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.