72 hours after initiating or increasing a dopamine-blocking agent. Four cardinal features (tetrad):

•Hyperthermia - typically >38°C, often >40°C

•Lead-pipe rigidity - generalised, severe, uniform; does not 'give way' on passive movement

•Autonomic instability - labile BP, tachycardia, diaphoresis, tachypnoea, urinary incontinence

•Altered consciousness - confusion and agitation through to stupor and coma

•Elevated CK - often markedly elevated (>1000 U/L, frequently tens of thousands); reflects rhabdomyolysis

🚨

Rigidity + hyperthermia in a patient on an antipsychotic = NMS until proven otherwise. Do not wait for the full tetrad before acting.

Investigations

•CK - markedly elevated (often >1000 U/L); confirms rhabdomyolysis

•U&E and creatinine - assess for AKI secondary to myoglobinuria

•Urine dipstick and myoglobin - 'blood' on dipstick without red cells = myoglobinuria; cola-coloured urine is a clinical clue

•FBC - leucocytosis common in NMS

•ECG - arrhythmias and QT prolongation

•Blood cultures and septic screen - exclude infectious cause of hyperthermia

•ABG - respiratory failure and metabolic acidosis

•CT head / LP if diagnosis uncertain - exclude structural CNS cause and encephalitis

Management

⚠️

Do NOT use paracetamol or aspirin as the primary antipyretic - hyperthermia is driven by muscle rigidity and impaired thermoregulation, not prostaglandins. Physical cooling and rigidity reduction are the definitive measures.

Step 1 · Immediate

1. 1Stop the offending antipsychotic immediately
2. 2Admit to HDU/ICU
3. 3Aggressive IV fluid resuscitation - target urine output >1 mL/kg/h to prevent AKI from myoglobinuria
4. 4Physical cooling measures

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Step 2 · Pharmacological (moderate-to-severe)

1. 1Lorazepam (IV benzodiazepine) - for agitation and rigidity reduction
2. 2Dantrolene - muscle relaxant; reduces rigidity and hyperthermia
3. 3Bromocriptine (dopamine agonist) - may be used to restore dopaminergic tone

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Step 3 · Complications

1. 1Nephrology input early if AKI develops
2. 2Monitor for DIC, respiratory failure, arrhythmias

Key Differentials

NMS vs serotonin syndrome vs malignant hyperthermia

Feature	NMS	Serotonin syndrome	Malignant hyperthermia
Cause	Dopamine D2 blockers	Serotonergic drugs (excess)	Volatile anaesthetics / suxamethonium
Onset	Hours to days	Hours (rapid)	Minutes (intraoperative)
Rigidity	Lead-pipe rigidity	Hyperreflexia, clonus (not lead-pipe)	Severe rigidity
Diaphoresis	Present	Present	Present

Prognosis and Recurrence

•Untreated NMS carries approximately 20% mortality; early recognition improves prognosis

•Higher mortality with severe hyperthermia, respiratory failure, AKI, and older age

•Recurrence risk ~30% on antipsychotic re-challenge

•Re-challenge: wait at least 2 weeks after full resolution; use lowest effective dose of a low-potency atypical antipsychotic; requires specialist input

📌

Previous NMS is the strongest single predictor of recurrence. Document all episodes clearly and recommend medical alert identification (e.g. MedicAlert bracelet).