Serotonin Syndrome
The clinical triad of autonomic instability, myoclonus, and bruxism is most consistent with serotonin syndrome, a potentially life-threatening condition caused by excessive serotonergic activity in the central nervous system. 1
Diagnosis
Use the Hunter Criteria for diagnosis, which requires the presence of a serotonergic agent plus one of the following 1:
- Spontaneous clonus
- Inducible clonus with agitation or diaphoresis
- Ocular clonus with agitation or diaphoresis
- Tremor and hyperreflexia
- Hypertonia, temperature above 38°C, and ocular or inducible clonus
Key Clinical Features
Mental status changes include agitated delirium, confusion, or altered consciousness ranging from mild confusion to coma in severe cases 1, 2.
Autonomic hyperactivity manifests as 1, 2:
- Elevated temperature (up to 41.1°C)
- Tachycardia and tachypnea
- Hypertension or blood pressure fluctuations (≥20 mm Hg diastolic or ≥25 mm Hg systolic change within 24 hours)
- Diaphoresis
- Mydriasis
- Nausea, diarrhea, flushing
Neuromuscular abnormalities include myoclonus, hyperreflexia, clonus (highly diagnostic), muscle rigidity, and tremor 1, 2. Clonus and hyperreflexia are considered highly diagnostic when occurring with serotonergic drug use 1.
Timing and Onset
Symptoms typically develop within minutes to hours (usually 6-24 hours) after starting or increasing the dose of a serotonergic medication or adding a second serotonergic agent 1.
Important Diagnostic Considerations
There are no pathognomonic laboratory or radiographic findings for serotonin syndrome 1. The diagnosis is entirely clinical based on history of serotonergic drug exposure and characteristic clinical features.
Differential Diagnosis
Distinguish from neuroleptic malignant syndrome (NMS), which presents with lead pipe rigidity (not clonus), delirium, and history of antipsychotic use rather than serotonergic agents 3. NMS shows hyperreflexia is absent, whereas serotonin syndrome characteristically shows hyperreflexia and clonus 1.
Exclude progressive encephalomyelitis with rigidity and myoclonus (PERM), which presents with muscle rigidity, stimulus-sensitive spasms, brainstem dysfunction, and is associated with glycine receptor antibodies (GlyR-Abs) 4. PERM has a more subacute course compared to the rapid onset of serotonin syndrome.
Treatment
Immediate Management
Discontinue all serotonergic agents immediately 5, 6.
For severe symptoms (hyperthermia >41.1°C, muscle rigidity, autonomic instability) 1:
- Administer cyproheptadine 12 mg orally initially
- Follow with 2 mg every 2 hours until symptom improvement
- Maintenance dose of 8 mg every 6 hours after initial control
- Pediatric dosing: 0.25 mg/kg per day
Cyproheptadine functions as a serotonin antagonist by competitively blocking serotonin at 5-HT2A receptors in the central nervous system 1.
Supportive Care
Benzodiazepines for agitation and muscle hyperactivity 1, 7.
Aggressive cooling measures for hyperthermia, noting that antipyretics are typically not efficacious as fever results from muscular hyperactivity rather than hypothalamic thermoregulation changes 1.
IV fluids for dehydration and to prevent complications from rhabdomyolysis 5.
Critical Care Considerations
For extreme cases with severe rigidity and hyperthermia 1:
- ICU admission required
- Consider intubation with paralysis using non-depolarizing agents
- Avoid succinylcholine due to risks of hyperkalemia and rhabdomyolysis
For hemodynamic instability, use direct-acting sympathomimetic amines (phenylephrine, norepinephrine) rather than indirect agents like dopamine 1.
Monitoring for Complications
Severe serotonin syndrome can cause 1:
- Rhabdomyolysis with elevated creatine kinase
- Metabolic acidosis
- Elevated serum aminotransferase
- Renal failure with elevated serum creatinine
- Seizures
- Disseminated intravascular coagulopathy
- Mortality rate approximately 11%
Clinical Pitfalls
Mild cases may be easily missed due to variable presentation 1. Patients can deteriorate rapidly, requiring close observation and preparation for rapid intervention 1.
Be aware of drug interactions: serotonin syndrome can occur with monotherapy at therapeutic doses, but more commonly results from combinations of serotonergic agents including SSRIs, tricyclic antidepressants, tryptophan, dextromethorphan, meperidine, and MAO inhibitors 2, 5.