Neuroleptic Malignant Syndrome

Neuroleptic Malignant Syndrome (NMS) is a life-threatening neurological disorder requiring emergent care. It is associated with the use of antipsychotic agents also called neuroleptics. The incidence rate for NMS in patients taking antipsychotics is 0.02 to 3%

Primary Category
Secondary Category


  • Neuroleptic Malignant Syndrome (NMS) is a life-threatening neurological disorder requiring emergent care.
  • It is associated with the use of antipsychotic agents also called neuroleptics
  • The incidence rate for NMS in patients taking antipsychotics is 0.02 to 3%
  • Characterized by muscle rigidity, fever, dysautonomia, and changes in cognitive functions
  • The incidence of NMS was 0.2-3.2% in the last century; dropped to 0.01-0.02% recently
  • A decreasing trend of mortality has been seen in recent years (mortality rates: 25% before 1984 and 5.6% in 2011)


  • Two major theories explain the pathogenesis of NMS
    • Central dopamine receptor blockade in the hypothalamus and/or basal ganglia is most commonly accepted theory
    • Another less favored theory proposes NMS may be caused by a spectrum of inherited defects in genes responsible for a variety of calcium regulatory proteins within sympathetic neurons. According to this theory, NMS is considered as a neurogenic form of malignant hyperthermia


  • NMS is exclusively seen as an adverse effect of medications with dopamine receptor-antagonist properties
    • Most often associated with high-potency first-generation antipsychotic drugs
    • Implication with other classes of antipsychotic drug has been noted including low potency and second-generation antipsychotic drugs
    • Antiemetic drugs have also been associated with NMS
    • Although association of NMS with antipsychotic agents is idiosyncratic, usual pattern of NMS onset is seen within the first 2 weeks of drug therapy
    • Another common pattern of NMS is seen in the re-introduction of anti-dopaminergic therapy after sudden withdrawal (such as patient started on full dose of medications after few days of vomiting).
  • NMS is also seen in removal of dopaminergic medications
    • Settings of withdrawal or dose reduction of Parkinson medication L-Dopa or dopamine agonist or switching to other agent
    • Sometimes considered as a separate syndrome called neuroleptic malignant-like syndrome or parkinsonism hyperpyrexia syndrome

Risk Factors

  • History of previous NMS occurrence is one of the strongest risk factors (15-20 percent in reported cases)
  • Antipsychotic dose association
    • Parenteral route
    • Higher titration rates
    • Total dose of drug administration
  • Certain psychiatric conditions like acute catatonia or extreme agitation
  • Systemic factors
    • Preexisting abnormalities of CNS dopamine activity or receptor function
    • Infection
    • Surgery
  • Metabolic factors
    • Dehydration
    • Physical exhaustion
    • Iron deficiency

Clinical Manifestations

  • Variable onset after starting antipsychotic therapy
    • 16% of cases develop within 24 hours
    • 66% develop within first week
    • Almost 100% cases develop within 30 days
  • Tetrad of symptoms mostly evolve over 1-3 days of onset
    • Mental status change (82% prevalence)
      • Agitated delirium
      • Confusion
      • Catatonic signs
      • Mutism
    • Motor abnormalities may include
      • Muscle rigidity
      • Lead-pipe rigidity
      • Cogwheel phenomenon
      • Myoclonic Tremors
      • Dystonias
      • Opisthotonus
      • Trismus
      • Chorea
      • Other dyskinesias
      • Sialorrhea
      • Dysarthria
      • Dysphagia
    • Hyperthermia
      • Typically >38ºC
      • Can increase more than 40ºC
      • Less consistent in NMS associated with second-generation antipsychotic agents
    • Autonomic instability
      • Tachycardia (88%)
      • High Blood pressure (61%)
      • Tachypnea (73%)


  • Elevated serum creatine kinase levels
    • High specificity in NMS
    • >1000 IU/L; can go up to 100,000 IU/L
  • WBC - 10,000 to 40,000/mm3
  • Mildly elevated lactate dehydrogenase, Alk. phos., liver transaminases
  • Myoglobinuria secondary to rhabdomyolysis
  • Low serum iron concentration
  • CSF analysis is normal in 95% of cases
  • Neuroimaging studies are normal
  • EEG may show generalized slowing consistent with metabolic encephalopathy

Diagnostic Criteria

  • Many diagnostic criteria for NMS have been proposed but had unresolved differences between them
  • One study developed a criteria using the Delphi Method; the criteria consists of signs and symptoms with their respective priority scores
    • Exposure to dopamine antagonist, or withdrawal from dopamine agonist within past 72 hours
    • Hyperthermia (>40ºC or >38ºC on at least 2 occasions, measured orally)
    • Mental status alteration
    • Raised CK levels (4x the normal limit)
    • Sympathetic nervous system lability, defined by at least 2 of the following
      • BP elevation (systolic or diastolic ≥25% above baseline)
      • BP fluctuation (≥20 mm Hg diastolic change or ≥25 mm Hg systolic change within 24 hours)
      • Diaphoresis
      • Urinary incontinence
    • Hypermetabolism consisting of
      • Raised heart-rate ≥25% above baseline
      • Respiratory rate ≥50% above baseline
    • Negative work-up for infectious, toxic, metabolic, or neurologic causes
  • DSM-IV-TR research criteria require following be present after recent administration of an antipsychotic
    • Severe muscle rigidity
    • Elevated temperature
    • As well as two associated signs, symptoms, or laboratory findings that are not better accounted for by a substance-induced, neurological, or general medical condition

Table 1: Differential Diagnosis

notion image

Differential Diagnosis

  • Infectious
    • Meningitis or encephalitis
    • Postinfectious encephalomyelitis syndrome
    • Brain abscess
    • Sepsis
  • Psychiatric
    • Idiopathic malignant catatonia
    • Agitated delirium
  • Neurologic
    • Benign extrapyramidal side effects
    • Nonconvulsive status epilepticus
    • Structural lesions, particularly involving the midbrain
  • Toxic or pharmacologic
    • Anticholinergic delirium
    • Salicylate poisoning
    • Malignant hyperthermia
      • Inhalation anesthetics
      • Succinylcholine
    • Serotonin syndrome
      • Monoamine oxidase inhibitors
      • Triptans
      • Linezolid
    • Substances of abuse
      • Amphetamines
      • Hallucinogens
    • Withdrawal
      • Dopamine agonists
      • Baclofen
      • Sedative-hypnotics
      • Alcohol
  • Endocrine
    • Thyrotoxicosis
    • Pheochromocytoma
  • Environmental
    • Heatstroke


  • Supportive care
    • Always start with the ABCs (airway, circulation and breathing support)
    • Stop causative agent
    • Start and maintain rehydration with IV fluids
    • Passive and active cooling, as needed, to resolve febrile state
    • Maintain blood pressure
    • DVT prophylaxis
    • Benzodiazepines for agitation
  • Mainstay treatment
    • Bromocriptine (often treatment of choice)
      • Dopamine agonist
      • Administered through a nasogastric tube
      • 2.5 mg 6-8 hourly
      • Maximum of 40 mg/day
      • Continue till 10 days after NMS is controlled; then taper slowly
    • Carbidopa-Levodopa (Sinemet)
      • Alternative to Bromocriptine
      • Treatment of choice in patients with concerns of Parkinsonism started on antipsychotic medications
      • Has to be given oral or via NG tube. Can mix in acidic solutions (orange juice or cranberry juice)
      • Usual starting dose is 25-100 mg every 6-8 hours.
      • Should be tapered off slowly
    • Benzodiazepines (better option in transient and mild situations)
      • Lorazepam - 1-2 mg IM/IV 4-6 hourly
      • Diazepam - 10 mg IV 8 hourly
    • Dantrolene
      • Direct acting muscle relaxant
      • 1-2.5 mg/kg IV
      • Maximum dose of 10mg/kg/day
      • Adverse effects
        • Hepatotoxicity
        • Should be avoided if LFTs are very abnormal
      • Continue till 10 days after NMS is controlled; then taper slowly
    • Amantadine (not routinely used at this point)
      • Dopaminergic and anticholinergic effects
      • Alternative to bromocriptine
      • 100 mg initially
      • Titrated upward to a maximum dose of 200 mg 12 hourly
  • How to restart antipsychotics after recovery from NMS
    • Wait at least 2 weeks
    • Using lower potency agents and newer antipsychotics
    • Avoid dehydration or concomitant lithium
    • Carefully monitoring of NMS symptoms
notion image
Adapted from Woodbury & Woodbury, 1992; cited in Strawn, J. R., Keck, P. E., & Caroff, S. N. (2007). Neuroleptic malignant syndrome. American Journal of Psychiatry, 164(6), 870-876, p. 874


  • Average period of resolution is 2 weeks
  • Persistence of residual catatonia and motor signs up to 6 months has been seen
  • Most patients recover without sequelae
  • Mortality rate is 5-20%
  • Strongest predictors of mortality are disease severity and complications
  • Duration of NMS episodes may be prolonged when long-acting depot antipsychotics are implicated

Further Reading

  1. J. R., Keck, P. E., & Caroff, S. N. (2007). Neuroleptic malignant syndrome. American Journal of Psychiatry, 164(6), 870-876, p. 874.


  1. J. R., Keck, P. E., & Caroff, S. N. (2007). Neuroleptic malignant syndrome. American Journal of Psychiatry, 164(6), 870-876, p. 874.
  1. Neuroleptic Malignant Syndrome; Strawn JR, Keck Jr PE, Caroff SN; Am J; Psychiatry, 2007
  1. Adnet, P. (2000). Neuroleptic malignant syndrome. British Journal of Anaesthesia. 85(1): 129-35. DOI: 10.1093/bja/85.1.129
  1. Modi S, Dharaiya D, Schultz L, Varelas P (2016). "Neuroleptic Malignant Syndrome: Complications, Outcomes, and Mortality". Neurocrit Care. 24 (1): 97–103. doi:10.1007/s12028-015-0162-5. PMID 26223336.
  1. Shalev A, Hermesh H, Munitz H (1989). "Mortality from neuroleptic malignant syndrome". J Clin Psychiatry. 50 (1): 18–25. PMID 2562951.
Berman, B.D. (2011). Neuroleptic Malignant Syndrome: A Review for Neurohospitalists. Neurohospitalist. 1(1): 41-47. doi: 10.1177/1941875210386491
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Umair Hamid MD

Written by

Umair Hamid MD

Neurology Resident at University of Illinois College of Medicine Peoria

    Danish Batti MD

    Written by

    Danish Batti MD

    Movement Disorders Neurologists and teaches physicians internationally, Directs an online mini-fellowship in Movement Disorders since 2017, Founding director of the International Neurology program at University of Nebraska Medical Center

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