Radu Saveanu, MD
David P. Kasick, MD
DESCRIPTION
Neuroleptic malignant syndrome (NMS) is a rare but potentially life-threatening reaction that occurs in patients who are treated with antipsychotic agents (neuroleptics). It appears that the cause of NMS is dopamine blockade, which would explain why this disorder has also been associated with drugs such as:
EPIDEMIOLOGY
Incidence
- Estimated incidence of NMS ranges from 0.01% to 0.02% of patients treated with neuroleptics. This may not be as prevalent as once thought.
- Reasons for this variability include:
- Diverse patient populations
- Different thresholds for diagnosing the disorder
- Variations in treatment practices
- Incidence of NMS is decreasing due to increased awareness, early detection and treatment, and efforts at prevention.
- Race
- African Americans may be at higher risk because they have a higher proportion of alleles that code for reduced CYP2D6 enzymatic activity (genetic polymorphisms exist in most of the CYPs).
- Age
- All ages are affected, although NMS most commonly occurs in adults aged 20–50.
- Sex
- NMS is more commonly seen in men, but this may be attributed to the fact that men are medicated more frequently and more aggressively with neuroleptics than women.
RISK FACTORS
- Dehydration
- History of prior episodes of NMS
- High doses of neuroleptics
- Intramuscular administration of neuroleptics
- Rapid rate of neuroleptic loading
- Catatonia
- Iron deficiency
- Use of other medications (especially lithium) in conjunction with neuroleptics
- Prolonged use of seclusion/restraints
- Electrolyte disturbances
- Presence of an organic dysfunction
- Presence of a mood disorder
Genetics
Genetic predisposition for developing NMS has been suggested by studies of dopamine D2 receptor gene polymorphisms.
GENERAL PREVENTION
Minimizing unnecessary use of neuroleptics reduces the risk of NMS.
PATHOPHYSIOLOGY
Dopamine D2 receptor antagonists are associated with this disorder, and it is assumed that NMS is caused by dopamine receptor blockade.
ETIOLOGY
- There is still a fair amount of controversy over the etiology of NMS.
- NMS has been conceptualized as a drug-induced form of malignant (potentially fatal) catatonia.
- Studies show that dopamine blockade could lead to hypothalamic dysfunction resulting in:
- Dopamine blockade in the striatum can cause:
- Tremor
- Rigidity
- Rhabdomyolysis (due to prolonged muscular hypertonicity)
HISTORY
Diagnostic Criteria for NMS
- Recent treatment with neuroleptics (within 7 days before onset)
- Hyperthermia (temperature above 38°C)
- Muscle rigidity
- Exclusion of systemic or neuropsychiatric illness
- And at least three of the following:
PHYSICAL EXAM
- Hyperthermia
- Generalized rigidity (lead pipe)
- Autonomic instability
- Mental status changes
- Profuse diaphoresis
DIAGNOSTIC TESTS AND INTERPRETATION
Lab
Initial Lab Tests (1)[C]
- CPK
- CBC
- Electrolytes, including calcium and magnesium
- Renal and hepatic function tests
- Urinalysis, including urine myoglobin
- Optional tests to be done if appropriate:
- Arterial blood gas
- Toxicology screen
- Coagulation studies
- Blood cultures
Imaging
Initial Approach
CT scan or MRI scan of the head (1)[C]
Diagnostic Procedures/Other
Lumbar puncture to rule out CNS infection (1)[C]
DIFFERENTIAL DIAGNOSIS
MEDICATION
First Line
- In most cases pharmacologic management is instituted if the course of the syndrome, following neuroleptic discontinuation, fails to improve with supportive measures alone (2)[C].
- Dopamine agonist agents have been shown in some studies to possibly decrease mortality and shorten the course of NMS (1)[C].
- Bromocriptine (Parlodel): A dopamine agonist
- Usually the starting dose is 2.5 mg PO t.i.d. The dose can be increased by 2.5–7.5 mg daily, up to a daily total of 45 mg in divided doses.
- Possible side effects include nausea, vomiting, possible exacerbation of psychotic symptoms.
- Caution should be used when administering to children younger than 15 years of age.
- Amantadine (Symmetrel)
- Usual adult dose is 200–300 mg PO daily in divided doses
- Sinemet
- Usual adult dose is 25/250 mg PO t.i.d. or q.i.d.
- Dantrolene (Dantrium)
- Dantrolene is a muscle relaxant and is specifically recommended for severe hyperthermia. It may be given IV or PO. Initial dose is 1–3 mg/kg IV followed by a total of up to 10 mg/kg/day IV in divided doses or 50–600 mg/day in divided oral doses. Dantrolene may be used in conjunction with bromocriptine if clinically indicated.
- Dantrolene may cause hepatitis, and liver function needs to be monitored.
- Precautions: Complications include:
- Benzodiazepines, administered orally or parenterally, have been shown in case reports and through clinical experience to improve symptoms and speed recovery, especially in milder cases (3)[C].
- Lorazepam (Ativan)
- First dose 1–2 mg IM or IV
- May be helpful in patients with primarily catatonic symptoms
- Can give 1–2 mg IM or IV every 4–6 hours if improvement is seen following initial dose
Second Line
ADDITIONAL TREATMENT
General Measures
- The most critical intervention is to discontinue all neuroleptic agents immediately.
- The discontinuation of other medications such as lithium or anticholinergic agents should be considered.
COMPLEMENTARY AND ALTERNATIVE THERAPIES
- Symptomatic treatment
- IV fluids to correct dehydration, hypotension, and electrolyte imbalance
- A cooling blanket and antipyretics to reduce the temperature
- If rhabdomyolysis occurs, it is important to hydrate patients and alkalinize the urine to prevent renal failure.
- Aspiration precautions
- Maintain good nutrition, as this may minimize rhabdomyolysis
- Adjunctive treatment
- Dialysis may be necessary if renal failure develops.
- Electroconvulsive therapy (ECT) has been found to be effective both in treating NMS and the underlying psychiatric condition (3)[C].
IN-PATIENT CONSIDERATIONS
Initial Stabilization
Most patients suspected of having NMS should be treated (at least initially) in the medical intensive care unit.
Admission Criteria
Patients may be transferred to a medical or psychiatric inpatient unit once their vital signs are stable, their hydration status and electrolyte imbalance corrected, CPK levels are falling, and there is no evidence of renal failure or cardiorespiratory compromise.
Discharge Criteria
Normalization of vital signs and physical exam
FOLLOW-UP RECOMMENDATIONS
Follow-up for the condition warranting the NMS-causing agent is urgent.
Patient Monitoring
Patients with NMS should be off neuroleptics for 2 weeks following resolution of the syndrome. Vital signs and CPK levels need to be monitored.
PATIENT EDUCATION
Every patient who has had NMS should be told that he or she is at risk for recurrence if challenged with any dopamine-blocking agent.
PROGNOSIS
- The clinical course of NMS usually lasts 2–14 days, although in the case of long-acting depot antipsychotic agents it may be prolonged up to 30 days.
- Mortality rate is 10–20% from complications listed above. In the absence of these complications the prognosis for full recovery is good.
- Patients who develop NMS are more likely to have a recurrence upon reintroduction of neuroleptic agents. To minimize the risk of a recurrence, several measures may be helpful:
- Try a neuroleptic from a different chemical class and with a lower D2 affinity, such as an atypical antipsychotic (risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole), although all atypical antipsychotics have been associated with the potential to cause NMS (4)[C].
- Clozapine is currently recommended for patients who need an antipsychotic and have a history of NMS (but the risk for agranulocytosis needs close monitoring with this agent). In addition, clozapine has also been associated with NMS (but less frequently).
- Consider alternative treatments with lithium, valproate, carbamazepine, or ECT.
- If an antipsychotic agent is necessary, use the lowest effective dose and increase the dose slowly.
- Obtain informed consent from the patient and family and discuss at length the risks, benefits, and side effects of treatment. In addition, closely monitor vital signs and CPK levels.
- Kishida I, Kawanishi C, Furuno T, et al. Association in Japanese patients between neuroleptic malignant syndrome and functional polymorphisms of the dopamine D2 receptor gene. Mol Psychiatry 2004;9(3):293–298.
SEE-ALSO
Neuroleptic midbrain syndrome
ICD9
333.92 Neuroleptic malignant syndrome