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:

• Amoxapine (an antidepressant)
• Antiemetics such as prochlorperazine (Compazine), promethazine (Phenergan), and metoclopramide (Reglan)

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:
  • Hyperthermia
  • Labile blood pressure
  • Tachycardia
• Dopamine blockade in the striatum can cause:
  • Tremor
  • Rigidity
  • Rhabdomyolysis (due to prolonged muscular hypertonicity)

[Outline]

• Information
• Description
• Epidemiology
  • Incidence
• Risk Factors
  • Genetics
• General Prevention
• Pathophysiology
• Etiology

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:
  • Change in mental status
  • Change in blood pressure
  • Creatinine phosphokinase (CPK) elevation or myoglobinuria
  • Leukocytosis
  • Metabolic acidosis
  • Tachycardia
  • Diaphoresis or sialorrhea
  • Tremors

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

• Catatonia
• Serotonin syndrome
• Heat exhaustion and heat stroke
• Malignant hyperthermia
• Delirium – secondary to anticholinergic toxicity
• Withdrawal of antiparkinsonian agents in a patient with Parkinson's disease
• Thyrotoxicosis
• CNS infections
• Drug toxicity: Amphetamines, phencyclidine, cocaine
• Intermittent acute porphyria
• Pheochromocytoma
• Tetany
• Parkinson's disease and other neurologic disorders

[Outline]

• History
• Physical Exam
• Diagnostic Tests and Interpretation
  • Lab
    • Initial Lab Tests (1)[c]
  • Imaging
    • Initial Approach
  • Diagnostic Procedures/Other
• 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:
  • Rhabdomyolysis
  • Renal failure
  • Aspiration pneumonia
  • Seizures
  • Respiratory or cardiac failure
  • Exacerbation of psychiatric illness following discontinuation of antipsychotic agent or treatment with dopamine agonists
• 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

• Subcutaneous heparin should be used to prevent pulmonary embolism or deep vein thrombosis.
• Iron deficiency anemia may aggravate NMS. Therefore, iron supplements should be prescribed for patients who are deficient.

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

[Outline]

• Medication
  • First Line
  • Second Line
• Additional Treatment
  • General Measures
• Complementary And Alternative Therapies
• In-Patient Considerations
  • Initial Stabilization
  • Admission Criteria
  • Discharge Criteria

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.

[Outline]

• Follow-Up Recommendations
  • Patient Monitoring
• Patient Education
• Prognosis

• 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

• NMS is a potentially life-threatening reaction to treatment with a dopamine-blocking agent.
• Fever and rigidity are key exam findings.
• Discontinuation of the offending agent, in the context of hospital-based supportive management, is a primary step in treatment.

1. Strawn JR, Keck PE Jr, Caroff SN. Neuroleptic malignant syndrome. Am J Psychiatry 2007;164(6):870–876.
2. Seitz DP, Gill SS. Neuroleptic malignant syndrome complicating antipsychotic treatment of delirium or agitation in medical and surgical patients: case reports and a review of the literature. Psychosomatics 2009;50(1):8–15.
3. Casamassima F, Lattanzi L, Perlis R, et al. Neuroleptic malignant syndrome: further lessons from a case report. Psychosomatics 2010;51(4):349–354.
4. Trollor J, Chen X, Sachdev P. Neuroleptic malignant syndrome associated with atypical antipsychotic drugs. CNS Drugs 2009;23(6):477–492.