Neuroleptic malignant syndrome

Neuroleptic malignant syndrome (NMS) is a clinical syndrome consisting of four primary features: rigidity, altered mental status, hyperthermia, and autonomic instability. It occurs in the setting of the use of dopamine-blocking agents or the withdrawal of dopamine-enhancing medications.

Neuroleptic malignant syndrome Epidemiology

Incidence of Neuroleptic malignant syndrome is estimated at 0.1% to 2%. There is a preponderance of young men with NMS, but this may be because of the increased frequency of schizophrenia and affective disorders in this group and the subsequent increased use of neuroleptics.

Other risk factors may include neuroleptic-induced catatonia, dehydration or malnutrition as a precipitating cause, and a history of elevated serum creatinine kinase (CK) during psychotic episodes not in association with Neuroleptic malignant syndrome.

Neuroleptic malignant syndrome Clinical Presentation

The motor symptoms consist most commonly of parkinsonian-type symptoms such as “lead-pipe” rigidity, but other symptoms include a tremor superimposed on the rigidity (“cogwheel rigidity”), akinesia, bradykinesia, and dystonia (e.g., blepharospasm, opisthotonus, oculogyric crises, trismus, and orobuccal dyskinesia). The altered mental status ranges from delirium to stupor or even coma.

A fever is seen in almost all cases (unlike malignant hyperthermia) and is usually greater than 38°C and often greater than 41°C. Arrhythmias, blood pressure fluctuations, and respiratory abnormalities constitute the main, potentially life-threatening autonomic features of Neuroleptic malignant syndrome.

Rare clinical manifestations include seizures, ataxia, and nystagmus. NMS usually evolves over 24 to 72 hours. Occasionally there can be a slower progression over days, but in the case of depot neuroleptics (e.g., intramuscular form of fluphenazine), progression over a couple of weeks has been reported.

The clinical course lasts 7 to 10 days, with a longer time if the inciting agent was depot neuroleptics, because of slower clearance. Laboratory abnormalities found in association with Neuroleptic malignant syndrome are leukocytosis in the range of 10 to 40,000 cells/αL and elevated serum creatinine kinase (CK) in the range of 200 to several thousand IU/L.

Cases of NMS with prominent medical complications and fatalities are widely described. Some of the causes for the morbidity and mortality of Neuroleptic malignant syndrome relate to its secondary complications. Because of the associated rhabdomyolysis, severe dehydration and prerenal acute renal failure can occur.

This is predictive of mortality, with aggressive hydration absolutely necessary (urine alkalinization is controversial). Because of rigidity and consequent immobility, as well as activation of the coagulation cascade to metabolic conditions created by the rhabdomyolysis, venous thromboembolism has been reported. Pulmonary embolism has been reported to cause almost one quarter of fatalities. In severe cases, aspiration pneumonia, respiratory failure, cardiac arrhythmias, and dysautonomia have been reported.

Some important clinical syndromes with a similar clinical picture form a differential for Neuroleptic malignant syndrome. Malignant hyperthermia appears in the setting of exposure to certain anesthetic agents such as halothane, isoflurane, sevoflurane, and desflurane, and depolarizing muscle relaxants like succinylcholine.

Acute lethal catatonia involves hyperthermia, akinesia, and rigidity, but this is usually preceded in the previous couple of weeks by behavioral changes. The serotonin syndrome occurs in the setting of an overexposure to selective serotonin reuptake inhibitors (SSRIs) or the combination use of SSRIs together with monoamine oxidase inhibitors, tricyclic antidepressants, or meperidine.

Precipitating Factors

Neuroleptic malignant syndrome is clearly medication related below. For the neuroleptic medication-related cases, the onset is not dose related and can occur many months after initiation of therapy. For patients who have been on dopamine agonists (most typically Parkinson patients), NMS typically occurs in the setting of a sudden withdrawal of the agonist agent or the change of dosage or change to a different agonist altogether.

Most of the Parkinson patients have had symptoms of their disease for more than 8 years. The perioperative period is a classic scenario for onset of Neuroleptic malignant syndrome because of the alterations in serum levels of the agonist related to changes when patients take their medications or to metabolic alterations. For patients who have been on dopamine-blocking agents, such as haloperidol, NMS can occur even after initial exposure.

Increased dosages of, changes in the particular agent, or parenteral administration of the neuroleptic are risk factors for the development of NMS in this group of patients. The etiology of NMS is consequently thought to be related to the acute blockade of the nigrostriatal and hypothalamic dopamine pathways in the brain.

COMT inhibitors: tolcapone, entacapone
Dopamine agonists: bromocriptine, pergolide, ropinirole, pramipexole, cabergoline, apomorphine
Neuroleptics: phenothiazines, butyrophenones, thiothixanes
Atypical antipsychotics: clozapine, olanzapine, risperidone, quetiapine
Antiemetics: metoclopramide, droperidol, prochlorperazine, promethazine
Others: reserpine, carbamazepine
Rare reported cases in: overdose of some tricyclic and SSRI antidepressants, overdose of citalopram, loxapine, diatrizoate, lithium
Rare reported cases in drug abuse: cocaine, amphetamines


Treatment involves first and foremost reversing the inciting cause and either discontinuing the neuroleptic/dopamine-mediating agent or reinstituting the dopaminergic therapy that may have been stopped. Supportive care is essential and possibly lifesaving, because of the secondary complications. Aggressive cooling, careful monitoring of cardiovascular functions, and high-volume intravenous fluid therapy necessitate intensive care hospitalization for all but the mild cases.

Pharmacologic therapy includes bromocriptine (a dopamine agonist) and/or dantrolene (a skeletal muscle relaxant) in addition to supportive care. These two medications are used independently or together. Pharmacologic therapy improves the prognosis of Neuroleptic malignant syndrome, decreasing time of resolution of symptoms from 16 days with supportive therapy alone to about 9 days.

Medication administration is started immediately and continued for 10 days after the resolution of symptoms. However, residual parkinsonian or catatonic symptoms can persist for weeks after the acute episode resolves.

Electroconvulsive therapy (ECT) has been reported to be beneficial in cases of Neuroleptic malignant syndrome refractory to other therapies. For such cases ECT has been reported to resolve symptoms after three to four treatments and is generally used for 6 days total.

Recurrence of Neuroleptic malignant syndrome has been reported. Some of the risk factors for recurrence when neuroleptics are restarted include higher potency of neuroleptics, restarting within 2weeks of an episode of NMS, higher initial dose, and use of concomitant lithium.

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