Topic Editor: Grant E. Fraser, M.D., FRACGP, FACRRM, ASTEM
Review Date: 10/1/2012
Definition 
Neuroleptic malignant syndrome (NMS) is a potentially life-threatening condition characterized by changes in mental status, hyperthermia, muscular rigidity, extrapyramidal signs, and autonomic dysregulation. It usually is the result of an adverse reaction to antipsychotic/neuroleptic drugs.
Description
- NMS is an uncommon but life-threatening neurologic emergency associated with antipsychotic treatment
- NMS is manifested by 4 significant symptoms: muscle rigidity, altered mental status, autonomic dysfunction, and fever
- Onset of symptoms may be seen within days to years from initiation of antipsychotics, but a majority of cases occurring within the first week of antipsychotic therapy
- Dopamine receptor blockade or decreased availability of dopamine itself is most likely to be responsible for the condition
Epidemiology
Incidence/prevalence
- The incidence of NMS is approximately 0.01% to 0.02% annually in the psychiatric population. Nearly 200 cases occur yearly in the U.S.
Gender
- Occurs more frequently in males than females (2:1), as males are more likely to receive neuroleptics
Age
- Patients aged 40 years have a higher incidence of NMS
Race
- There is no racial predilection
Risk factors
- Abrupt discontinuation of dopaminergic agents
- Administration of drugs by IM route
- Advancing age
- Akasthasia
- Catatonia
- Dehydration
- Exposure to dopamine antagonists
- Iron deficiency
- Male gender
- Newly administered neuroleptic
- Previous episode of NMS
- Psychomotor agitation
- Rapid increase in dose
- Structural abnormality of brain
Etiology
- NMS most commonly occurs as an adverse reaction to treatment with neuroleptics such as phenothiazines, butyrophenones and thiothixene. Approximately 1% of all patients treated with neuroleptics develop NMS
- NMS has also been reported with atypical (second-generation) antipsychotics (e.g., amisulpride, aripiprazole, olanzapine, paliperidone, quetiapine, risperidone and ziprasidone)
- NMS has also occurred with abrupt withdrawal of drugs which affect the central dopaminergic system, such as those used to treat Parkinson disease (e.g., dopamine agonists, levodopa)
- Some other drugs capable of causing NMS include metoclopramide, antidepressants, and lithium
- The exact pathophysiology of NMS is unknown, but an imbalance of neurotransmitters is suspected
- The most likely cause is dopamine receptor blockade. Other causes such as sudden withdrawal of dopaminergic agents or agonists, decreased availability of dopamine, and sympathoadrenal dysfunction have been identified
[Outline]
History
- Abrupt discontinuation of antiparkinsonian medications
- History of neuroleptic use
- Presence of risk factors
- Recent initiation of neuroleptics
- Recent neuroleptic dose increase
Physical findings on examination
- Agitation
- Altered level of consciousness
- Catatonia
- Delirium
- Diaphoresis
- Dysphagia
- Extrapyramidal symptoms
- Hypersalivation (sialorrhea)
- Hypertension or hypotension
- Hyperthermia
- Incontinence
- Muscle rigidity (lead pipe)
- Obtunded state
- Skin pallor
- Tachycardia
- Tachypnea
- Tremor
The diagnostic criteria for NMS as listed in the DSM-IV-TR:
A. Severe muscle rigidity and elevated temperature associated with the use of antipsychotics
B. Two or more of the following symptoms
- Changes in level of consciousness, ranging from confusion to coma
- Diaphoresis
- Dysphagia
- Elevated or labile blood pressure
- Incontinence
- Laboratory evidence of muscle injury (elevated CK)
- Leukocytosis
- Mutism
- Tachycardia
- Tremor
C. The above symptoms (A and B) are not caused by any other substance, medical condition, or mental disorder
[Outline]
NMS is often difficult to distinguish from other disorders that mimic the symptoms of NMS. Laboratory abnormalities with NMS are non-specific. Recently, a few rating scales for assessment of NMS have been introduced based on factors like severity of hyperthermia, muscle rigidity, mental status alteration, and elevation of serum CK, but are not widely used in clinical practice.
Blood test findings
Other laboratory test findings
- Urinalysis: Presence of occult blood with no RBCs on microscopic, suggests myoglobinuria and rhabdomyolysis
- Cerebrospinal fluid (CSF): Elevated levels of CSF protein may be present in patients with NMS
Radiographic findings
- Chest x-ray
- Chest x-ray may be indicated if aspiration pneumonia is a concern
- Computed tomography (CT)
- Head CT may be indicated to rule out a structural lesion or before a lumbar puncture if decreased GCS or a focal neurological deficit is present
[Outline]
General treatment items
- If NMS is suspected, all antipsychotics and dopamine antagonists must be discontinued
- Pharmacological treatment
- Bromocriptine and/or amantadine can be useful in treatment of NMS caused by withdrawal of anti-Parkinson medications
- Skeletal muscle relaxants such as dantrolene are more commonly the mainstay of treatment
- Benzodiazepines (e.g., diazepam or lorazepam) may be preferred in patients who do not respond well to other drugs. These agents reduce NMS-associated agitation
- Patients who have altered mental status should:
- Receive thiamine (if no other obvious cause present)
- If hypoglycemic receive dextrose
- If pinpoint pupils or other suspicion of narcotic intoxication, receive naloxone
- Non-pharmacological treatment
- Electroconvulsive therapy has been used for patients refractory to pharmacological treatment; however risks such as cardiac arrest and ventricular fibrillation have occurred
- Supportive measures
- Circulatory and ventilatory support should be provided if required
- Cooling blankets, ice packs, mist fans and antipyretics may be useful in controlling hyperthermia
- If Rhabdomyolysis is present, vigorous hydration with intravenous (IV) fluids (lactated ringers solution or normal saline) is necessary to prevent acute renal failure
- Nasogastric administration of fluids, medications, and nutrition may be required in dysphagic patients
Medications indicated with specific doses
Dantrolene is effective in 80% of cases and can be combined with benzodiazepines and dopamine agonists
Dopamine agonists
Antiviral agents-Anti-influenzaMuscle relaxantsBenzodiazepines-Long half-life (25-100 hr)Benzodiazepines-Medium half-life (10-15 hr)Disposition
Admission criteria
- Patients with NMS need to be admitted; generally to the intensive care unit
[Outline]
Prevention
- High doses of antipsychotic medications must be avoided. The dose of antipsychotics must be minimized, with agitation being treated early
- Dopaminergic drugs should not be discontinued abruptly
- Dehydration must be prevented as it may predispose patients to NMS
Prognosis
- If no complications occur, the prognosis is excellent with complete recovery expected within 2 weeks
- Early detection and aggressive treatment of NMS significantly improves prognosis
- Poor prognosis is expected with high fever and kidney failure
- Recurrence of NMS may occur in about 15% of cases on initiation of antipsychotic medications
Pregnancy/Pediatric effects on condition
- NMS occurs infrequently during pregnancy in women who take neuroleptics. Treatment is unchanged as compared to non-pregnant patients
Abbreviations
ICD-9-CM
- 333.92 Neuroleptic malignant syndrome
ICD-10-CM
- G21.0 Malignant neuroleptic syndrome
[Outline]
