What are the features of Neuroleptic Malignant Syndrome (NMS)?

Features of Neuroleptic Malignant Syndrome (NMS)

Neuroleptic Malignant Syndrome is characterized by four hallmark features: hyperthermia, altered mental status, muscle rigidity, and autonomic instability, which can be life-threatening if not promptly recognized and treated. 1

Core Clinical Manifestations

Tetrad of Cardinal Features

• Hyperthermia

  • Fever up to 41°C (105.8°F) or higher
  • May be absent in rare cases 2

• Altered Mental Status

  • Ranges from alert mutism to agitation, delirium, stupor, or coma
  • Often one of the earliest manifestations 3

• Muscle Rigidity

  • "Lead pipe" rigidity is most common
  • May also present as akinesia, dyskinesia, or waxy flexibility
  • Typically appears early in the syndrome progression 3

• Autonomic Instability

  • Tachycardia
  • Blood pressure fluctuations (≥20 mmHg diastolic or ≥25 mmHg systolic within 24 hours)
  • Diaphoresis
  • Pallor
  • Cardiac dysrhythmias
  • Sialorrhea (excessive salivation)
  • Dysphagia
  • May precede other symptoms 1

Additional Neurological Manifestations

• Tremors
• Involuntary movements
• Positive Babinski sign
• Chorea
• Seizures
• Opisthotonos
• Trismus
• Oculogyric crisis 1

Laboratory Findings

• Elevated Creatine Kinase (CK)

  • ≥4 times upper limit of normal
  • Indicates muscle breakdown

• Leukocytosis

  • Typically 15,000-30,000 cells/mm³

• Other Abnormalities

  • Electrolyte disturbances consistent with dehydration
  • Elevated liver enzymes (alkaline phosphatase, LDH, transaminases)
  • Metabolic acidosis
  • Myoglobinuria 1

Diagnostic Criteria

According to a Delphi panel of international NMS experts, the following point system can aid diagnosis:

• Exposure to dopamine antagonist or withdrawal of dopamine agonist within 3 days (20 points)
• Hyperthermia >100.4°F on ≥2 occasions (18 points)
• Rigidity (17 points)
• Mental status alteration (13 points)
• Creatine kinase elevation ≥4 times upper limit of normal (10 points)
• Sympathetic nervous system lability (10 points)
• Hypermetabolism (5 points)
• Negative workup for infectious, toxic, metabolic, or neurologic causes (7 points) 1

Temporal Progression

Research indicates a common progression pattern in 70.5% of cases:

1. Mental status changes or muscle rigidity (initial manifestations in 82.3% of cases)
2. Hyperthermia
3. Autonomic dysfunction 3

Risk Factors

• Patient Factors

  • Young adults
  • Male gender (2:1 male-to-female ratio)
  • Dehydration
  • Physical exhaustion
  • Preexisting organic brain disease 1

• Medication Factors

  • Concomitant use of multiple psychotropic agents
  • Use of long-acting depot antipsychotics
  • Abrupt discontinuation of dopaminergic agents 4
  • Can occur with both typical and atypical antipsychotics
  • Has been reported with non-antipsychotic medications with dopamine-blocking properties (e.g., metoclopramide) 5

Differential Diagnosis

NMS must be distinguished from other conditions with similar presentations:

• Serotonin syndrome
• Malignant hyperthermia
• Lethal catatonia
• Central nervous system infections
• Heat stroke
• Toxic encephalopathy 1, 6

Clinical Pearls and Pitfalls

• Atypical Presentations: NMS can present without all cardinal features; cases without fever have been reported 2
• Early Recognition: Mental status changes and rigidity often appear first and should prompt consideration of NMS in patients on antipsychotics 3
• Medication History: Essential to identify exposure to dopamine antagonists or withdrawal of dopamine agonists 1
• Mortality Risk: While mortality has decreased from 76% in the 1960s to <15% currently, NMS remains a medical emergency 1
• Recurrence Risk: Patients with a history of NMS are at increased risk for recurrence, though reintroducing the original precipitating drug may not always trigger NMS 1, 6

Early recognition of NMS is crucial for improving outcomes, as prompt discontinuation of the offending agent and supportive care can significantly reduce morbidity and mortality associated with this potentially life-threatening condition.