NEUROLEPTIC MALIGNANT SYNDROME DEFINITION A life-threatening idiosyncratic reaction characterized by muscle rigidity and hyperthermia, related to acute dopamine depletion, either from the use of neuroleptic drugs or of dopamine antagonists, or the withdrawal of dopamine agonists. TOXIC CAUSES Exposure to therapeutic doses of potent neuroleptic drugs (eg, haloperidol, fluphenazine) or the sudden cessation of dopamine agonists such as amantidine. Reported risk factors include dehydration and the concurrent use of lithium and tricyclic antidepressants. CLINICAL FEATURES Extreme hyperpyrexia, lead-pipe muscular rigidity, autonomic dysfunction (tachycardia, elevated or fluctuating blood pressure), sweating, tachypnoea, respiratory failure, altered mental status (confusion, delirium, stupor and coma), extrapyramidal signs (e.g. cogwheel hypertonia). Acute myoglobinuric renal failure may occur. The condition is fatal in up to 12 % of cases DIFFERENTIAL DIAGNOSIS Anticholinergic poisoning Catatonia CNS infections CNS mass lesions Ethanol or sedative-hypnotic drug withdrawal Extrapyramidal symptoms with fever Heat-stroke (environmental or exertional) Malignant hyperthermia Metal fume fever Psychiatric disorders Septicaemia Strychnine poisoning Thyroid storm Tetanus Tetany RELEVANT INVESTIGATIONS Laboratory tests are generally non-specific, but may be used to exclude alternative diagnoses. Arterial blood gases - metabolic acidosis is usually present. Creatinine phosphokinase activity - commonly elevated; marked elevations may indicate a serious risk of acute renal failure. CT scan of the head may be obtained to rule out CNS lesions. Electrolytes - hyperkalaemia, hyper- or hyponatraemia, hypocalcaemia. Liver function tests are not characteristic, but may be elevated. Lumbar puncture to rule out CNS infection. Renal function - urea, creatinine. Standard fever work-up to rule out infections. Urinalysis - urinary myoglobin or myoglobin casts may be present White blood cell count - leukocytosis may be present, (between 12,000 and 30,000 /mm3, with or without left shift). TREATMENT 1. Intravenous fluids should be given to rapidly expand intravascular volume which is depleted due to dehydration, fever, shivering, tremors and vasodilation. Crystalloid solutions are preferred. 2. Cooling measures should be instituted immediately to control hyperthermia. 3. Muscle relaxants should be administered when hypertonia is present. Dantrolene has been reported successful in several case reports, and is given at a dose of 1 mg/kg IV push, then repeated every 1 to 3 minutes until muscle relaxation is obtained (total dose not to exceed 10 mg/kg). In certain cases, muscle paralysis (with pancurorium) may be required. 4. The dopamine agonist, bromocriptine, may be given orally or by gastric tube, at a dose of 2.5 to 10 mg from 2 to 6 times per day (total dose of 5 to 30 mg/day). 5. Calcium channel blockers, such as nifedipine have been reported to reverse many NMS signs, such as hypertension, fever, tachycardia, urinary incontinence, rigidity and stupor. The mechanism is not yet clear. LONG-TERM COMPLICATIONS Brain damage (coma, brain lesions, irreversible brain damage). AUTHOR(S)/REVIEWERS Author: Dr Anthony Wong, Director, Jabaquara Poisons Center, Sao Paulo, Brazil. Peer review: Berlin 10/95, Cardiff 9/96: V. Afanasiev, M. Burger, T. Della Puppa, L. Fruchtengarten, K. Olsen, J. Szajewski.