Neuroleptic malignant syndrome

Overview

Neuroleptic Malignant Syndrome (NMS) is a rare but potentially life-threatening neurological emergency associated with the use of antipsychotic (neuroleptic) medications. It is characterized by a combination of hyperthermia (elevated body temperature), severe muscle rigidity, altered mental status, and autonomic dysfunction (such as blood pressure fluctuations and rapid heart rate). NMS typically develops over a period of hours to days and requires immediate medical intervention to prevent serious complications or death.

Although rare, with an estimated incidence of 0.01% to 0.02% in patients taking neuroleptic drugs, NMS can occur with both typical (first-generation) and atypical (second-generation) antipsychotics. It can also occur with sudden withdrawal of dopaminergic medications in conditions like Parkinson’s disease. Early recognition and prompt treatment are critical to improving outcomes.

Causes

Neuroleptic Malignant Syndrome is most commonly triggered by the use of medications that block dopamine receptors in the brain, particularly D2 receptors. The exact mechanism is not completely understood, but the disorder is thought to result from a sudden, severe reduction in central dopamine activity, which disrupts thermoregulation and muscle control.

Common Causes and Risk Factors

• Antipsychotic medications: Especially high-potency typical antipsychotics like haloperidol, fluphenazine, and chlorpromazine

• Atypical antipsychotics: Such as risperidone, olanzapine, and clozapine (though less common)

• Withdrawal of dopaminergic drugs: Especially in Parkinson’s disease (e.g., levodopa, dopamine agonists)

• Rapid dose escalation or high doses: Sudden increases in medication dosage may elevate risk

• Dehydration and agitation: May predispose patients to NMS

• Concomitant use of lithium or antidepressants: May increase the risk when used with neuroleptics

Symptoms

Symptoms of NMS typically develop within the first two weeks of starting or increasing the dose of an antipsychotic medication, but can occur at any time. The classic tetrad of NMS symptoms includes:

1. Hyperthermia

• High fever, often > 38.5°C (101.3°F), and sometimes > 40°C (104°F)

• Fever is often one of the earliest and most prominent signs

2. Muscle Rigidity

• “Lead-pipe” rigidity throughout the body

• Resistance to passive movement and joint stiffness

3. Altered Mental Status

• Agitation, confusion, delirium, stupor, or coma

• Fluctuations in consciousness may occur

4. Autonomic Dysfunction

• Elevated or labile blood pressure

• Tachycardia (rapid heart rate)

• Tachypnea (rapid breathing)

• Excessive sweating (diaphoresis)

• Urinary incontinence or retention

Laboratory Findings

• Elevated creatine kinase (CK), often > 1000 IU/L, due to muscle breakdown (rhabdomyolysis)

• Leukocytosis (increased white blood cells)

• Elevated liver enzymes and myoglobinuria (may lead to acute kidney injury)

• Metabolic acidosis and electrolyte imbalances

Diagnosis

There is no single test to definitively diagnose Neuroleptic Malignant Syndrome. Diagnosis is clinical and based on recognition of the characteristic signs and symptoms in a patient who is taking or has recently taken dopamine antagonists or discontinued dopaminergic drugs.

Diagnostic Criteria (Modified Levenson Criteria)

Diagnosis is supported by:

• Exposure to a dopamine antagonist or withdrawal from a dopaminergic drug

• Hyperthermia

• Muscle rigidity

• Elevated creatine kinase levels

• Autonomic instability and mental status changes

Additional Diagnostic Tools

• Blood tests: CK, WBC count, renal function, liver enzymes, electrolytes

• Urinalysis: Detects myoglobinuria due to rhabdomyolysis

• Neuroimaging or lumbar puncture: To rule out other causes of encephalopathy or fever (e.g., meningitis, stroke)

Treatment

NMS is a medical emergency requiring immediate discontinuation of the offending drug and initiation of supportive care. Hospitalization, often in an intensive care unit (ICU), is usually necessary.

Supportive Care

• Discontinuation of causative agent: Immediate cessation of neuroleptic or withdrawal of dopamine agonist

• Hydration: IV fluids to prevent kidney damage from rhabdomyolysis

• Cooling measures: Antipyretics, cooling blankets, ice packs for hyperthermia

• Monitoring: Vital signs, electrolyte balance, renal and liver function

Pharmacologic Treatment

• Dantrolene: A muscle relaxant that reduces rigidity and heat production

• Bromocriptine or Amantadine: Dopamine agonists that may help restore dopamine activity

• Benzodiazepines: For sedation and muscle relaxation

Other Interventions

• Dialysis or hemofiltration: In cases of acute renal failure due to rhabdomyolysis

• Mechanical ventilation: For respiratory distress or altered mental status

Prognosis

With prompt recognition and treatment, the prognosis of Neuroleptic Malignant Syndrome can be favorable. Most patients begin to improve within 24–72 hours of treatment initiation, although full recovery may take days to weeks. Without treatment, the condition can lead to serious complications such as:

• Rhabdomyolysis and acute kidney failure

• Respiratory failure

• Sepsis or disseminated intravascular coagulation (DIC)

• Cardiac arrhythmias and sudden death

The mortality rate for untreated NMS ranges from 10–20%, but with modern medical interventions, it has decreased significantly. Long-term outcomes are generally good if the condition is managed early. However, reintroduction of antipsychotics should be done cautiously, ideally with different agents at the lowest effective dose, and under close supervision.

Education and awareness among healthcare professionals and patients are crucial in preventing recurrence and managing risk factors associated with NMS.