Neuroleptic malignant syndrome

  • Occurs in patients on dopamine receptor-blocking medication
  • Parkinsonism-hyperpyrexia syndrome is a neuroleptic malignant-like syndrome that can occur in patients with Parkinson’s disease whose dopaminergic medication is abruptly discontinued
  • Fever, movement disorder, autonomic disorder and mental status changes are the most well recognized signs
  • Leukocytosis, elevated creatine phosphokinase, elevated hepatic transaminases, and metabolic acidosis may be present
  • NMS may be caused by any antipsychotic including atypicals and clozapine
  • May occur in the same day or as late as years after initiation of the offending drug
  • 50% of patients with NMS develop the syndrome within 1 week of administration
  • 3% of patients with NMS develop the syndrome after 6 months from initiation of the drug
  • NMS may occur after addition of other medications such as antiemetics, donepezil, lithium, and serotonin reuptake inhibitors, without adjustment of the neuroleptic dose
  • The incidence of NMS is 0.5% per year
  • Male:female ratio is 1.5-2:1
  • NMS may occur at any age and is clinically identical in children and adults
  • The exact pathophysiology of NMS is unknown
  • There is no known way to prevent NMS
  • NMS risk appears to be lower with low potency antipsychotics and oral vs depot preparations

Diagnosis

DSM-IV diagnostic criteria for NMS

Required for diagnosis: all 3 major criteria or 2 major and 4 minor criteria

Major criteria

  1. Fever
  2. Muscle rigidity
  3. Use of antipsychotic medication

Minor criteria

  • Diaphoresis
  • Labile blood pressure
  • Tachycardia
  • Incontinence
  • Dysphagia
  • Mutism
  • Tremor
  • Leukocytosis
  • Elevated CPK

Laboratory findings

There are no specific for NMS laboratory findings. Findings may include any of the following:

  • CPK, LDH, transaminases, aldolase elevations
  • Myoglobinuria
  • Leukocytosis
  • Metabolic acidosis
  • Hypoxia
  • Low serum iron
  • Elevated catecholamines

EEG

  • May show generalized slowing of base rhythm

Differential

  • Infection
  • Serotonin syndrome
  • Encephalitis
  • Drug withdrawal syndromes (eg delirium tremens)
  • Generalized dystonia
  • Malignant catatonia
  • Malignant hyperthermia

Workup

  • Complete blood count
  • Electrolytes
  • CPK, hepatic transaminases, LDH, myoglobin
  • Chest X-Ray
  • Urinalysis
  • Blood and urine cultures
  • CSF studies to rule out encephalitis may be required
  • Evaluation for SLE or other collagen vascular disease may be required
  • Toxicology screens may prove neuroleptic exposure if history is uncertain

A trial of IV anticholinergics (benztropine or diphenhydramine) may be useful in distinguishing generalized acute dystonia from NMS.

Brain imaging is not indicated. Few case reports exist of transient increases in T2 signal in basal ganglia, cerebellum and brain stem, thalamus, corpus callosum, white and gray matter. These resolve with the resolution of the clinical syndrome.

Management

Management is mostly supportive. There are no evidence-based treatment recommendations and drug treatment of NMS is controversial. Antipyretics, various dopaminergic agents dantrolene have shown various degrees of effectiveness.

The following is a management suggestion.

  • Admit to ICU
  • Discontinue any offending medication or, if Parkinsonic patient, resume the discontinued drug
  • Rule out or treat infection
  • Hydrate, maintain euvolemia
  • Treat fever with antipyretics and passive cooling
  • If rigidity causes rhabdomyolysis or fever is unmanageable, anesthetize and paralyze
  • Alkalinize urine with sodium hydrogen carbolate
  • Specific treatment:
    • If there are signs of catatonia, administer intravenous lorazepam 1-2 mg every 4-6 hours
    • If severe catatonia, consider electroconvulsive therapy (6-10 bilateral treatments) in addition to lorazepam
    • If there are no signs of catatonia:
      • Administer 5 mg bromocriptine 3 times/day and titrate up to 15 mg 3 times/day if needed
      • Alternatively, give 1-3 mg/kg dantrolene and titrate up to 10 mg/kg/day in divided doses, orally or IV

Complications

  • Mortality from NMS is mainly from pneumonia and acute renal failure from myoglobinuria following rhabdomyolysis
  • Mortality has declined, probably due to earlier recognition, from as high as 76% before 1970 to 4-22% after 1980



References

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  • Neuroleptic malignant syndrome: review and analysis of 115 cases. Biol Psychiatry 1987;22:1004-20. doi: 10.1016/0006-3223(87)90010-2
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  • An international concensus study of neuroleptic malignant syndrome diagnostic criteria using the Delphi method. J Clin Psychiatry 2011;72:1222-8. doi: 10.4088/JCP.10m06438
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  • Neuroleptic malignant syndrome in Parkinson’s disease after withdrawal or alteration of dopaminergic therapy. Arch Int Med 1991;151:794-6
  • Neuroleptic malignant syndrome-an 11-year longitudinal case-control study. Can J Psychiatry 2012;57(8):512-8 doi: 10.1177/070674371205700810
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  • Movement disorder emergencies. J Neurol 2008;255 Suppl4:2-13.doi: 10.1007/s00415-008-4002-9
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