Neuroleptic Malignant Syndrome – Causes, Symptoms, Diagnosis, Treatment and Ongoing care
- Life-threatening condition that may develop anytime during therapy with neuroleptics—from a few days to many years (but 2/3 of cases occur within the 1st week)
- Muscular rigidity from dopamine antagonism in the nigrostriatal pathway
- Hyperthermia due to blockage of hypothalamic thermoregulation (more likely in the setting of benzodiazepine withdrawal)
- Autonomic dysfunction
- May be indistinguishable from other causes of drug-induced hyperthermia (e.g., malignant hyperthermia, serotonin syndrome, anticholinergic toxins, or sympathomimetic poisoning)
- The incidence has been variably reported from prospective studies as 0.01–3.0% (1).
- 2,000 new cases annually in US (2)
- Predominant sex: Male > Female
- Predominant age: <40 years of age
0.15% ± 0.05% among patients receiving neuroleptics
- Intramuscular administration of medication (3)
- Newly administered medication (3)
- Rapid dose increase (3)
- Psychomotor agitation (3)
- Prior episodes of neuroleptic malignant syndrome (NMS)
- Age and gender correspond with the distribution of exposure to neuroleptic agents.
- Some studies show a genetic predisposition to NMS.
- Polymorphisms: Loss of del allele in 141C Ins/Del of the dopamine D2 receptor gene and Ser9Gly in the dopamine D3 receptor gene (4)
- Exact mechanism unknown
- Most likely due to dopamine blockade (2)
- Rare complication of treatment with neuroleptics: Phenothiazines (e.g., Fluphenazine), butyrophenones (e.g., Haloperidol), and thiothixene
- Also seen with atypical antipsychotics (e.g., clozapine, risperidone, olanzapine) (56)
- Occurs in approximately 1% of patients treated with neuroleptics (especially haloperidol)
- Also has been associated with withdrawal from dopamine agonists in Parkinson disease
- Neuroleptic use or an increase in dose
- Discontinuation of antiparkinsonian drugs
- Extrapyramidal symptoms: Dysphagia, short shuffling gait, resting tremor, and the significant skeletal muscle rigidity—lead-pipe rigidity (these symptoms are less likely with clonazapine-induced NMS) (5)
- Hyperthermia (temperature may be as high as 106–107°F [41°C])
- Altered level of consciousness
- Autonomic instability (e.g., diaphoresis, tachycardia, tachypnea, labile blood pressure)
Diagnostic Tests & Interpretation
White blood cell determination, creatine phosphokinase, lactate dehydrogenase, liver function tests, and urine myoglobin
- Chest x-ray (if aspiration pneumonia is suspected)
- Head computed tomography scan before lumber puncture
Lumbar puncture to rule out other causes of fever or altered mental status
- Meningitis, encephalitis, sepsis
- Malignant hyperthermia, severe dystonic reaction
- Lethal catatonia
- Serotonin syndrome
- Anticholinergic poisoning, salicylate poisoning
- Sympathomimetic poisoning
- Neuroleptic-induced tardive dyskinesia
- Heat stroke
- Strychnine poisoning
- Vascular central nervous system event
- Thyrotoxicosis, pheochromocytoma
- Acute intermittent porphyria
- Nonconvulsive status epilepticus
- Discontinue offending agent immediately (2).
- Provide supportive care (3):
- Maintain renal function.
- Regulate temperature.
- Dopamine agonists can be used, but their role in NMS is still uncertain:
- Bromocriptine: May play a role in longer-term management; 5–10 mg p.o. b.i.d.; maximum 40 mg/d
- Amantadine: 100 mg p.o. b.i.d.; increase as needed to a maximum of 400 mg/d
- Skeletal muscle relaxant: Dantrolene: May play a role in longer-term management; 100–200 mg/d p.o.; maximum 400 mg/d or 0.8–2.5 mg/kg q6h; maximum 10 mg/kg/d
- Benzodiazepines are the drugs of choice:
- Diazepam: 5 mg IV q5min
- Lorazepam: 1 mg IV q5min
- Electroconvulsive therapy may be used for refractory symptoms (2).
- Neither bromocriptine nor dantrolene has a rapid onset, and neither has been demonstrated to alter outcome.
- Volume repletion
- Correct electrolyte abnormalities.
- Relief of muscle rigidity
- Recognize complications (e.g., rhabdomyolysis, respiratory failure, acute renal failure); mortality can be as high as 50%.
Issues for Referral
- The patient’s psychiatric disease should be evaluated by a psychiatrist during withdrawal of neuroleptic medications.
- All patients should be transferred to an acute-care facility where intensive monitoring is available.
- Nephrologist should be consulted in the setting of renal failure.
- Airway intervention and circulatory support as needed; ventilation may be difficult because of chest wall rigidity
- IV, supplemental O2, cardiac monitor
- Immediate IV benzodiazepines (e.g., diazepam, lorazepam): May require repeated large doses
- If symptoms are not controlled within a few minutes, rapid-sequence intubation and neuromuscular blockade are necessary. Nondepolarizing neuromuscular blockers (e.g., vecuronium, rocuronium, pancuronium) are preferable to succinylcholine.
- Cool the patient, and treat seizures if they occur. Measures to control hyperthermia: Ice packs, mist and fan, cooling blankets, and so on
- Aggressive IV fluid therapy with lactated Ringer solution or normal saline (NS)
- Check fingerstick glucose.
- All patients with the diagnosis should be admitted.
- Patients often will require intensive care.
Hydration with intravenous NS (3)
- Allow 2 weeks after recovery to rechallenge neuroleptic:
- Rechallenge should not be with the medication implicated in the original NMS episode (3).
- Start at low dose, and titrate gradually.
- Carefully monitor for signs and symptoms of recurrent NMS (2).
- Discuss risk–benefit ratio of restarting therapy vs a recurrence of NMS (2).
- NMS information service: www.nmsis.org.
- Mortality rate is estimated at 5–11.6% (dropped from 25% in 1984) (7).
- Signs that may warn of a poor prognosis include temperature over 104°F and kidney failure.
- In absence of complications, the prognosis for recovery is good; most patients recover in 15 days (8).
- Prognosis is better when NMS is detected early.
- Renal failure
- Cardiac arrest
- Respiratory failure
- Hepatic failure
- Uncontrolled psychosis
- Persistent neuropsychiatric complications (3)
- Death (3)
1. Petersén A, Lundberg L. Neuroleptic malignant syndrome–rare diagnosis with high mortality. Lakartidningen. 2009;106(18–19):1273–6.
2. Strawn JR, Keck PE, Caroff SN. Neuroleptic malignant syndrome. Am J Psychiatry. 2007;164:870–6.
3. 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;50:8–15.
4. Mihara K, Kondo T, Suzuki A, et al. Relationship between functional dopamine D2 and D3 receptors gene polymorphisms and neuroleptic malignant syndrome. Am J Med Genet B Neuropsychiatr Genet.2003;117:57–60.
5. Trollor JN, Chen X, Sachdev PS. Neuroleptic malignant syndrome associated with atypical antipsychotic drugs. CNS Drugs. 2009;23:477–92.
6. Neuhut R, Lindenmayer JP, Silva R et al. Neuroleptic malignant syndrome in children and adolescents on atypical antipsychotic medication: a review. J Child Adolesc Psychopharmacol. 2009;19:415–22.
7. Shalev A, Hermesh H, Munitz H. Mortality from neuroleptic malignant syndrome. J Clin Psychiatry. 1989;50:18–25.
8. Caroff SN, Mann SC. Neuroleptic malignant syndrome. Med Clin North Am. 1993;77:185–202.
Halloran LL, Bernard DW. Management of drug-induced hyperthermia. Curr Opin Pediatr. 2004;16:211–5.
Silva RR, Munoz DM, Alpert M, et al. Neuroleptic malignant syndrome in children and adolescents. J Am Acad Child Adolesc Psychiatry. 1999;38:187–94.
See Also (Topic, Algorithm, Electronic Media Element)
Algorithms: Delirium; Coma
333.92 Neuroleptic malignant syndrome
15244003 neuroleptic malignant syndrome (disorder)
- 2/3 of cases occur within the 1st week of starting a neuroleptic, but NMS may occur after years.
- NMS may be triggered by discontinuation of Parkinson medications.
- Elevated serum creatinine kinase is the most consistent lab abnormality in patients with NMS (3).