Neuroleptic Malignant Syndrome

Aka: Neuroleptic Malignant Syndrome

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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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