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==Background==
==Background==
*Life threatening neurologic emergency associated with the use of neuroleptic agents<ref>Su YP, Chang CK, Hayes RD, Harrison S, Lee W, Broadbent M, et al. Retrospective chart review on exposure to psychotropic medications associated with neuroleptic malignant syndrome. Acta Psychiatr Scand. Nov 15 2013</ref><ref>Trollor JN, Chen X, Sachdev PS. Neuroleptic malignant syndrome associated with atypical antipsychotic drugs. CNS Drugs. 2009;23(6):477-92</ref>
[[File:NMS clinical features.jpg|thumb|Patient exhibiting NMS symptoms: hyperthermia, significant extrapyramidal symptoms, various autonomic symptoms, and impaired consciousness.]]
**Can occur with single dose, increasing dose, or same dose as usual <ref>Dunkley, E. J. C., Isbister, G. K., Sibbritt, D., Dawson, A. H. and Whyte, I. M. (2003) ‘The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity’, QJM, 96(9), pp. 635–642. doi: 10.1093/qjmed/hcg109</ref>
*Life-threatening neurologic emergency associated with dopamine receptor blockade<ref>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</ref>
**Most often seen with "typical" high potency antipsychotics ([[haloperidol]])
*Can occur with single dose, dose increase, or stable chronic dosing
***also occurs with newer "atypicals" ([[risperidone]], [[olanzapine]])
*Onset typically 1-3 days after exposure (but can occur weeks later)
***antiemetics ([[metoclopramide]], [[promethazine]])
*Causative agents:
***withdrawal of anti-Parkinson medication
**"Typical" high-potency antipsychotics: haloperidol (most common), chlorpromazine, fluphenazine
*Develops over 1-3 days
**"Atypical" antipsychotics: risperidone, olanzapine, quetiapine, aripiprazole<ref>Trollor JN, et al. Neuroleptic malignant syndrome associated with atypical antipsychotic drugs. ''CNS Drugs''. 2009;23(6):477-92. PMID 19480467</ref>
*Majority of deaths occur from complications of muscle rigidity
**Antiemetics: metoclopramide, promethazine, droperidol
*Mortality rates up to 5 to 20% <ref>Shalev A. Mortality from neuroleptic malignant syndrome. J Clin Psychiatry. 1989;50(1):18-25.</ref>
**Withdrawal of dopaminergic agents (levodopa, bromocriptine) in Parkinson's disease
*Mortality: 5-20%<ref>Shalev A. Mortality from neuroleptic malignant syndrome. ''J Clin Psychiatry''. 1989;50(1):18-25. PMID 2562951</ref>
*Most deaths from '''complications of severe muscle rigidity''' (rhabdomyolysis → renal failure, respiratory failure)


==Clinical Features==
==Clinical Features==
[[File:PMC3703349 CRIM.DENTISTRY2013-542130.002.png|thumb|Patient exhibiting NMS symptoms: hyperthermia, significant extrapyramidal symptoms, various autonomic symptoms, and impaired consciousness.]]
*Develops over 1-3 days (distinguishes from serotonin syndrome which is more acute)
*Develops over 1-3 days
*Classic tetrad<ref>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</ref>:
*Tetrad of:<ref>Gurrera RJ, Velamoor V, Cernovsky ZZ. A Validation Study of the International Consensus Diagnostic Criteria for Neuroleptic Malignant Syndrome. J Clin Psychopharmacol. Aug 22 2013</ref>
 
**[[Altered mental status]] - [[agitated delirium]] progressing to stupor/[[coma]]
===1. Altered Mental Status===
**Muscle rigidity - generalized, "lead pipe" rigidity
*Agitated delirium progressing to stupor and coma
**[[Hyperthermia]] >38C (87%); >40C (40%)
*May be earliest feature
**Autonomic instability - [[tachycardia]], [[hypertension]], diaphoresis
 
===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===
===Complications===
*[[Dehydration]]
*[[Rhabdomyolysis]] → [[acute kidney injury]] (major cause of morbidity)
*[[Electrolyte imbalance]]
*Dysrhythmias, [[ACS]]
*[[Acute renal failure]] ([[rhabdomyolysis]])
*Respiratory failure (chest wall rigidity, aspiration)
*[[Dysrhythmias ]]
*[[DIC]], [[seizures]], hepatic failure, [[sepsis]]
*[[ACS]]
*[[Respiratory failure]]
**Chest wall rigidity, aspiration [[pneumonia]], [[PE]]
*[[DIC]]
*[[Seizure]] ([[hyperthermia]], [[electrolyte derangements]])
*[[Hepatic failure]]
*[[Sepsis]]


==Differential Diagnosis==
==Differential Diagnosis==
*[[Serotonin Syndrome]]
{| class="wikitable"
**Serotonin syndrome more likely to have hyperreflexia, myoclonus, ataxia, nausea and vomiting, diarrhea
|-
**Rigidity and hyperthermia, if present, is less severe than in NMS; more commonly presents with clonus and hyperreflexia
! Feature !! '''NMS''' !! '''[[Serotonin syndrome]]''' !! '''[[Malignant hyperthermia]]''' !! '''Anticholinergic toxicity'''
*[[Malignant Hyperthermia]]
|-
**Distinguish by clinical setting (use of inhalational anesthetics or sux)
| Onset || Days || Hours || Minutes (OR) || Hours
**Hyperthermia, muscle rigidity, and dysautonomia is similar to NMS though more fulminant
|-
*[[Anticholinergic Toxicity]]
| Rigidity || Lead-pipe || Clonus/hyperreflexia || Generalized || Absent
**Diaphoresis, rigidity, elevated CK are absent
|-
**Flushing, mydriasis, bladder distension are common
| Skin || Diaphoresis || Diaphoresis || Mottled/diaphoresis || Dry, flushed
*[[Sympathomimetics]]
|-
**Rigidity is not seen
| CK || >1000 || Mildly elevated || Markedly elevated || Normal
|-
| Pupils || Normal || '''Mydriasis''' || Normal || '''Mydriasis'''
|-
| Bowel sounds || Normal/decreased || '''Hyperactive''' || Normal || '''Absent'''
|}


{{Movement disorder DDX}}
{{Altered mental status and fever DDX}}
{{AMS and fever DDX}}


==Evaluation==
==Evaluation==
*Total CK
*CK: typically >1000 IU/L; correlates with degree of rigidity; may exceed 100,000
**Typically >1000
*CBC: leukocytosis (WBC >10K typical, may exceed 40K)
**Correlates with degree of rigidity
*BMP: hypocalcemia, hypomagnesemia, [[hyperkalemia]], metabolic acidosis
*CBC
*LFTs: transaminitis common
**[[leukocytosis|WBC >10K]] is typical
*Serum iron: low iron level supports NMS diagnosis (distinguishes from serotonin syndrome)
*Chemistry
*Urinalysis: myoglobinuria from [[rhabdomyolysis]]
**May show [[hypocalcemia]], [[hypomagnesemia]], [[hyperkalemia]], [[metabolic acidosis]]
*Coagulation studies: DIC screening
*[[Urinalysis]]
*Blood cultures: rule out [[sepsis]]
**Myoglobinuria (from rhabdo)
*CT head/LP: rule out CNS infection; CSF may show mildly elevated protein
*[[LFTs]]
**Transaminitis
*[[head CT|CT]]/[[LP]]
**CSF may have mildly elevated protein


{{Serotonin syndrome vs neuroleptic malignant syndrome}}
===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==
==Management==
*The causative agent should be stopped
===Immediate===
*Discontinue all dopamine blocking agents
*'''Stop all dopamine-blocking agents immediately'''
*If precipitant is a dopaminergic therapy (L-dopa or Carbidopa) it can be restarted later at lower doses as an outpatient
*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


===Supportive Care===
===Agitation and Rigidity===
*Agitation should be controlled with [[Benzodiazepines]]
*Benzodiazepines first-line:
**Lorazepam 2 mg IV q5 min until agitation and muscle rigidity resolves
**Lorazepam 2 mg IV q5min until agitation and muscle rigidity resolve
*[[Fluid resuscitation]]
*For severe cases with respiratory failure or chest wall rigidity:
*Cooling measures
**'''Intubation with NON-DEPOLARIZING paralytic''' (rocuronium, vecuronium)
*Intubation and paralysis for severe cases, chest wall rigidity or respiratory failure
**AVOID succinylcholine (risk of [[hyperkalemia]] from rhabdomyolysis)
**Use NON-DEPOLARIZING paralytic agent


===Directed Medical Therapy<ref>Addonizio G, Susman VL, Roth SD. Neuroleptic malignant syndrome: review and analysis of 115 cases. Biol Psychiatry. Aug 1987;22(8):1004-20 </ref>===
===Directed Medical Therapy===
''Controversial with unclear and disputed efficacy''
*Efficacy controversial — limited to case reports/series<ref>Addonizio G, et al. Neuroleptic malignant syndrome: review and analysis of 115 cases. ''Biol Psychiatry''. 1987;22(8):1004-20. PMID 3620091</ref>
*[[Dantrolene]] (skeletal muscle relaxant) - Consider only in patients with severe rigidity
*Dantrolene (skeletal muscle relaxant):
**May cause hepatotoxicity in patients with liver disease
**Consider for severe rigidity with hyperthermia >40°C
**0.25-2mg/kg IV q6-12hr, max dose 10mg/kg/day
**0.25-2 mg/kg IV q6-12h (max 10 mg/kg/day)
*[[Bromocriptine]] (dopamine agonist)
**Monitor LFTs (hepatotoxicity risk)
**2.5mg PO q6-8hr, max dose 40mg/day
*Bromocriptine (dopamine agonist):
*[[Amantadine]] (alternative to bromocriptine)
**2.5 mg PO/NGT q6-8h (max 40 mg/day)
**100mg PO initially; titrate up as needed to max dose 200mg q12hr
**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===
===Electroconvulsive Therapy===
*Limited case series suggest that ECT can be effective in NMS refractory to pharmacotherapy<ref>Morcos N et al., Electroconvulsive therapy for neuroleptic malignant syndrome: a case series. J ECT. 2019.</ref>
*Consider for refractory NMS unresponsive to pharmacotherapy<ref>Morcos N et al. Electroconvulsive therapy for neuroleptic malignant syndrome: a case series. ''J ECT''. 2019;35(4):225-230. PMID 31651674</ref>
 
===Monitoring===
*Serial CK, renal function, electrolytes
*Continuous cardiac monitoring
*Treat [[hyperkalemia]] aggressively if present


==Disposition==
==Disposition==
*Admit, usually to ICU
*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==
==See Also==
 
*[[Serotonin syndrome]]
*[[Malignant hyperthermia]]
*[[Rhabdomyolysis]]
*[[Anticholinergic toxicity]]
*[[Heat stroke]]


==References==
==References==
<references/>
<references/>
*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


[[Category:Psychiatry]]
[[Category:Psychiatry]]
[[Category:Toxicology]]
[[Category:Toxicology]]

Revisión actual - 09:30 22 mar 2026

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

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

  1. ↑ 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
  2. ↑ Trollor JN, et al. Neuroleptic malignant syndrome associated with atypical antipsychotic drugs. CNS Drugs. 2009;23(6):477-92. PMID 19480467
  3. ↑ Shalev A. Mortality from neuroleptic malignant syndrome. J Clin Psychiatry. 1989;50(1):18-25. PMID 2562951
  4. ↑ 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
  5. ↑ Addonizio G, et al. Neuroleptic malignant syndrome: review and analysis of 115 cases. Biol Psychiatry. 1987;22(8):1004-20. PMID 3620091
  6. ↑ 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
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