Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome is a rare, life-threatening idiosyncratic reaction to dopamine receptor antagonists, or to abrupt withdrawal of dopaminergic therapy. It combines hyperthermia, severe muscle rigidity, altered mental state and autonomic instability. Incidence is 0.01 to 3% of patients exposed to antipsychotics, and mortality, once 20 to 30%, is now 5 to 10%.

Causes: antipsychotics (high-potency first generation drugs such as haloperidol and fluphenazine most often, but any antipsychotic including atypical agents), and antiemetics (metoclopramide, prochlorperazine, promethazine, droperidol). Withdrawal of levodopa or dopamine agonists in Parkinson disease causes a similar parkinsonism-hyperpyrexia syndrome.

Risk factors: dehydration, agitation, rapid dose escalation, intramuscular depot injection, high potency drugs, a history of the syndrome, iron deficiency, catatonia, organic brain disease and hot weather.

Onset is usually within 2 weeks of starting or increasing the drug, evolving over 1 to 3 days. The syndrome lasts 7 to 10 days after oral drugs and up to 3 weeks after depots.

Complications: rhabdomyolysis, acute kidney injury, respiratory failure, aspiration pneumonia, disseminated intravascular coagulation, venous thromboembolism, cardiac arrest and seizures.

• Fever over 38 degrees Celsius (often over 40), diaphoresis
• Lead-pipe muscular rigidity, tremor, dystonia, bradykinesia, mutism
• Altered mental status from agitation and delirium to stupor and coma
• Autonomic instability: tachycardia, labile blood pressure, tachypnea, incontinence, pallor or flushing
• Hyporeflexia or normal reflexes (no clonus), and bradykinesia, which separate it from serotonin syndrome
• Red flags: temperature over 40 degrees Celsius, creatine kinase over 5000 units/L, respiratory compromise and oliguria

1. Clinical diagnosis: exposure to a dopamine antagonist within 72 hours, hyperthermia over 38 degrees Celsius, rigidity, altered mental status, raised creatine kinase (at least 4 times the upper limit), autonomic instability, tachypnea and negative work-up for other causes.
2. Laboratory tests: creatine kinase (often 1000 to over 100,000 units/L), myoglobin, urea, creatinine, electrolytes, calcium, liver tests, lactate, coagulation studies, blood count (leukocytosis 10 to 40 × 10^9/L) and serum iron (often low).
3. Exclusion tests: blood and urine cultures, chest radiograph, lumbar puncture, CT head, EEG, thyroid function and toxicology screen.
4. ECG and urine for myoglobin.

Differentials: serotonin syndrome, malignant hyperthermia, anticholinergic toxicity, lethal catatonia, heat stroke, central nervous system infection, thyroid storm, sympathomimetic poisoning, status epilepticus.

1. Stop the offending drug and give intensive supportive care in a high-dependency or intensive care unit, with cooling (evaporative or ice packs for temperature above 40 degrees Celsius).
2. Fluids: IV 0.9% saline 1 to 2 L bolus, then 200 to 300 mL/h to keep urine above 1 mL/kg/h. Correct electrolytes.
3. Benzodiazepines: lorazepam 1 to 2 mg IV every 4 to 6 hours (or diazepam 5 to 10 mg IV).
4. Moderate to severe disease (add one or both):
   • Dantrolene 1 to 2.5 mg/kg IV bolus, then 1 mg/kg every 6 hours (maximum 10 mg/kg a day), reduced as symptoms improve. Monitor liver tests, and avoid with calcium channel blockers.
   • Bromocriptine 2.5 mg orally or by nasogastric tube every 8 hours, titrated to 40 mg daily. It may worsen psychosis, and withdrawal can cause relapse.
   • Amantadine 100 mg orally every 8 hours is an alternative.
5. Refractory cases: electroconvulsive therapy (6 to 10 treatments), also used for the underlying catatonia.
6. Complications:
   • Respiratory failure: intubation with a non-depolarizing paralytic (avoid succinylcholine).
   • Acute kidney injury: hydration, and renal replacement therapy for hyperkalemia, acidosis or oliguria.
   • Thromboprophylaxis: enoxaparin 40 mg SC once daily.
7. Parkinsonism-hyperpyrexia syndrome: restart levodopa or the dopamine agonist at the previous dose, by nasogastric tube if needed.
8. Rechallenge with antipsychotics: wait at least 2 weeks after resolution (longer after depots), use a low-potency or atypical drug at a low dose with slow titration, and monitor temperature, rigidity and creatine kinase.

Follow-up: psychiatry review, documentation of the reaction as an allergy-type alert, and monitoring of renal function and creatine kinase until normal.