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==Background==
==Background==
*Life threatening neurologic emergency associated with the use of neuroleptic agents
[[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
*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>
**May also occur with withdrawal of anti-Parkinson medication or use of antiemetics
*Can occur with single dose, dose increase, or stable chronic dosing
*Develops over 1-3 days
*Onset typically 1-3 days after exposure (but can occur weeks later)
*Majority of deaths occur from complications of muscle rigidity
*Causative agents:
**"Typical" high-potency antipsychotics: haloperidol (most common), chlorpromazine, fluphenazine
**"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>
**Antiemetics: metoclopramide, promethazine, droperidol
**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==
*Tetrad of:
*Develops over 1-3 days (distinguishes from serotonin syndrome which is more acute)
#Altered Mental Status
*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>:
##Agitated delirium progressing to stupor/coma
#Muscular Rigidity
##Generalized, "lead pipe" rigidity
#Hyperthermia
##>38C (87%)
##>40C (40%)
#Autonomic Instability
##Tachycardia
##Hypertension
##Diaphoresis


==DDX==
===1. Altered Mental Status===
#[[Serotonin Syndrome]]
*Agitated delirium progressing to stupor and coma
##More likely to have hyperreflexia, myoclonus, ataxis, N/V, diarrhea
*May be earliest feature
##Rigidity and hyperthermia, if present, is less severe than in NMS
#[[Malignant Hyperthermia]]
##Distinguish by clinical setting (use of inhalational anesthetics or sux)
##Hyperthermia, muscle rigidity, and dysautonomia is similar to NMS though more fulminant
#Anticholinergic Toxidrome
##Diaphoresis, rigidity, elevated CK are absent
##Flushing, mydriasis, bladder distension are common
#Sympathomimetics
##Rigidity is not seen
#Meningitis/encephalitis
#Delirium Tremens
#Heat Stroke


==Work-Up==
===2. Muscle Rigidity===
#Total CK
*Generalized "lead-pipe" rigidity (distinguishing feature from serotonin syndrome)
##Typically >1000
*May cause chest wall rigidity → respiratory failure
##Correlates with degree of rigidity
#CBC
##WBC >10K is typical
#Chemistry
##May show hypocalcemia, hypomagnesemia, hyperkalemia, metabolic acidosis
#UA
##Myoglobinuria (from rhabdo)
#LFT
##Transaminitis
#CT/LP
##CSF may have mildly elevated protein


==Treatment==
===3. Hyperthermia===
#Stop causative agent
*>38°C in 87% of cases; >40°C in 40%
##If precipitant is discontinuation of dopaminergic therapy, it should be restarted
*Can exceed 42°C
#Supportive Care
##Fluid resuscitation
##Cooling measures
###Consider paralysis with nondepolarizing agents
##Agitation control with benzos
##Blood pressure control with clonidine or nitroprusside
#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>
##Controversial; efficacy is unclear and disputed
###Dantrolene
####Skeletal muscle relaxant; may cause hepatotoxicity in pts w/ liver disease
####Consider only in pts with severe rigidity
####Give 0.25-2mg/kg IV q6-12hr
###Bromocriptine
####Dopamine agonist
####Give 2.5mg NG q6-8hr
###Amantadine
####Alternative to bromocriptine
####Give 100mg PO/NG initially; titrate up as needed to max dose 200mg q12hr
###ECT


==Complications==
===4. Autonomic Instability===
#Dehydration
*Tachycardia, labile blood pressure, diaphoresis
#Electrolyte imbalance
*Sialorrhea (drooling), urinary incontinence
#ARF (rhabdo)
#Dysrhythmias
#ACS
#Respiratory failure
##Chest wall rigidity, aspiration PNA, PE
#DIC
#Seizure (hyperthermia, electrolyte derangements)
#Hepatic failure
#Sepsis


==Source==
===Complications===
<references>
*[[Rhabdomyolysis]] → [[acute kidney injury]] (major cause of morbidity)
*Dysrhythmias, [[ACS]]
*Respiratory failure (chest wall rigidity, aspiration)
*[[DIC]], [[seizures]], hepatic failure, [[sepsis]]


[[Category:Psych]]
==Differential Diagnosis==
[[Category:Tox]]
{| class="wikitable"
|-
! 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'''
|}
 
{{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<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 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<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==
*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==
*[[Serotonin syndrome]]
*[[Malignant hyperthermia]]
*[[Rhabdomyolysis]]
*[[Anticholinergic toxicity]]
*[[Heat stroke]]
 
==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: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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