Neuroleptic malignant syndrome
Background
File:NMS clinical features.jpg
Patient exhibiting NMS symptoms: hyperthermia, significant extrapyramidal symptoms, various autonomic symptoms, and impaired consciousness.
- Life-threatening neurologic emergency associated with dopamine receptor blockade[1]
- Can occur with single dose, dose increase, or stable chronic dosing
- Onset typically 1-3 days after exposure (but can occur weeks later)
- Causative agents:
- "Typical" high-potency antipsychotics: haloperidol (most common), chlorpromazine, fluphenazine
- "Atypical" antipsychotics: risperidone, olanzapine, quetiapine, aripiprazole[2]
- Antiemetics: metoclopramide, promethazine, droperidol
- Withdrawal of dopaminergic agents (levodopa, bromocriptine) in Parkinson's disease
- Mortality: 5-20%[3]
- Most deaths from complications of severe muscle rigidity (rhabdomyolysis → renal failure, respiratory failure)
Clinical Features
- Develops over 1-3 days (distinguishes from serotonin syndrome which is more acute)
- Classic tetrad[4]:
1. Altered Mental Status
- Agitated delirium progressing to stupor and coma
- May be earliest feature
2. Muscle Rigidity
- Generalized "lead-pipe" rigidity (distinguishing feature from serotonin syndrome)
- May cause chest wall rigidity → respiratory failure
3. Hyperthermia
- >38°C in 87% of cases; >40°C in 40%
- Can exceed 42°C
4. Autonomic Instability
- Tachycardia, labile blood pressure, diaphoresis
- Sialorrhea (drooling), urinary incontinence
Complications
- Rhabdomyolysis → acute kidney injury (major cause of morbidity)
- Dysrhythmias, ACS
- Respiratory failure (chest wall rigidity, aspiration)
- DIC, seizures, hepatic failure, sepsis
Differential Diagnosis
| Feature | NMS | Serotonin syndrome | Malignant hyperthermia | Anticholinergic toxicity |
|---|---|---|---|---|
| Onset | Days | Hours | Minutes (OR) | Hours |
| Rigidity | Lead-pipe | Clonus/hyperreflexia | Generalized | Absent |
| Skin | Diaphoresis | Diaphoresis | Mottled/diaphoresis | Dry, flushed |
| CK | >1000 | Mildly elevated | Markedly elevated | Normal |
| Pupils | Normal | Mydriasis | Normal | Mydriasis |
| Bowel sounds | Normal/decreased | Hyperactive | Normal | Absent |
Template:Altered mental status and fever DDX
Evaluation
- CK: typically >1000 IU/L; correlates with degree of rigidity; may exceed 100,000
- CBC: leukocytosis (WBC >10K typical, may exceed 40K)
- BMP: hypocalcemia, hypomagnesemia, hyperkalemia, metabolic acidosis
- LFTs: transaminitis common
- Serum iron: low iron level supports NMS diagnosis (distinguishes from serotonin syndrome)
- Urinalysis: myoglobinuria from rhabdomyolysis
- Coagulation studies: DIC screening
- Blood cultures: rule out sepsis
- CT head/LP: rule out CNS infection; CSF may show mildly elevated protein
NMS vs Serotonin Syndrome
- History of neuroleptic drug → NMS; serotonergic drug → serotonin syndrome
- NMS: lead-pipe rigidity, slow onset (days), elevated CK, low iron
- SS: clonus/hyperreflexia, rapid onset (hours), hyperactive bowel sounds, diarrhea
Management
Immediate
- Stop all dopamine-blocking agents immediately
- If precipitated by withdrawal of dopaminergic therapy (levodopa): restart at lower dose
- Aggressive IV fluid resuscitation (goal UOP >1-2 mL/kg/hr for rhabdomyolysis)
- Active cooling measures for hyperthermia >40°C
Agitation and Rigidity
- Benzodiazepines first-line:
- Lorazepam 2 mg IV q5min until agitation and muscle rigidity resolve
- For severe cases with respiratory failure or chest wall rigidity:
- Intubation with NON-DEPOLARIZING paralytic (rocuronium, vecuronium)
- AVOID succinylcholine (risk of hyperkalemia from rhabdomyolysis)
Directed Medical Therapy
- Efficacy controversial — limited to case reports/series[5]
- Dantrolene (skeletal muscle relaxant):
- Consider for severe rigidity with hyperthermia >40°C
- 0.25-2 mg/kg IV q6-12h (max 10 mg/kg/day)
- Monitor LFTs (hepatotoxicity risk)
- Bromocriptine (dopamine agonist):
- 2.5 mg PO/NGT q6-8h (max 40 mg/day)
- Continue for 10 days after NMS resolves to prevent relapse
- Amantadine (alternative to bromocriptine):
- 100 mg PO initially; titrate to 200 mg q12h
Electroconvulsive Therapy
- Consider for refractory NMS unresponsive to pharmacotherapy[6]
Monitoring
- Serial CK, renal function, electrolytes
- Continuous cardiac monitoring
- Treat hyperkalemia aggressively if present
Disposition
- Admit to ICU for all suspected cases
- Symptoms typically resolve over 7-10 days (longer with depot antipsychotics — up to 2-4 weeks)
- After recovery, cautious rechallenge with a different, low-potency antipsychotic may be attempted after 2 weeks
- Psychiatric consultation for medication management
See Also
References
- ↑ Su YP, et al. Retrospective chart review on exposure to psychotropic medications associated with neuroleptic malignant syndrome. Acta Psychiatr Scand. 2014;130(1):52-60. PMID 24256459
- ↑ Trollor JN, et al. Neuroleptic malignant syndrome associated with atypical antipsychotic drugs. CNS Drugs. 2009;23(6):477-92. PMID 19480467
- ↑ Shalev A. Mortality from neuroleptic malignant syndrome. J Clin Psychiatry. 1989;50(1):18-25. PMID 2562951
- ↑ Gurrera RJ, et al. A validation study of the international consensus diagnostic criteria for NMS. J Clin Psychopharmacol. 2013;33(6):747-54. PMID 24100788
- ↑ Addonizio G, et al. Neuroleptic malignant syndrome: review and analysis of 115 cases. Biol Psychiatry. 1987;22(8):1004-20. PMID 3620091
- ↑ Morcos N et al. Electroconvulsive therapy for neuroleptic malignant syndrome: a case series. J ECT. 2019;35(4):225-230. PMID 31651674
- Strawn JR, et al. Neuroleptic malignant syndrome. Am J Psychiatry. 2007;164(6):870-876. PMID 17541044
- Berman BD. Neuroleptic malignant syndrome: a review for neurohospitalists. Neurohospitalist. 2011;1(1):41-47. PMID 23983836