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Introduction

  • 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)

Pathophysiology

  • 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

Etiology

  • 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%)

Investigations

  • Elevated serum creatine kinase levels
    • High specificity in NMS
    • >1000 IU/L; can go upto 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

Management

  • 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

Prognosis

  • 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.

Bibliography

  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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