NEUROLEPTIC MALIGNANT SYNDROME

Neuroleptic Malignant Syndrome

Background

- incidence ~ 1% of patients on neuroleptics

- also occurs in Parkinson’s disease patients with sudden decrease in dosage of dopaminergic agents

- most commonly within 3-9 days of initiation of therapy but can occur at any time during treatment or with dose increase

- thought to be an idiosyncratic drug reaction., NOT thought to be related to dose or duration of treatment

- can occur with typical and atypical/newer antipsychotics, but greater risk with high potency dopamine antagonists, such as haloperidol

Pathophysiology

Two major theories:

1. Dopaminergic depletion or blockade in basal ganglia (tone) and hypothalamus (thermoregulation)

2. Primary skeletal muscle defect similar to malignant hyperthermia.

Clinical features

*** NO DEFINITE DIAGNOSTIC CRITERIA

MAJOR = fever (>38.5), rigidity (lead pipe), CK (>1000)

- the absence of these findings puts the diagnosis into question

MINOR = tachycardia, abnormal BP (high or labile), tachypnea, altered LOC, diaphoresis, leukocytosis (10-40 with left shift)

- classic triad = hyperthermia, encephalopathy (typically mute), skeletal muscle rigidity

- autonomic instability prominent feature, including postural drop, diaphoresis and tachycardia

- in addition to rigidity can have dystonia, akinesia, dysarthria, chorea

- can have +ve Babinski's

- typically develops over 24-72 h but may be insidious

- duration on average ~ 2 weeks

- risk continues 10-20d after d/c neuroleptic (longer with depot forms of neuroleptic agents)

- myoglobinuria (rhabdomyolysis), hyperkalemia, hyponatremia, hypernatremia, thrombocytopenia and DIC can occur

- at risk for DVT/PE

- other lab abnormalities may include: high LDH, low serum iron, proteinuria, transaminase elevation, thrombocytosis, hypocalcemia

Mortality

- 10-30%, increases with renal failure

DDx

- malignant hyperthermia

- serotonin syndrome

- severe extrapyramidal symptoms / Parkinson’s disease

- acute dystonic reaction

- infection / sepsis, especially CNS infection

- heat stroke

- toxicities: lithium, anticholinergic, MAOI in combination with TCAs or narcotics

- vasculitis

- drug allergy

- status epilepticus

- lethal catatonia

Investigations

- CBC, lytes, urea, crt, calcium, albumin, INR/PTT, LFTs, TSH/free T4, CK, urine myoglobin, blood/urine cultures

- CXR, ECG

- should do an LP (normal in NMS)

- consider non-contrast CT head (normal in NMS)

- EEG

Treatment

- ABCs

- withdrawal of neuroleptic meds

- aggressive hydration

- cooling / reduction of fever / antipyretics

- Rule out infection (CSF, blood, urine)!

- Rx electrolyte abnormalities

- Rx rhabdomyolysis appropriately

- feeding / NG tube if at risk of aspiration

- DVT prophylaxis

- drugs:

- bromocryptine (dopamine agonist) start at 2.5 mg TID-QID PO / NG, can increase to 40mg/d

***MONITOR FOR HYPOTENSION

+/- OR

- dantrolene (peripheral muscle relaxant) 2 mg/kg IV q5-10 min up to 10mg/kg/day to treat rigidity (blocks Ca²⁺ release from sarcoplasmic reticulum of muscle cells)

- other proposed Rx: amantadine, sinemet, pancuronium, tegretol, anaesthesia, plasmapheresis, ECT, benzos

- NOTE: no good treatment studies, benefit questionable

***AVOID DOPAMINE ANTAGONISTS e.g maxeran, domperidone

- a brief course of steroids (1g methylprednisolone IV daily x3 days) may speed resolution in Parkinson’s disease patient’s with NMS (J Neurol Neurosurg Psychiatry. 2003 May;74(5):574-6)

Reintroduction of antipsychotic agents

- must weigh benefit vs. risks

- wait a minimum of 2 weeks before restarting

- use lower potency agents or atypicals (e.g. clozapine, quetiapine, olanzapine, risperidone)

- monitor closely for NMS symptoms

References

ER Med Clinics of NA 18(2), 2000

Br. J. Anaesth. 85(1):129-135, 2000

Psych. Serv. 49(9):1163-1172, 1998

Last update: August 2003

Reviewed by: pending review

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