neuroleptic malignant syndrome (NMS)

see also:

• heat illness and heat stroke
• anti-psychotic medications
• toxicology
• CMAJ. 2010 Dec 14; 182(18): E834–E838. Neuroleptic malignant syndrome: a neuroimmunologic hypothesis
• Curr Neuropharmacol. 2015 May; 13(3): 395–406. Neuroleptic Malignant Syndrome: A Review from a Clinically Oriented Perspective

• 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.

• 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

• 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

• serotonin syndrome
  • features which distinguish NMS from serotonin syndrome include bradykinesia, muscle rigidity, and a high white blood cell count
• heat illness and heat stroke
• malignant hyperthermia
• encephalopathy
• seizures
• Note: mechanical restraint or IM injections may cause a CK rise up to 600IU/L but rarely more than this, so a CK higher than 600IU/L is suggestive of NMS and not just to the restraint or IM injections

• 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

• cease dopamine antagonists including phenothiazines
• supportive care including cooling if febrile
• vigorous early Rx with antiparkinsonian drugs
• muscle relaxants (eg. diazepam, +/- dantrolene or bromocriptine)
• IV fluids as per rhabdomyolysis Rx regime if CK is high