Neuroleptic Malignant Syndrome

Many antipsychotics as well as some antiemetics can be causative (see table Medications That Can Cause Neuroleptic Malignant Syndrome). The factor common to all medication-related causes is a decrease in dopaminergic transmission; however, the reaction is not allergic but idiosyncratic. The etiology and mechanism are unknown despite investigation of several genetic polymorphisms affecting drug metabolism (1). Risk factors appear to include high medication doses, rapid dose increases, parenteral administration, and switching from one potentially causative medication to another.

Neuroleptic malignant syndrome can also occur in patients withdrawing from levodopa or dopamine agonists.Neuroleptic malignant syndrome can also occur in patients withdrawing from levodopa or dopamine agonists.

Symptoms of neuroleptic malignant syndrome begin most often during the first 2 weeks of treatment with neuroleptic medications but may occur earlier or after many years.

The 4 characteristic symptoms usually develop over a few days and often in the following order:

• 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).

• 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.

• Hyperthermia: Temperature is usually > 38° C and often > 40° C.

• Autonomic hyperactivity: Autonomic activity is increased, tending to cause tachycardia, arrhythmias, tachypnea, and labile hypertension.

Elevated creatine kinase or frank rhabdomyolysis can result from muscle rigidity.

• History and physical examination

• Exclusion of other disorders and complications

Neuroleptic malignant syndrome should be suspected based on clinical findings. Early manifestations can be missed because mental status changes may be overlooked or dismissed in patients with psychosis (1). The Diagnostic and Statistical Manual of Mental Disorders (DSM)-5-TR criteria require exposure to a dopamine antagonist or dopamine agonist withdrawal within the past 72 hours, hyperthermia, and diaphoresis. "Lead pipe" rigidity is also a prominent feature, and may be associated with other neurologic findings such as tremors, dystonia, myoclonus, dysarthria, dysphagia and altered mental status. Autonomic instability (eg, tachycardia, blood pressure elevation and/or fluctuation), tachypnea and respiratory distress may also been seen.). The Diagnostic and Statistical Manual of Mental Disorders (DSM)-5-TR criteria require exposure to a dopamine antagonist or dopamine agonist withdrawal within the past 72 hours, hyperthermia, and diaphoresis. "Lead pipe" rigidity is also a prominent feature, and may be associated with other neurologic findings such as tremors, dystonia, myoclonus, dysarthria, dysphagia and altered mental status. Autonomic instability (eg, tachycardia, blood pressure elevation and/or fluctuation), tachypnea and respiratory distress may also been seen.

Other disorders can cause similar findings. For example:

• Serotonin syndrome tends to cause rigidity, hyperthermia, and autonomic hyperactivity, but it is usually caused by selective serotonin reuptake inhibitors (SSRIs) or other serotonergic medications, and patients typically have hyperreflexia and sometimes myoclonus. Also, temperature elevations and muscle rigidity are usually less severe than in neuroleptic malignant syndrome, onset may be rapid (eg, < 24 hours), and nausea and diarrhea may precede serotonin syndrome.

• Malignant hyperthermia and withdrawal of intrathecal baclofen can cause findings similar to those of neuroleptic malignant syndrome, but they are usually easily differentiated by history. and withdrawal of intrathecal baclofen can cause findings similar to those of neuroleptic malignant syndrome, but they are usually easily differentiated by history.

• Nonconvulsive status epilepticus can cause altered mental status, rigidity, and hyperthermia. Electroencephalography should be obtained to exclude status epilepticus.

• Systemic infections, including sepsis, pneumonia, and central nervous system infection, can cause altered mental status, hyperthermia, and tachypnea and tachycardia, but generalized motor abnormalities are not expected. Also, in neuroleptic malignant syndrome, 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, blood urea nitrogen, creatinine, glucose, calcium, magnesium, and creatine kinase, urine myoglobin, and usually neuroimaging and cerebrospinal fluid analysis. There are no confirmatory tests, but patients should have testing for complications, including serum electrolytes, blood urea nitrogen, creatinine, glucose, calcium, magnesium, and creatine kinase, urine myoglobin, and usually neuroimaging and cerebrospinal fluid analysis.

• Discontinuation of the causative medication

• Rapid cooling

• Aggressive management of airway, secretions, fluid balance, blood pressure and autonomic hyperactivity, and electrolyte abnormalities

• Administration of dopamine agonists (bromocriptine or amantidine)Administration of dopamine agonists (bromocriptine or amantidine)

• Use of medications for muscle rigidity (dantrolene, lorazepam)Use of medications for muscle rigidity (dantrolene, lorazepam)

In patients with neuroleptic malignant syndrome, the causative medication is stopped and complications are treated supportively, usually in an intensive care unit (ICU) (1). Correction of electrolyte abnormalities and volume status may require dialysis. Severe hyperthermia is treated aggressively, mainly with physical cooling (see Heatstroke: Treatment). Some patients may require tracheal intubation (see Airway Establishment and Control/Tracheal Intubation) and induced coma. Benzodiazepines or dexmedetomidine can be used to control agitation. An alpha-2 agonist (eg clonidine) or calcium channel blocker (eg clevidipine) can be used to manage hypertension. Adjunctive medication therapy can be used, although efficacy has not been shown in clinical trials. Benzodiazepines can also be used to reduce mild cases of muscle rigidity. Dantrolene can be given for worsening or persistent muscle rigidity as well as hyperthermia. Bromocriptine or amantadine can be given orally or via nasogastric tube to help restore some dopaminergic activity. This condition may not respond to even rapid and aggressive therapy, and mortality in treated cases is approximately 5% at 30 days and 15% at 1 year () and induced coma. Benzodiazepines or dexmedetomidine can be used to control agitation. An alpha-2 agonist (eg clonidine) or calcium channel blocker (eg clevidipine) can be used to manage hypertension. Adjunctive medication therapy can be used, although efficacy has not been shown in clinical trials. Benzodiazepines can also be used to reduce mild cases of muscle rigidity. Dantrolene can be given for worsening or persistent muscle rigidity as well as hyperthermia. Bromocriptine or amantadine can be given orally or via nasogastric tube to help restore some dopaminergic activity. This condition may not respond to even rapid and aggressive therapy, and mortality in treated cases is approximately 5% at 30 days and 15% at 1 year (2).