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neuroleptic malignant syndrome (NMS)


  • see also serotonin syndrome (this link gives comparative DDx features)
  • this is a life threatening disorder in patients who are extremely sensitive to the extrapyramidal effects of neuroleptics such as the phenothiazines, and is believed to be due to excessively rapid blockade of postsynaptic dopamine receptors
  • first described in 1960 by French clinicians
  • occurs in an estimated 0.07% to 3.23% of patients treated with antipsychotic medication
  • occurs more frequently during either the initial months of treatment or after a dosage change
  • has been reported to occur at all standard doses of antipsychotics, including atypicals, and all routes of administration.

Risk factors

  • genetic predisposition (perhaps via reduced function of the dopamine receptor D2) may be a factor
    • PH NMS
    • FH NMS or catatonic syndrome
    • muscle chanellopathy
  • Lewy body dementia patients are very sensitive to neuroleptics
  • males aged under 40yrs may have 2x increased risk but this may be due to higher incidence of use of neuroleptics
  • post partum women may have increased risk
  • advanced age
  • medical comorbidity
  • use of high-potency neuroleptics
  • rapid increase in the dosage of neuroleptics
  • use of parenteral neuroleptics
  • use of long-acting forms of neuroleptics
  • abrupt reduction in dopaminergic drugs (such as levodopa) for Parkinson's disease
  • mechanical restraint
  • dehydration
  • low iron levels

Clinical features

  • initial symptom is marked Parkinsonian-like muscle rigidity
    • usually generalized, symmetric, and could present from a mild increase in tone to extreme generalized body rigidity, such as opisthotonos.
    • focal increases of muscular tone can also be present in the form of blefarospasm, oculogyric crisis, trismus, nystagmus, dysphagia, dysarthria, or aphonia.
    • later causes raised CK (usually over 600UI/L) due to rhabdomyolysis
  • symptoms peak at around 3 days from onset but can last 40 days although mostly resolves within 3-14 days if uncomplicated.
  • sweating leading to dehydration, although if sweating is impaired (as it often is with anticholinergic drugs), fever is even more likely to ensue, often reaching dangerous levels
  • fever >38°C without chills but with raised inflammatory markers such as WCC, CRP, fibrinogen, ESR
    • fever is usually very high, without major fluctuations or daily peaks and responds poorly to conventional antipyretic drugs
    • stress leukocytosis & fever may erroneously suggest sepsis
  • delirium or sudden changes in mental status (agitation, delirium, or coma)
  • autonomic instability (low or high BP, tachypnea, tachycardia, fecal incontinence) due to midbrain dysfunction
  • early recognition and improved Rx has reduced mortality to around 10%
  • complications may include:
    • aspiration pneumonitis
    • kidney failure due to myoglobinuria from the rhabdomyolysis
    • reversible dilated myocardiopathy (Takotsubo myocardiopathy)
    • disseminated intravascular coagulation
    • multiorgan failure
  • post-recovery memory impairment is common and usually temporary though may become persistent

Differential diagnosis


DSM 5 criteria 2013

  • 1.Hyperthermia (oral temperature >38.0°C on at least 2 occasions)
  • 2.Rigidity
  • 3.CK > 4-times the upper limit
  • 4.Changes in mental status (delirium, altered consciousness)
  • 5.Autonomic activation, including: tachycardia (>25% above baseline), diaphoresis, blood pressure elevation (systolic or diastolic ≥25% above baseline), or fluctuation (≥20mmHg diastolic change or ≥25mmHg systolic change), urinary incontinence, pallor, tachypnea (>50% above baseline)


  • FBE, U&E, CK, CRP, LFTs, troponin, CaMgP (consider Zn)
  • urinalysis
  • consider septic workup if sepsis cannot be excluded
  • CT brain to exclude I/cranial causes


nms.txt · Last modified: 2019/12/23 05:56 by

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