II. Definition

  1. Life-threatening reaction to Antipsychotic agents
  2. Presents with Muscle rigidity and Tremor, Altered Level of Consciousness, Hypertension and fever

III. Epidemiology

  1. Incidence: 0.01 to 0.02%

IV. Pathophysiology

  1. Decreased CNS levels of Dopamine or CNS Dopamine receptor blockade

V. Causes

  1. Dopaminergic agent withdrawal (e.g. Sinemet withdrawal)
  2. Dopamine receptor blockade (e.g. metoclopramide, Promethazine)
  3. Antipsychotic agents (higher risk at higher dose)
    1. Higher risk with higher potency first generation agents (although can occur with any Antipsychotic)
      1. Haloperidol (Haldol) or Haloperidol decanoate
      2. Perphenazine (Trilafon)
      3. Thiothixene HCl (Navane)
      4. Fluphenazine HCl (Prolixin)
      5. Trifluoperazine (Stelazine)
    2. Atypical Antipsychotics
      1. Clozapine (most common)
      2. Occurs with other Atypical Antipsychotics, but less commonly
        1. Risperidone
        2. Olanzapine
        3. Quetiapine
        4. Ziprasidone
        5. Aripiprazole

VI. Risk Factors

  1. Dopamine blocking agent initiation
  2. Multiple agents
  3. Pregnancy

VII. Symptoms

  1. Onset within 30 days of starting causative agent
  2. Classic triad
    1. Fever
    2. Muscle rigidity (contrast with Clonus in Serotonin Syndrome)
    3. Altered Level of Consciousness
  3. Neurologic findings
    1. Diffuse Muscle rigidity (at onset) or "Lead pipe" rigidity
    2. Muscle Tremor
    3. Altered Level of Consciousness (Agitation, Delirium)
    4. Bradykinesia and Bradyreflexia (contrast with Serotonin Syndrome)
  4. Autonomic Dysfunction
    1. High Fever
    2. Diaphoresis
    3. Hypertension
    4. Tachycardia

VIII. Diagnosis: DSM 5 Criteria

  1. Major criteria (all required)
    1. Exposure to Dopamine blocking agent
    2. Severe Muscle rigidity
    3. Fever
  2. Other criteria (at least of 2 of the following)
    1. Diaphoresis
    2. Dysphagia
    3. Tremor
    4. Incontinence
    5. Altered Level of Consciousness
    6. Mutism
    7. Tachycardia
    8. Elevated or labile Blood Pressure
    9. Leukocytosis
    10. Creatine Phosphokinase increase
  3. References
    1. (2013) DSM 5, APA

IX. Differntial Diagnosis

  1. Serotonin Syndrome
    1. Typically results from serotonergic drug Overdose (e.g. SSRI) or serotonergic Drug Interactions
    2. In contrast to NMS, Serotonin Syndrome presents with hyperreflexia, motor restlessness, Clonus

X. Labs

  1. Comprehensive metabolic panel
    1. Including Electrolytes, Serum Creatinine
  2. Creatine Phosphokinase (CPK)
    1. Increase related to Muscle rigidity
  3. Arterial Blood Gas (ABG) or Venous Blood Gas (VBG)
    1. May demonstrate Metabolic Acidosis
  4. Urinalysis
    1. Myoglobinuria in Rhabdomyolysis (urine blood positive on dipstick, without RBCs on microscopy)

XI. Management

  1. Correct causative factors
    1. Withdraw causative Antipsychotic Medication immediately
    2. If secondary to cessation of Dopaminergic agent (e.g. Sinemet), consider restarting the medication
  2. Lower Temperature (active cooling may be needed)
    1. See Heat Stroke for similar protocol
  3. Fluids and Electrolytes
    1. Aggressive fluid Resuscitation to prevent Rhabdomyolysis
    2. Correct Electrolyte abnormalities
  4. Other measures
    1. Supportive care
    2. Paralysis and intubation may be needed for severe rigidity, Autonomic Dysfunction, Agitation
    3. Control Hypertension
    4. Benzodiazepines for Agitation
    5. Dantrolene
      1. Dosing
        1. Adult: 1-3 mg/kg IV
        2. Child: 0.5-1 mg/kg IV
      2. May reduce NMS symptom duration but does not alter mortality or morbidity
      3. Consider in severe cases
      4. May be used in combination with agents with Dopamine activity (see below)
    6. Agents with Dopamine activity that have been used in NMS
      1. Bromocriptine (2.5 to 5 mg orally twice to three times daily)
      2. Amantadine
      3. Levadopa
      4. Apomorphine
  5. Avoid unhelpful measures
    1. Gastric Decontamination is not indicated (NMS is not due to Overdose ingestion)
    2. Hemodialysis is not indicated for drug elimination
  6. Disposition
    1. Intensive Care unit admission

XII. Prognosis

  1. Mortality: 10-30%

XIII. References

  1. Corbett (2017) Crit Dec Emerg Med 31(3):24
  2. Glauser and Peters (2016) Crit Dec Emerg Med 30(4): 17-27

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Related Studies

Ontology: Neuroleptic Malignant Syndrome (C0027849)

Definition (MSHCZE) Soubor příznaků charakterizovaný zvýšením tělesné teploty, svalovou rigiditou a změnou stavu vědomí, může být komplikován rhabdomyolýzou, akutním selháním ledvin, kardiovaskulárním kolapsem aj. Předpokládá se, že je způsoben poruchou rovnováhy neurotransmiterů při podávání látek, které ovlivňují dopaminergní receptory v mozku (léčba neuroleptiky, metoklopramidem, vysazení levodopy). Léčba je podpůrná, je možno podávat dantrolen, bromokriptin, levodopu nebo amantadin. (cit. Velký lékařský slovník online, 2013 http://lekarske.slovniky.cz/ )
Definition (NCI) A rare, life-threatening disorder that is caused by neuroleptic medications. It is characterized by fever, muscular cramps and rigidity, autonomic nervous system dysfunction, and changes in the mental status that may lead to coma.
Definition (NCI_NCI-GLOSS) A life-threatening condition that may be caused by certain drugs used to treat mental illness, nausea, or vomiting. Symptoms include high fever, sweating, unstable blood pressure, confusion, and stiffness.
Definition (MSH) A potentially fatal syndrome associated primarily with the use of neuroleptic agents (see ANTIPSYCHOTIC AGENTS) which are in turn associated with dopaminergic receptor blockade (see RECEPTORS, DOPAMINE) in the BASAL GANGLIA and HYPOTHALAMUS, and sympathetic dysregulation. Clinical features include diffuse MUSCLE RIGIDITY; TREMOR; high FEVER; diaphoresis; labile blood pressure; cognitive dysfunction; and autonomic disturbances. Serum CPK level elevation and a leukocytosis may also be present. (From Adams et al., Principles of Neurology, 6th ed, p1199; Psychiatr Serv 1998 Sep;49(9):1163-72)
Concepts Disease or Syndrome (T047)
MSH D009459
ICD9 333.92
ICD10 G21.0
SnomedCT 68977009, 192826000, 15244003
DSM4 333.92
English Neuroleptic Malignant Syndrome, Neuroleptic Malignant Syndromes, Syndrome, Neuroleptic Malignant, Syndromes, Neuroleptic Malignant, NEUROLEPTIC MALIGNANT SYNDROME, neuroleptic malignant syndrome (diagnosis), neuroleptic malignant syndrome, Neuroleptic malignant, NMS (Neuroleptic Malignant Syndrome), Neuroleptic malgnt synd, Neuroleptic Malignant Syndrome [Disease/Finding], malignant neuroleptic, neuroleptic malignant, malignant neuroleptic syndrome, nms, NMSs (Neuroleptic Malignant Syndrome), NMS, Malignant neuroleptic syndrome, Neuroleptic malignant syndrome, Neuroleptic malignant syndrome (disorder), NMS - Neuroleptic malignant syndrome, malignant; neuroleptic syndrome, syndrome; malignant neuroleptic, Neuroleptic malignant syndrome -RETIRED-
Spanish SINDROME NEUROLEPTICO MALIGNO, SNM, síndrome neuroléptico maligno - RETIRADO - (concepto no activo), síndrome neuroléptico maligno - RETIRADO -, síndrome neuroléptico maligno (trastorno), síndrome neuroléptico maligno, Síndrome neuroléptico maligno, Síndrome Neuroléptico Maligno
Dutch neuroleptica maligne, maligne neurolepticasyndroom, maligne; neuroleptisch syndroom, syndroom; maligne neuroleptisch, neuroleptisch maligne syndroom, Maligne neuroleptisch syndroom, Neuroleptisch syndroom, maligne, Syndroom, neuroleptisch, maligne
French S. neuroleptique malin, SNM, SYNDROME MALIN DES NEUROLEPTIQUE, Syndrome malin des neuroleptiques, SMN (Syndrome Malin des Neuroleptiques)
German NMS, Malignes Neuroleptika-Syndrom, NEUROLEPTISCHES SYNDROM MALIGNE, malignes neuroleptisches Syndrom, Malignes neuroleptisches Syndrom
Italian Neurolettica maligna, Sindrome neurolettica maligna, Sindrome maligna da neurolettici (SMN), Sindrome maligna da neurolettici
Portuguese Síndrome maligna de neuroléptico, SINDROME NEUROLEPTICO MALIGNO, Síndrome neuroléptica maligna, Síndrome Maligna Neuroléptica
Swedish Neuroleptiskt malignt syndrom
Japanese アクセイショウコウグン, 神経遮断薬による悪性症候群, 神経弛緩薬性悪性症候群, 神経遮断薬悪性症候群, 神経遮断薬性悪性症候群, 悪性症候群
Czech neuroleptický maligní syndrom, NMS, Maligní neuroleptický syndrom, Neuroleptický maligní
Finnish Neuroleptioireyhtymä
Korean 악성 신경마비성 증후군
Polish Zespół neuroleptyczny złośliwy
Hungarian Neurolepticus malignus syndroma, Malignus neuroleptikus syndroma
Norwegian Malignt nevroleptikasyndrom