What are the clinical features of serotonin syndrome?

Clinical Features of Serotonin Syndrome

Serotonin syndrome presents with a characteristic clinical triad: mental status changes, autonomic hyperactivity, and neuromuscular abnormalities that develop within 6-24 hours of starting, increasing, or combining serotonergic medications. 1

Mental Status Changes

The neuropsychiatric manifestations range from mild to severe:

• Agitated delirium is the most common mental status presentation 1
• Confusion occurs frequently and may progress to altered consciousness 1
• Severe cases can deteriorate to coma, particularly when hyperthermia exceeds 41.1°C 1
• Mental status changes typically appear within the first 24-48 hours after medication initiation or dose escalation 1, 2

Neuromuscular Abnormalities (Most Diagnostic Features)

The neuromuscular findings are the most specific for diagnosis:

• Clonus and hyperreflexia are considered highly diagnostic when occurring with serotonergic drug use 1, 2
• Myoclonus (muscle twitching) occurs in 57% of cases and is the most common finding 3
• Spontaneous clonus, inducible clonus, or ocular clonus are key diagnostic features in the Hunter Criteria 1, 2
• Tremor frequently accompanies hyperreflexia 1
• Muscle rigidity develops in moderate to severe cases, particularly in the lower extremities 1, 3
• Hyperreflexia is characteristically present (distinguishing it from neuroleptic malignant syndrome where reflexes are normal or decreased) 1

Autonomic Hyperactivity

The autonomic manifestations reflect excessive sympathetic activity:

• Hyperthermia can reach 41.1°C in severe cases 1
• Tachycardia and tachypnea are common autonomic signs 1
• Hypertension or blood pressure fluctuations (≥20 mm Hg diastolic or ≥25 mm Hg systolic change within 24 hours) 1
• Profuse diaphoresis (sweating) is a hallmark feature 1, 3
• Mydriasis (dilated pupils) occurs with autonomic hyperactivity 1
• Shivering may accompany the fever 3
• Gastrointestinal symptoms including vomiting and diarrhea can occur 3

Severity Spectrum

Mild Cases

• Present with tremor, mild hyperreflexia, diaphoresis, and mild agitation 2
• May be easily missed due to variable presentation 1

Moderate Cases

• Include more pronounced neuromuscular findings with clonus, marked hyperreflexia, and autonomic instability 2
• Require hospitalization with continuous cardiac monitoring 2

Severe Cases (Medical Emergency)

• Rapid onset of severe hyperthermia (>41.1°C) 1
• Severe muscle rigidity 1
• Multiple organ failure including rhabdomyolysis, metabolic acidosis, renal failure, seizures, and disseminated intravascular coagulopathy 1
• Mortality rate approximately 11% 1, 2
• 25% of patients require intubation and ICU admission 2

Temporal Pattern

• Symptoms typically develop within minutes to hours, usually 6-24 hours after starting or increasing a serotonergic medication 1, 2
• The condition is non-idiosyncratic, meaning it can occur with addition of a new drug, increased dosage, or addition of a second serotonergic agent 1
• The first 24-48 hours represent the highest-risk period requiring vigilant monitoring 3

Diagnostic Considerations

Hunter Criteria (Preferred Diagnostic Tool)

The Hunter Criteria have 84% sensitivity and 97% specificity and require a serotonergic agent plus one of the following: 2

• Spontaneous clonus
• Inducible clonus with agitation or diaphoresis
• Ocular clonus with agitation or diaphoresis
• Tremor and hyperreflexia
• Hypertonia with temperature >38°C and ocular or inducible clonus

Key Pitfall

There are no pathognomonic laboratory or radiographic findings for serotonin syndrome—diagnosis is purely clinical 1

Critical Differential Diagnosis

Distinguish from neuroleptic malignant syndrome (NMS), which presents with lead pipe rigidity, normal or decreased reflexes, and history of antipsychotic use rather than serotonergic agents 1