Neuroleptic Malignant Syndrome

A rare neuropsychiatric syndrome associated with administration of antipsychotic or other central dopamine (D2) receptor antagonists, and characterized by hyperthermia, muscular rigidity, autonomic dysfunction and altered consciousness.

Epidemiology

Neuroleptic malignant syndrome (NMS) occurs in 1/5,000 to 10,000 patients treated with antipsychotics or other central dopamine (D2) receptor antagonists (all age groups; male:female ratio 2:1 in some studies; higher incidence rates have been reported in the past). The incidence may be lower with newer less potent antipsychotics and with reduced severity of symptoms, particularly for clozapine.

Clinical description

In about 16% of patients, the syndrome occurs within 24 hours after the initiation of the antipsychotic treatment, 66% within the first week, and less commonly within or after 30 days on stable medication regimens. Manifestations include hyperthermia, muscular rigidity and tremor, mental status alteration and autonomic dysfunction. Other signs may include profuse diaphoresis, tachycardia, tachypnea, labile blood pressure, acidosis, incontinence, and elevated serum creatine kinase (CK) and transaminases from rhabdomyolysis with risk of subsequent renal failure. Once symptoms develop, they last on average 7-10 days after discontinuation of oral triggering drugs, with peak intensity within the first 72 hours. Risk factors include prior NMS episodes, physical exhaustion, agitation, dehydration, pre-existing catatonia, use of restraints, use of high doses, high potency drugs, acute parenteral forms of antipsychotics, and rapid antipsychotic dosage increase.

Etiology

The syndrome is thought to result from acute central dopamine receptor blockade. All antipsychotic agents, typical or atypical, may trigger the syndrome, although potent antipsychotics (haloperidol, fluphenazine) are more frequently associated. Dopamine blocking agents used in non-psychiatric settings (metoclopramide, prochlorperazine, droperidol) and dopamine depleting agents (tetrabenazine) have also been implicated.

Diagnostic methods

Diagnosis is based on clinical signs of the syndrome in the context of treatment with dopamine blocking agents, and the exclusion of alternative etiologies via thorough investigation with laboratory and imaging tests. Although elevated CK is a frequent correlate of muscle dysfunction in NMS, it is nonspecific. The likelihood of an NMS diagnosis can be assessed using the International Expert Consensus (IEC) criteria which are based on priority scores assigned to major clinical features (antipsychotic exposure, hyperthermia, rigidity, mental status changes, CK elevation, etc.). A total cut-off threshold score of ≥74 on the IEC criteria offers 69.6% sensitivity and 90.7% specificity in diagnosing NMS.

Differential diagnosis

The differential diagnosis is of prime importance. It includes malignant hyperthermia of anesthesia, serotonin syndrome, parkinsonism hyperpyrexia syndrome, heat stroke, idiopathic malignant catatonia, infections (sepsis, meningitis, encephalitis), autoimmune disorders (limbic encephalitis with NMDA receptor antibodies, lupus cerebritis) delirium tremens, status epilepticus, salicylate poisoning, endocrinopathies, stroke, and brain trauma.

Management and treatment

Immediate cessation of the antipsychotic medication and supportive measures (volume resuscitation, physical cooling) are essential in management. Specific treatments are unproven. Benefits in cases treated empirically based on phenomenology, severity and duration of symptoms with benzodiazepines, dopaminergic agents (bromocriptine, amantadine), dantrolene (in cases with extreme hyperthermia, rigidity and rhabdomyolysis) and electroconvulsive therapy have been reported. Careful monitoring for cardiorespiratory failure, renal failure, aspiration pneumonia and coagulopathies is required. Ventilatory assistance and dialysis may be required.

Prognosis

After discontinuation of oral psychotropic agents, resolution usually occurs within 1-2 weeks in most uncomplicated cases. However, the syndrome is still potentially lethal. Death may result from sudden cardiorespiratory arrest, aspiration pneumonia, pulmonary emboli, myoglobinuric renal failure, or disseminated intravascular coagulation. Mortality rate is estimated at 5-10% with adverse outcomes more likely with potent antipsychotics, older age and pre-existing cardiorespiratory disease. Most patients recover completely but amnestic syndromes, extrapyramidal and cerebellar disorders, peripheral neuropathy, myopathy and contractures have been reported in rare cases.