1. Neuroleptic malignant syndrome (NMS)
Neuroleptic malignant syndrome is characterized by altered mental status, muscle
rigidity, hyperthermia, and autonomic hyperactivity that occur when certain
neuroleptic drugs are used. Clinically, neuroleptic malignant syndrome resembles
malignant hyperthermia. Diagnosis is clinical. Treatment is aggressive supportive
care.
Among patients taking neuroleptic drugs, about 0.02 to 3% develop neuroleptic
malignant syndrome. Patients of all ages can be affected.
Etiology
Many antipsychotics and antiemetics can be causative. The factor common to all drug
causes is a decrease in dopaminergic transmission; however, the reaction is not
allergic but rather idiosyncratic. Etiology and mechanism are unknown.
Risk factors appear to include high drug doses, rapid dose increases, parenteral
administration, and switching from one potentially causative drug to another. NMS
can also occur in patients withdrawing from levodopa or dopamine agonists.
Drugs that can cause neuroleptic malignant syndrome
Class Drugs
Antipsychotics, traditional Chlorpromazine
Fluphenazine
Haloperidol
Loxapine
Mesoridazine
Molindone
Perphenazine
Pimozide
Thioridazine
Thiothixene
Trifluoperazine
Antipsychotics, newer Aripiprazole
Clozapine
Olanzapine
Paliperidone
Quetiapine
Risperidone
Ziprasidone
Antiemetics Domperidone
Droperidol
Metoclopramide
Prochlorperazine
Promethazine
Symptoms and Signs
Symptoms begin most often during the first 2 wk of treatment but may occur earlier
or after many years.

2. The 4 characteristic symptoms usually develop over a few days and often in the
following 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 complications
The diagnosis 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.
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, urine
myoglobin, and usually neuroimaging and CSF analysis. EEG may be done to exclude
nonconvulsive status epilepticus.
Treatment
Rapid cooling, control of agitation, and other aggressive supportive measures
The causative drug is stopped and complications are treated supportively, usually in
an ICU. Severe hyperthermia is treated very aggressively, mainly with physical
cooling. Some patients may require tracheal intubation and induced coma.
Benzodiazepines, given IV in high doses, can be used to control agitation. Adjunctive
drug therapy can be used, although efficacy has not been shown in clinical trials.

3. Dantrolene (0.25 to 2 mg/kg IV q 6 to 12 h; maximum of 10 mg/kg/24 h) can be given
for hyperthermia. Bromocriptine (2.5 mg q 6 to 8 h) or, alternatively, amantadine (100
to 200 mg q 12 h) can be given po or via NGT to help restore some dopaminergic
activity. This condition may not respond to even rapid and aggressive therapy, and
mortality in treated cases is about 10 to 20%.