Neuroleptic malignant syndrome: Difference between revisions
 
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==Background==
==Background==
Related to Dopamine Blockade in:
*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>
#Anterior Hypothalamus --> Hyperthermia
**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>
#Frontal Lobe --> AMS
**Most often seen with "typical" high potency antipsychotics ([[haloperidol]])
#Nigrostriatal Pathways --> Rigidity
***also occurs with newer "atypicals" ([[risperidone]], [[olanzapine]])
#Sympathetic Nervous System --> Autonomic Instability
***antiemetics ([[metoclopramide]], [[promethazine]])
***withdrawal of anti-Parkinson medication
*Develops over 1-3 days
*Majority of deaths occur from complications of muscle rigidity
*Mortality rates up to 5 to 20% <ref>Shalev A. Mortality from neuroleptic malignant syndrome. J Clin Psychiatry. 1989;50(1):18-25.</ref>


===Potential Pitfalls===
==Clinical Features==
#Overlooking the AMS in a “psych pt”
[[File:PMC3703349 CRIM.DENTISTRY2013-542130.002.png|thumb|Patient exhibiting NMS symptoms: hyperthermia, significant extrapyramidal symptoms, various autonomic symptoms, and impaired consciousness.]]
#Delay in obtaining rectal temp
*Develops over 1-3 days
#Use of physical restraints
*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>
#Isometric contractions leads increased metabolism, worsening rhabdo and hyperthermia
**[[Altered mental status]] - [[agitated delirium]] progressing to stupor/[[coma]]
#Use of high potency antipsychotics in the ER
**Muscle rigidity - generalized, "lead pipe" rigidity
**[[Hyperthermia]] >38C (87%); >40C (40%)
**Autonomic instability - [[tachycardia]], [[hypertension]], diaphoresis


==Diagnosis==
===Complications===
Classic Tetrad of Symptoms:
*[[Dehydration]]
# Altered Mental Status
*[[Electrolyte imbalance]]
# Muscular Rigidity
*[[Acute renal failure]] ([[rhabdomyolysis]])
# Fever
*[[Dysrhythmias ]]
# Autonomic Instability
*[[ACS]]
*[[Respiratory failure]]
**Chest wall rigidity, aspiration [[pneumonia]], [[PE]]
*[[DIC]]
*[[Seizure]] ([[hyperthermia]], [[electrolyte derangements]])
*[[Hepatic failure]]
*[[Sepsis]]


===Clinical History===
==Differential Diagnosis==
Drug Exposure:
*[[Serotonin Syndrome]]
#Typical high potency antipsychotics (haloperidol)
**Serotonin syndrome more likely to have hyperreflexia, myoclonus, ataxia, nausea and vomiting, diarrhea
#Atypical neuroleptics (risperidone, olanzapine, clozapine)
**Rigidity and hyperthermia, if present, is less severe than in NMS; more commonly presents with clonus and hyperreflexia
#Antiemetics (metochlopromide, promethazine)
*[[Malignant Hyperthermia]]
#Withdrawal of anti-Parkinson medication
**Distinguish by clinical setting (use of inhalational anesthetics or sux)
**Hyperthermia, muscle rigidity, and dysautonomia is similar to NMS though more fulminant
*[[Anticholinergic Toxicity]]
**Diaphoresis, rigidity, elevated CK are absent
**Flushing, mydriasis, bladder distension are common
*[[Sympathomimetics]]
**Rigidity is not seen


{{Movement disorder DDX}}
{{AMS and fever DDX}}


Timing:
==Evaluation==
#Symptoms typically occur within 4-14d following initiation of med or an increase in dosing; can occur years after initiating therapy
*Total CK
**Typically >1000
**Correlates with degree of rigidity
*CBC
**[[leukocytosis|WBC >10K]] is typical
*Chemistry
**May show [[hypocalcemia]], [[hypomagnesemia]], [[hyperkalemia]], [[metabolic acidosis]]
*[[Urinalysis]]
**Myoglobinuria (from rhabdo)
*[[LFTs]]
**Transaminitis
*[[head CT|CT]]/[[LP]]
**CSF may have mildly elevated protein


{{Serotonin syndrome vs neuroleptic malignant syndrome}}


Laboratory Examination (non-specific):
==Management==
#Total CK > 1000
*The causative agent should be stopped
#WBC > 10K
*Discontinue all dopamine blocking agents
#Mildly elevated LDH, LFTs
*If precipitant is a dopaminergic therapy (L-dopa or Carbidopa) it can be restarted later at lower doses as an outpatient
#Renal Insufficiency
#CSF with mildly elevated Protein
#Low Serum Iron


===Supportive Care===
*Agitation should be controlled with [[Benzodiazepines]]
**Lorazepam 2 mg IV q5 min until agitation and muscle rigidity resolves
*[[Fluid resuscitation]]
*Cooling measures
*Intubation and paralysis for severe cases, chest wall rigidity or respiratory failure
**Use NON-DEPOLARIZING paralytic agent


===Diagnostic Criteria===
===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>===
DSM-IV:
''Controversial with unclear and disputed efficacy''
#Recent administration of antipsychotic
*[[Dantrolene]] (skeletal muscle relaxant) - Consider only in patients with severe rigidity
#Elevated Temp (> 40C)
**May cause hepatotoxicity in patients with liver disease
#Muscle Rigidity
**0.25-2mg/kg IV q6-12hr, max dose 10mg/kg/day
#At least 2 other signs/symptoms or lab findings c/w NMS
*[[Bromocriptine]] (dopamine agonist)
**2.5mg PO q6-8hr, max dose 40mg/day
*[[Amantadine]] (alternative to bromocriptine)
**100mg PO initially; titrate up as needed to max dose 200mg q12hr


==DDx==
===Electroconvulsive Therapy===
#Delirium tremens
*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>
#Heat Stroke (altered CNS, temp >40)
#Meningitis
#Malignant Hyperthermia (genetic d/o; 1h post general anesthetic; hyperthermia up to 45deg C, rigidity, tachy, skin cyanosis with mottling)


==Treatment==
==Disposition==
#ABCs
*Admit, usually to ICU
#Stop the Offending Agent
#Aggressive Cooling Measures
#Fluid Resuscitation
#Supportive Care
#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)
==See Also==


==Woodbury Stages==
Incorporates severity of disease with treatment


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


==Complications==
[[Category:Psychiatry]]
arrhthmias, renal failure, seizures, pneumonia, DIC, death
[[Category:Toxicology]]
 
===Prognosis===
Most resolve within 2 weeks, without long term sequelae
 
Poorer prognosis in those with high peak and/or long duration of hyperthermia
 
Mortality of 10-20%
 
==Source==
Pani 6/2009 based on Rosen's
 
[[Category:Neuro]]

Latest revision as of 22:44, 21 September 2022

Background

  • Life threatening neurologic emergency associated with the use of neuroleptic agents[1][2]
  • Develops over 1-3 days
  • Majority of deaths occur from complications of muscle rigidity
  • Mortality rates up to 5 to 20% [4]

Clinical Features

Patient exhibiting NMS symptoms: hyperthermia, significant extrapyramidal symptoms, various autonomic symptoms, and impaired consciousness.

Complications

Differential Diagnosis

  • Serotonin Syndrome
    • 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
  • 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 Toxicity
    • Diaphoresis, rigidity, elevated CK are absent
    • Flushing, mydriasis, bladder distension are common
  • Sympathomimetics
    • Rigidity is not seen

Movement Disorders and Other Abnormal Contractions

Altered mental status and fever

Evaluation

Serotonin syndrome vs Neuroleptic malignant syndrome

  • History of a new serotonergic drug or a dose increase of a serotonergic drug are helpful
  • Serotonin syndrome is usually much more acute in onset than NMS which may develop over days or weeks
  • Presence of ‘lead pipe’ rigidity is typical of NMS, while serotonin syndrome typically manifests with tremor and hyperreflexia
  • Elevations in CK, LFTs, and WBC, coupled with a low iron level, distinguishes NMS from serotonin syndrome among patients taking both neuroleptic and serotonin agonist medications simultaneously

Management

  • The causative agent should be stopped
  • Discontinue all dopamine blocking agents
  • If precipitant is a dopaminergic therapy (L-dopa or Carbidopa) it can be restarted later at lower doses as an outpatient

Supportive Care

  • Agitation should be controlled with Benzodiazepines
    • Lorazepam 2 mg IV q5 min until agitation and muscle rigidity resolves
  • Fluid resuscitation
  • Cooling measures
  • Intubation and paralysis for severe cases, chest wall rigidity or respiratory failure
    • Use NON-DEPOLARIZING paralytic agent

Directed Medical Therapy[6]

Controversial with unclear and disputed efficacy

  • Dantrolene (skeletal muscle relaxant) - Consider only in patients with severe rigidity
    • May cause hepatotoxicity in patients with liver disease
    • 0.25-2mg/kg IV q6-12hr, max dose 10mg/kg/day
  • Bromocriptine (dopamine agonist)
    • 2.5mg PO q6-8hr, max dose 40mg/day
  • Amantadine (alternative to bromocriptine)
    • 100mg PO initially; titrate up as needed to max dose 200mg q12hr

Electroconvulsive Therapy

  • Limited case series suggest that ECT can be effective in NMS refractory to pharmacotherapy[7]

Disposition

  • Admit, usually to ICU

See Also

References

  1. ↑ 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
  2. ↑ Trollor JN, Chen X, Sachdev PS. Neuroleptic malignant syndrome associated with atypical antipsychotic drugs. CNS Drugs. 2009;23(6):477-92
  3. ↑ 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
  4. ↑ Shalev A. Mortality from neuroleptic malignant syndrome. J Clin Psychiatry. 1989;50(1):18-25.
  5. ↑ 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
  6. ↑ Addonizio G, Susman VL, Roth SD. Neuroleptic malignant syndrome: review and analysis of 115 cases. Biol Psychiatry. Aug 1987;22(8):1004-20
  7. ↑ Morcos N et al., Electroconvulsive therapy for neuroleptic malignant syndrome: a case series. J ECT. 2019.
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