What is the workup for serotonin syndrome?

Workup for Serotonin Syndrome

The diagnosis of serotonin syndrome should be confirmed using the Hunter criteria, which have superior sensitivity (84%) and specificity (97%) compared to other diagnostic criteria, requiring a patient to have taken a serotonergic drug within the past 5 weeks and presenting with specific symptoms such as tremor and hyperreflexia, spontaneous clonus, or muscle rigidity with temperature >38°C. 1

Diagnostic Criteria (Hunter Criteria)

A patient must have taken a serotonergic agent within the past 5 weeks AND have one or more of the following:

• Spontaneous clonus
• Inducible clonus PLUS agitation or diaphoresis
• Ocular clonus PLUS agitation or diaphoresis
• Tremor AND hyperreflexia
• Hypertonia AND temperature >38°C AND ocular or inducible clonus 1, 2

Clinical Assessment

1. History

• Medication review (focus on serotonergic agents):
  • SSRIs, SNRIs, TCAs, MAOIs
  • Opioids (particularly tramadol)
  • Over-the-counter medications (dextromethorphan)
  • Supplements (St. John's wort) 1, 3
• Timing of medication changes or additions
• Recent dose increases
• Intentional overdose possibility

2. Physical Examination

Look for the clinical triad:

• Mental status changes:

  • Agitation, confusion, delirium, coma 4

• Neuromuscular abnormalities:

  • Tremor, hyperreflexia, clonus (spontaneous, inducible, ocular)
  • Muscle rigidity, myoclonus
  • Ataxia 1, 4

• Autonomic hyperactivity:

  • Hyperthermia (temperature >38°C)
  • Tachycardia, hypertension (or hypotension)
  • Diaphoresis, flushing
  • Mydriasis
  • Diarrhea 4, 3

Laboratory and Diagnostic Tests

• Complete blood count
• Comprehensive metabolic panel
• Creatine kinase (to assess for rhabdomyolysis)
• Coagulation studies
• Urinalysis
• Urine and serum toxicology screens
• Arterial blood gas (in severe cases)
• Electrocardiogram 1, 5

Differential Diagnosis

Rule out other conditions with similar presentations:

• Neuroleptic malignant syndrome
• Malignant hyperthermia
• Anticholinergic toxicity
• Sympathomimetic toxicity
• Sepsis
• Decompensated hyperthyroidism
• Central nervous system infection 4

Severity Assessment

Categorize severity to guide management:

• Mild: Mild hypertension and tachycardia, mydriasis, diaphoresis, shivering, tremor, myoclonus, hyperreflexia
• Moderate: Hyperthermia (40°C), hyperactive bowel sounds, ocular clonus, agitation, hypervigilance
• Severe: Hyperthermia (>41.1°C), delirium, muscle rigidity, substantial hypertension, respiratory failure 1, 5

Common Pitfalls and Caveats

• Serotonin syndrome is frequently misdiagnosed due to its nonspecific symptoms 4
• Not all three components of the clinical triad may be present simultaneously 5
• Physical restraints should be avoided as they may worsen hyperthermia and lactic acidosis 1
• Diphenhydramine should not be used as a substitute for cyproheptadine in treatment 1
• The mortality rate is approximately 11% when not promptly treated, highlighting the importance of rapid diagnosis 1
• Almost all fatalities involving SSRIs have involved co-ingestion of other substances 1

Remember that serotonin syndrome is not an idiosyncratic drug reaction but a predictable and preventable adverse pharmacological effect, making early recognition crucial for favorable outcomes 5.