What are the symptoms of neuroleptic malignant syndrome?

Symptoms of Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS) is characterized by a tetrad of symptoms: hyperthermia, altered mental status, muscle rigidity, and autonomic instability. 1

Core Clinical Features

Mental Status Changes

• Altered mental status ranging from alert mutism to agitation, delirium, stupor, or coma 1
• Mental status changes are one of the earliest signs and a key diagnostic feature 1

Hyperthermia

• Fever up to 41°C (105.8°F) or higher 1
• Temperature elevations typically occur on multiple occasions 1
• Hyperthermia results from D2 receptor blockade in the hypothalamus, causing increased set point and impaired heat dissipation 1

Muscle Rigidity

• "Lead pipe" rigidity is the most common neurologic finding 1
• Other motor abnormalities may include:
  • Akinesia or bradykinesia 1, 2
  • Dyskinesia or waxy flexibility 1
  • Intermittent tremors 1
  • Involuntary movements 1

Autonomic Dysfunction

• Manifestations often appear before other symptoms and include 1:
  • Tachycardia (heart rate increase ≥25% above baseline) 1
  • Blood pressure instability (fluctuations of ≥20 mm Hg diastolic or ≥25 mm Hg systolic within 24 hours) 1
  • Diaphoresis (excessive sweating) 1
  • Pallor 1
  • Cardiac dysrhythmias 1
  • Sialorrhea (excessive salivation) 1
  • Dysphagia (difficulty swallowing) 1
  • Tachypnea (respiratory rate ≥50% above baseline) 1
  • Urinary incontinence 1

Laboratory Findings

• Elevated creatine kinase (≥4 times upper limit of normal) due to muscle breakdown 1, 3
• Leukocytosis (15,000-30,000 cells/mm³) 1
• Electrolyte abnormalities consistent with dehydration 1
• Elevated liver enzymes (alkaline phosphatase, lactic dehydrogenase, transaminases) 1
• Metabolic acidosis 1
• Myoglobinuria 3

Less Common Neurologic Signs

• Positive Babinski sign 1
• Chorea 1
• Seizures 1
• Opisthotonos (severe hyperextension and spasticity) 1
• Trismus (lockjaw) 1
• Oculogyric crisis (fixed upward gaze) 1

Important Clinical Considerations

• NMS is a clinical diagnosis without pathognomonic laboratory criteria 1
• Symptoms typically appear abruptly and can have a dramatic course 4
• Early recognition is crucial as mortality rates can reach 10-15% if not promptly treated 1, 5
• Prodromal signs may precede full syndrome, particularly worsening alterations in consciousness 4
• NMS should be considered in any patient presenting with fever and altered mental status who is taking or may have taken an antipsychotic 1
• Symptoms typically last from a few days to two weeks after neuroleptic withdrawal in cases with favorable outcomes 4

Diagnostic Criteria

According to a Delphi panel of international NMS experts, the following point system can aid diagnosis 1:

• 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)

Differential Diagnosis Considerations

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

Risk Factors

• Young adult males (2:1 male predominance) 1
• Coadministration of multiple psychotropic agents 1
• Dehydration 1
• Physical exhaustion 1
• Preexisting organic brain disease 1
• Use of long-acting depot antipsychotics 1
• Rapid dose titration of neuroleptics 4
• Abrupt discontinuation of antiparkinsonism agents 3, 2