Neuroleptic malignant syndrome

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Neuroleptic malignant syndrome (NMS) is a rare, life-threatening adverse drug event associated with dopamine blocking agents (e.g., antipsychotic medications). The clinical presentation often comprises a constellation of fever, autonomic instability, leukocytosis, tremor, elevated enzymes, and rigidity. While NMS is a diagnosis of exclusion, laboratory studies to support the diagnosis may show elevated creatine kinase (CPK), myoglobinuria, leukocytosis, and metabolic acidosis. Numerous diagnostic criteria have been proposed, but their clinical utility is debated. Management includes discontinuation of the culprit medication, supportive measures, and, in some cases, pharmacotherapy (e.g, dantrolene, bromocriptine, lorazepam).

NMS is an adverse drug event associated with dopamine blocking agents.

• Causative agents ^[2]
  • High-potency first-generation antipsychotics (most common association)
  • Second-generation antipsychotics
  • Other dopamine antagonists, e.g., metoclopramide, promethazine ^[3]
• Risk factors ^[2]
  • A genetic predisposition is suspected.
  • Possible pharmacological factors include high dosages and/or parenteral administration of causative agents. ^[2][3]

Standard therapeutic doses of antipsychotics or other dopamine receptor antagonists can cause NMS. ^[4]

• The underlying mechanism is not well understood. A disruption of numerous neurotransmitter pathways is suspected.
  • Central D₂ receptor blockade in the nigrostriatal pathway and hypothalamus, resulting in movement disorders and impaired thermoregulation
  • Increased sympathetic tone disrupts autonomic regulation and increases muscle tone and metabolism.
  • Increased release of calcium from the SR of striated muscle cells, resulting in increased contractility and muscle breakdown

Symptom progression ^[3]

• Onset: insidious, within 2–4 weeks of initiation of medication
• Sequence: cognitive changes precede systemic manifestations
• Resolution: gradually, within 7–10 days of stopping the culprit medication

The clinical presentation of NMS is heterogenous and varies widely; e.g., fulminant symptoms that develop over hours, and catatonia lasting > 1 month have both been described in case reports. ^[3]

Typical presentation ^[2][3]

• Mental status changes (encephalopathy)
  • Delirium (e.g., reduced vigilance)
  • Confusion
  • Stupor
  • Catatonia
• Parkinsonism
  • Muscle rigidity (lead-pipe rigidity)
  • Akinesia
  • Tremor
• Hyperthermia: High-grade fever is common. ^[4]
• Autonomic instability
  • Tachycardia, dysrhythmias, labile blood pressure
  • Tachypnea
  • Diaphoresis, often with a greasy appearance ^[2]
  • Sialorrhea
  • Urinary incontinence

In contrast to serotonin syndrome, patients with NMS do not present with clonus or hyperreflexia. ^[2]

FALTER: Fever, Autonomic instability, Leukocytosis, Tremor, Elevated enzymes (creatine kinase, transaminases), and Rigidity are common findings in neuroleptic malignant syndrome.

General principles

• NMS is a diagnosis of exclusion.
• Obtain a focused clinical evaluation including a comprehensive medication history.
• Obtain diagnostic studies to support the diagnosis or identify an alternative cause.
• Consider the use of diagnostic criteria. ^[2]

The diagnosis of neuroleptic malignant syndrome is primarily clinical and based on typical signs and symptoms of NMS (e.g., hyperthermia, rigidity, autonomic dysfunction), supportive laboratory findings (e.g., elevated creatine kinase), and the exclusion of differential diagnoses.

Laboratory studies ^[2][3]

• Blood tests
  • ↑↑ Creatine kinase (typically > 4 × ULN)
  • Liver enzymes: ↑ transaminases, ↑ ALP, ↑ LDH
  • CBC: leukocytosis, often with left shift
  • CMP
    • Metabolic acidosis
    • ↑ BUN and creatinine in AKI
    • Electrolytes: ↓ calcium, ↑ potassium, ↓ or ↑ sodium
  • ↑ ESR and CRP
  • ↓ Serum iron and zinc concentrations
• Urine studies: myoglobinuria

Additional studies ^[3]

Obtain as needed to rule out differential diagnoses of NMS.

• Neuroimaging: typically normal
• CSF analysis: typically normal
• EEG: generalized slowing

• Toxic and pharmacological
  • Other types of drug-induced hyperthermia
    • Serotonin syndrome
    • Anticholinergic syndrome
    • Malignant hyperthermia
  • Drug toxicity
    • Lithium toxicity
    • Salicylate poisoning
  • Withdrawal syndromes (e.g., alcohol withdrawal)
• Infectious
  • CNS infections (e.g., brain abscess, encephalitis, meningitis)
  • Sepsis
  • Tetanus
  • Rabies
• Neuropsychiatric
  • Lethal catatonia
  • Hyperactive delirium
  • Nonconvulsive status epilepticus
  • Midbrain structural lesions
• Endocrine
  • Thyrotoxicosis
  • Pheochromocytoma
• Other: heat stroke

The differential diagnoses listed here are not exhaustive.

Approach

• Discontinue suspected causative agent (e.g., antipsychotics).
• Initiate supportive measures for all patients.
• Consider admission to ICU for patients with:
  • Autonomic instability
  • High fever
  • Dehydration and/or electrolyte disturbances
• Consult psychiatry or neurology for guidance on pharmacotherapy.
• Consider electroconvulsive therapy for patients refractory to supportive care and pharmacotherapy.

Supportive measures ^[5]

• Facilitate heat dissipation.
  • Prevent and treat dehydration, e.g., with IV fluid therapy.
  • Reduce ambient temperature; apply cooling blankets.
  • Remove physical restraints.
• Keep the head of bed > 45 degrees to reduce the risk of aspiration. ^[2]
• Provide DVT prophylaxis.

Pharmacotherapy ^[3][5]

Evidence of the benefits of pharmacotherapy is primarily based on small, retrospective studies.

• Dantrolene (off-label) : for severe NMS ^[3]
• Dopamine agonists, e.g., bromocriptine (off-label) , amantadine (off-label) , or apomorphine: for moderate or severe NMS ^[3]
• Benzodiazepines, e.g., lorazepam (off-label) : can be used to treat mild symptoms of NMS and/or psychomotor agitation ^[3]
• Calcium-channel blockers: for hypertension ^[5]

Antipsychotic medications should only be resumed under specialist care and after informed consent has been given about the risk of recurrent NMS with continued use of antipsychotics. ^[5]

Coadministration of dantrolene and calcium channel blockers can cause cardiovascular collapse. ^[3]

• Rhabdomyolysis
• Aspiration pneumonia
• Disseminated intravascular coagulation
• Takotsubo cardiomyopathy
• Venous thromboembolism

We list the most important complications. The selection is not exhaustive.