Serotonin Syndrome: Clinical Features and Diagnosis
Clinical Presentation
Serotonin syndrome is diagnosed by recognizing the clinical triad of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities occurring after exposure to serotonergic medications. 1
Mental Status Changes
- Agitated delirium is the most common presentation 1
- Confusion ranging from mild to severe 1
- Altered consciousness that can progress to coma in severe cases 1
Autonomic Hyperactivity
- Hyperthermia (temperature up to 41.1°C or 106°F) 1
- Tachycardia and tachypnea 1
- Hypertension or blood pressure fluctuations (≥20 mm Hg diastolic or ≥25 mm Hg systolic change within 24 hours) 1
- Profuse diaphoresis 1
- Mydriasis (dilated pupils) 1
Neuromuscular Abnormalities
- Clonus (spontaneous, inducible, or ocular) - the most diagnostic feature 1, 2
- Hyperreflexia - highly diagnostic when present with serotonergic drug use 1, 2
- Myoclonus (present in 57% of cases) 2
- Muscle rigidity 1
- Tremor 1
Diagnostic Criteria
Use the Hunter Criteria for diagnosis, which have 84% sensitivity and 97% specificity, superior to older diagnostic tools. 1
Hunter Criteria Requirements
The patient must have taken a serotonergic agent PLUS one of the following: 1, 2, 3
- Spontaneous clonus (anywhere in the body)
- Inducible clonus PLUS agitation OR diaphoresis
- Ocular clonus PLUS agitation OR diaphoresis
- Tremor AND hyperreflexia together
- Hypertonia PLUS temperature >38°C (100.4°F) PLUS ocular or inducible clonus
Modified Dunkley Criteria (Alternative)
Requires serotonergic drug use within the last 5 weeks PLUS any of: 1
- Tremor and hyperreflexia
- Spontaneous clonus
- Muscle rigidity, temperature >38°C, and either ocular clonus or inducible clonus
- Ocular clonus and either agitation or diaphoresis
Timing and Onset
Symptoms typically develop within 6-24 hours (though can occur within minutes to hours) after starting a serotonergic medication, increasing the dose, or adding a second serotonergic agent. 1, 2, 3
Severity Classification
Mild Serotonin Syndrome
Moderate Serotonin Syndrome
Severe Serotonin Syndrome (Medical Emergency)
- Rapid onset of severe hyperthermia (>41.1°C) 1
- Severe muscle rigidity 1
- Multiple organ failure 1
- Mortality rate approximately 11% 1, 2, 3
- 25% of patients require intubation and ICU admission 2, 3
Key Diagnostic Considerations
No Pathognomonic Laboratory Findings
There are no specific laboratory or radiographic tests that confirm serotonin syndrome - diagnosis is purely clinical. 1
Physical Examination Pearls
- Clonus and hyperreflexia are the most diagnostic physical findings when occurring with serotonergic drug exposure 1, 2, 3
- Check for inducible clonus by rapidly dorsiflexing the foot 5
- Assess for ocular clonus (spontaneous horizontal eye movements) 1
- Reflexes are characteristically hyperreflexic (often with clonus) 1
Critical Differential Diagnosis
Neuroleptic Malignant Syndrome (NMS)
Key distinguishing features: 1, 3
- NMS presents with "lead pipe" rigidity (vs. hyperreflexia/clonus in serotonin syndrome)
- NMS has normal or decreased reflexes (vs. hyperreflexia in serotonin syndrome) 1
- NMS follows antipsychotic use (vs. serotonergic agents)
- NMS has delirium without the prominent neuromuscular hyperactivity
Other Conditions to Exclude
- Progressive encephalomyelitis with rigidity and myoclonus (PERM) - has more subacute course and glycine receptor antibodies 1
- Malignant hyperthermia 2, 3
- Anticholinergic syndrome 2, 3
- Withdrawal syndromes 2, 3
- Sepsis 6
- Decompensated hyperthyroidism 6
Common Pitfalls
The presentation is extremely variable, and mild cases are easily missed. 1 Clinicians must maintain high suspicion in any patient taking serotonergic medications who develops the triad of symptoms, even if subtle. 7
Serotonin syndrome is non-idiosyncratic - it can occur with addition of a new drug, increased dosage, or combining serotonergic agents, not just overdoses. 1, 2