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==Background==
==Background==
Related to Dopamine Blockade in:
[[File:NMS clinical features.jpg|thumb|Patient exhibiting NMS symptoms: hyperthermia, significant extrapyramidal symptoms, various autonomic symptoms, and impaired consciousness.]]
#Anterior Hypothalamus --> Hyperthermia
*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>
#Frontal Lobe --> AMS
*Can occur with single dose, dose increase, or stable chronic dosing
#Nigrostriatal Pathways --> Rigidity
*Onset typically 1-3 days after exposure (but can occur weeks later)
#Sympathetic Nervous System --> Autonomic Instability
*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)


===Potential Pitfalls===
==Clinical Features==
#Overlooking the AMS in a “psych pt”
*Develops over 1-3 days (distinguishes from serotonin syndrome which is more acute)
#Delay in obtaining rectal temp
*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>:
#Use of physical restraints
#Isometric contractions leads increased metabolism, worsening rhabdo and hyperthermia
#Use of high potency antipsychotics in the ER


==Diagnosis==
===1. Altered Mental Status===
Classic Tetrad of Symptoms:
*Agitated delirium progressing to stupor and coma
# Altered Mental Status
*May be earliest feature
# Muscular Rigidity
# Fever
# Autonomic Instability


===Clinical History===
===2. Muscle Rigidity===
Drug Exposure:
*Generalized "lead-pipe" rigidity (distinguishing feature from serotonin syndrome)
#Typical high potency antipsychotics (haloperidol)
*May cause chest wall rigidity → respiratory failure
#Atypical neuroleptics (risperidone, olanzapine, clozapine)
#Antiemetics (metochlopromide, promethazine)
#Withdrawal of anti-Parkinson medication


===3. Hyperthermia===
*>38°C in 87% of cases; >40°C in 40%
*Can exceed 42°C


Timing:
===4. Autonomic Instability===
#Symptoms typically occur within 4-14d following initiation of med or an increase in dosing; can occur years after initiating therapy
*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]]


Laboratory Examination (non-specific):
==Differential Diagnosis==
#Total CK > 1000
{| class="wikitable"
#WBC > 10K
|-
#Mildly elevated LDH, LFTs
! Feature !! '''NMS''' !! '''[[Serotonin syndrome]]''' !! '''[[Malignant hyperthermia]]''' !! '''Anticholinergic toxicity'''
#Renal Insufficiency
|-
#CSF with mildly elevated Protein
| Onset || Days || Hours || Minutes (OR) || Hours
#Low Serum Iron
|-
| 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}}


===Diagnostic Criteria===
==Evaluation==
DSM-IV:
*CK: typically >1000 IU/L; correlates with degree of rigidity; may exceed 100,000
#Recent administration of antipsychotic
*CBC: leukocytosis (WBC >10K typical, may exceed 40K)
#Elevated Temp (> 40C)
*BMP: hypocalcemia, hypomagnesemia, [[hyperkalemia]], metabolic acidosis
#Muscle Rigidity
*LFTs: transaminitis common
#At least 2 other signs/symptoms or lab findings c/w NMS
*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


==DDx==
===NMS vs Serotonin Syndrome===
#Delirium tremens
*History of neuroleptic drug → NMS; serotonergic drug → serotonin syndrome
#Heat Stroke (altered CNS, temp >40)
*NMS: lead-pipe rigidity, slow onset (days), elevated CK, low iron
#Meningitis
*SS: clonus/hyperreflexia, rapid onset (hours), hyperactive bowel sounds, diarrhea
#Malignant Hyperthermia (genetic d/o; 1h post general anesthetic; hyperthermia up to 45deg C, rigidity, tachy, skin cyanosis with mottling)


==Treatment==
==Management==
#ABCs
===Immediate===
#Stop the Offending Agent
*'''Stop all dopamine-blocking agents immediately'''
#Aggressive Cooling Measures
*If precipitated by withdrawal of dopaminergic therapy (levodopa): restart at lower dose
#Fluid Resuscitation
*Aggressive IV fluid resuscitation (goal UOP >1-2 mL/kg/hr for rhabdomyolysis)
#Supportive Care
*Active cooling measures for hyperthermia >40°C
#Benzos: for agitation
#Dantrolene:
##direct skeletal muscle relaxant
##(Showed improvement in 80% cases)
##Dosage: 10mg/kg per day
##Relative Contraindication in pts on CCB (can lead to cardiovascular collapse)
#Bromocriptine:
##dopamine agonist to counteract central blockade
##Max: 40mg/day
#Amantadine:
##dopamine agonist and anticholinergic agent
##Max 400mg/day
#Consider ECT


Retrospective analysis: suggests pts on dantrolene +/- bromocriptine have a faster recovery (9days vs 12Days)
===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)


==Woodbury Stages==
===Directed Medical Therapy===
Incorporates severity of disease with treatment
*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


#(I-III: supportive care +/- benzos)
===Electroconvulsive Therapy===
#Stage IV (Moderate NMS): All four features present
*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>
##TX: benzos, bromocriptine
#Stage V (Severe NMS) Tetrad with more severe hyperthermia
##TX: benzos, dantrolene, bromocriptine, consider ECT


==Complications==
===Monitoring===
arrhthmias, renal failure, seizures, pneumonia, DIC, death
*Serial CK, renal function, electrolytes
*Continuous cardiac monitoring
*Treat [[hyperkalemia]] aggressively if present


===Prognosis===
==Disposition==
Most resolve within 2 weeks, without long term sequelae
*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


Poorer prognosis in those with high peak and/or long duration of hyperthermia
==See Also==
*[[Serotonin syndrome]]
*[[Malignant hyperthermia]]
*[[Rhabdomyolysis]]
*[[Anticholinergic toxicity]]
*[[Heat stroke]]


Mortality of 10-20%
==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


==Source==
[[Category:Psychiatry]]
Pani 6/2009 based on Rosen's
[[Category:Toxicology]]
 
[[Category:Airway/Resus]]
[[Category:Neuro]]

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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