Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS) is a rare, idiosyncratic, and potentially life-threatening reaction to antipsychotic drugs. Neuroleptic malignant syndrome presents with ≥ 2 of the following cardinal symptoms: fever, altered mental status, muscle rigidity, and autonomic dysfunction. It is important to promptly identify this condition because of its high morbidity and mortality rates. Diagnosis is based on positive clinical and laboratory findings, along with the exclusion of other possible causes. Management involves discontinuing antipsychotic medication, supportive care, and pharmacologic options.

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Neuroleptic malignant syndrome (NMS) is a life-threatening neurologic disorder associated with the use of antipsychotics that presents as a classic tetrad:

  • Fever
  • Altered mental status
  • Autonomic instability
  • Muscle rigidity


  • Incidence 0.01%–0.07% of people taking antipsychotics
  • 10% mortality rate if left untreated
  • If renal failure is present, the mortality rate increases to 50%.


  • NMS is an idiosyncratic reaction to neuroleptic (antipsychotic) drugs.
  • Antipsychotics primarily modulate the dopamine (D2) pathway.
  • Typical antipsychotics have a greater likelihood of leading to NMS than atypical antipsychotics:
    • Common 1st-generation “typical” antipsychotics:
      • Haloperidol (Haldol)
      • Droperidol
      • Chlorpromazine (Thorazine)
    • Common 2nd-generation “atypical” antipsychotics:
      • Risperidone (Risperdal)
      • Olanzapine (Zyprexa)
      • Quetiapine (Seroquel)
      • Clozapine (Clozaril)
      • Ziprasidone (Geodon)
      • Aripiprazole (Abilify)
  • Other medications that can trigger NMS:
    • Amoxapine, dosulepin (tricyclic antidepressants)
    • Droperidol, metoclopramide (antiemetics)
    • Diatrizoate (contrast agent)
    • Promethazine (antihistamine)
    • Tetrabenazine (treatment of hyperkinetic movement disorders) 
    • Lithium
    • Phenelzine (monoamine oxidase inhibitor)
    • Sudden withdrawal of dopaminergic drugs (antiparkinson medications such as levodopa)

Pathophysiology and Clinical Presentation


  • Exact underlying mechanism remains unclear.
  • Sudden decrease in the central dopaminergic activity:
    • Significant D2 receptor blockage
    • Abrupt withdrawal of D2 receptor agonist
  • D2 blockade in various structures of the nervous system causes the characteristic symptoms:
    • Hypothalamus → fever
    • Nigrostriatal pathways → rigidity
    • Spinal cord → rigidity and tremor

Clinical presentation

Cardinal features of the neuroleptic malignant syndrome include:

  • Fever (> 40°C)
  • Alteration in the level of consciousness:
    • Encephalopathy
    • Delirium
    • Stupor
    • Coma
  • Autonomic dysregulation:
    • Diaphoresis (excessive sweating)
    • Tachycardia, tachypnea, or hypertension
    • Sialorrhea (excessive salivation)
    • Hypoxemia
  • Severe muscular rigidity, also known as “lead pipe rigidity”

Other signs and symptoms are as follows:

  • Dysphagia (trouble swallowing)
  • Dyspnea
  • Symptoms of Parkinson’s disease (e.g., tremors, bradykinesia, rigidity)
  • Sustained feeling of motion/restlessness
  • Uncontrollable, repetitive, stereotypical writhing movements, usually of the tongue
  • Urinary incontinence

Diagnosis and Management

Laboratory findings in NMS

The diagnosis of NMS is mainly clinical. Laboratory investigations are performed to rule out other conditions or complications.

Laboratory findings associated with NMS:

  • Leukocytosis (increased WBCs)
  • Elevated CK, due to the severe muscle rigidity
  • Elevated potassium 
  • Abnormal liver function
  • Myoglobinuria


NMS is an acute medical emergency and should be treated as such.

The 1st step should be to stop the antipsychotic agent or restart the dopamine agent.

  • Control fever:
    • Antipyretics 
    • Cooling blankets
    • Ice packs
  • Medical therapy:
    • Benzodiazepines: 1st-line for agitation and seizures
    • Dantrolene:
      • Treats muscular rigidity
      • Inhibits the ryanodine receptor
      • Prevents release of Ca2+ from the sarcoplasmic reticulum of skeletal muscle
      • Leads to muscle relaxation
    • Dopamine agonists (bromocriptine, amantadine)
  • Supportive care, such as admitting the patient to the ICU
  • Symptoms should start subsiding immediately after the discontinuation of the causative agent and resolve within 10 days.
  • Different antipsychotics can be safely re-administered in most cases after 2 weeks.

Differential Diagnosis

The most relevant differential diagnoses for NMS are serotonin syndrome and malignant hyperthermia, and it is important to distinguish between them.

  • Serotonin syndrome: characterized by fever, autonomic dysfunction, and rigidity/spasticity related to overdoses by selective serotonin reuptake inhibitors (SSRIs) or some other antidepressant. Serotonin syndrome presents with more GI symptoms (e.g., nausea, vomiting). Management is nearly the same as for NMS. 
  • Malignant hyperthermia: rare complication triggered by certain inhaled anesthetics or paralytics. Suspect in the operating room or during anesthesia procedure. Management is nearly the same as for NMS and is clinically indistinguishable except for the specific drugs that trigger the syndrome.

Other conditions that present with altered mental status, autonomic dysfunction, and fever:

  • Meningitis: infection of the meninges, the protective membranes around the brain, most often caused by Streptococcus pneumoniae or Haemophilus influenzae. Meningitis presents with fever, stiff neck, and headache. Diagnosis is by lumbar puncture for CSF evaluation. Management consists of the rapid administration of antibiotics.
  • Encephalitis: inflammation of the brain, usually caused by viral agents. Often presents as only mild flu-like signs and symptoms, such as a fever or headache, or no symptoms at all. Diagnosis is by spinal tap and brain imaging. Management consists of antiviral medications and supportive care, such as bed rest, fluid therapy, and antiinflammatory drugs.
  • Toxic encephalopathy: neurologic disorder caused by exposure to neurotoxic organic solvents, such as heavy metals, neurotoxic drugs, or cyanotoxins. The clinical presentation is varied, including altered mental status, memory loss, and visual problems. Diagnosis is made by exclusion, and management is mainly supportive. 
  • Heatstroke: elevation of core body temperature above the normal diurnal range of 36ºC–37.5ºC due to the failure of thermoregulation. Heatstroke presents as severe neurologic dysfunction, marked elevated core temperature, absent sweating, hot and flushed skin, tachycardia, hypotension, tachypnea, and nausea. Management involves volume resuscitation and rapid cooling of the patient. 
  • Status epilepticus: medical emergency characterized by a single seizure lasting > 5 minutes or ≥ 2 seizures within a 5-minute period without a return to a normal lucid state. EEG supports the diagnosis, and management includes antiseizure drugs (e.g., diazepam, lorazepam, phenytoin).
  • Thyrotoxicosis: classic physiologic manifestations of excess thyroid hormones. Thyrotoxicosis presents as signs of an increased metabolic rate and overactivity of the sympathetic nervous system. Diagnosis is made by measuring the levels of thyroid-stimulating hormone (TSH) and free thyroxine (T4) and triiodothyronine (T3). Management depends on the cause but may be pharmacologic, surgical, or with radioiodine.


  1. Berman BD. (2011). Neuroleptic malignant syndrome: a review for neurohospitalists. The Neurohospitalist 1(1):41–47.
  2. Simon LV, Hashmi MF, Callahan AL. (2020). Neuroleptic malignant syndrome. StatPearls.
  3. Wijdicks EFM. (2019). Neuroleptic malignant syndrome. UpToDate. Retrieved February 1, 2021, from

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