Neuroleptic malignant syndrome (NMS)Neuroleptic malignant syndrome is characterized by altered mental status, musclerigidity, hyperthermia, and autonomic hyperactivity that occur when certainneuroleptic drugs are used. Clinically, neuroleptic malignant syndrome resemblesmalignant hyperthermia. Diagnosis is clinical. Treatment is aggressive supportivecare.Among patients taking neuroleptic drugs, about 0.02 to 3% develop neurolepticmalignant syndrome. Patients of all ages can be affected.EtiologyMany antipsychotics and antiemetics can be causative. The factor common to all drugcauses is a decrease in dopaminergic transmission; however, the reaction is notallergic but rather idiosyncratic. Etiology and mechanism are unknown.Risk factors appear to include high drug doses, rapid dose increases, parenteraladministration, and switching from one potentially causative drug to another. NMScan also occur in patients withdrawing from levodopa or dopamine agonists.Drugs that can cause neuroleptic malignant syndromeClass DrugsAntipsychotics, traditional Chlorpromazine Fluphenazine Haloperidol Loxapine Mesoridazine Molindone Perphenazine Pimozide Thioridazine Thiothixene TrifluoperazineAntipsychotics, newer Aripiprazole Clozapine Olanzapine Paliperidone Quetiapine Risperidone ZiprasidoneAntiemetics Domperidone Droperidol Metoclopramide Prochlorperazine PromethazineSymptoms and SignsSymptoms begin most often during the first 2 wk of treatment but may occur earlieror after many years.
The 4 characteristic symptoms usually develop over a few days and often in thefollowing order: 1. Altered mental status: Usually the earliest manifestation is a change in mental status, often an agitated delirium, and may progress to lethargy or unresponsiveness (reflecting encephalopathy). 2. Motor abnormalities: Patients may have generalized, severe muscle rigidity (sometimes with simultaneous tremor, leading to cogwheel rigidity), or, less often, dystonias, chorea, or other abnormalities. Reflex responses tend to be decreased. 3. Hyperthermia: Temperature is usually > 38° C and often > 40° C. 4. Autonomic hyperactivity: Autonomic activity is increased, tending to cause tachycardia, arrhythmias, tachypnea, and labile hypertension.Diagnosis o Clinical evaluation o Exclusion of other disorders and complicationsThe diagnosis should be suspected based on clinical findings. Early manifestationscan be missed because mental status changes may be overlooked or dismissed inpatients with psychosis.Other disorders can cause similar findings. For example: 1. Serotonin syndrome o Tends to cause rigidity, hyperthermia, and autonomic hyperactivity, but it is usually caused by SSRIs, and patients typically have hyperreflexia. Also, temperature elevations and muscle rigidity are usually less severe than in NMS, and nausea and diarrhea may precede serotonin syndrome. 2. Malignant hyperthermia & withdrawal of intrathecal baclofen o Can cause findings similar to those of NMS, but they are usually easily differentiated by history. 3. Systemic infections, including sepsis, pneumonia, and CNS infection, o can cause altered mental status, hyperthermia, and tachypnea and tachycardia, but generalized motor abnormalities are not expected. Also, in NMS, unlike most infections, altered mental status and motor abnormalities tend to precede hyperthermia.There are no confirmatory tests, but patients should have testing for complications,including serum electrolytes, BUN, creatinine, glucose, Ca, Mg, and CK, urinemyoglobin, and usually neuroimaging and CSF analysis. EEG may be done to excludenonconvulsive status epilepticus.TreatmentRapid cooling, control of agitation, and other aggressive supportive measuresThe causative drug is stopped and complications are treated supportively, usually inan ICU. Severe hyperthermia is treated very aggressively, mainly with physicalcooling. Some patients may require tracheal intubation and induced coma.Benzodiazepines, given IV in high doses, can be used to control agitation. Adjunctivedrug therapy can be used, although efficacy has not been shown in clinical trials.
Dantrolene (0.25 to 2 mg/kg IV q 6 to 12 h; maximum of 10 mg/kg/24 h) can be givenfor hyperthermia. Bromocriptine (2.5 mg q 6 to 8 h) or, alternatively, amantadine (100to 200 mg q 12 h) can be given po or via NGT to help restore some dopaminergicactivity. This condition may not respond to even rapid and aggressive therapy, andmortality in treated cases is about 10 to 20%.