Can Serotonin Syndrome Occur Without Fever or Hyperthermia?
Yes, serotonin syndrome can absolutely occur without fever or hyperthermia, and this is particularly important to recognize in elderly patients on quetiapine, as the presentation can be highly variable and mild cases are easily missed.
Clinical Presentation Variability
The presentation of serotonin syndrome is extremely variable, and mild cases may be easily missed 1. While the classic teaching emphasizes hyperthermia as part of the syndrome, fever is not required for diagnosis and focusing solely on temperature can lead to dangerous delays in recognition.
The Clinical Triad Does Not Mandate Fever
Serotonin syndrome is characterized by a clinical triad of:
- Mental status changes (confusion, agitation, delirium) 1, 2
- Neuromuscular abnormalities (clonus, hyperreflexia, myoclonus, tremor, muscle rigidity) 1, 2
- Autonomic hyperactivity (which can include elevated temperature, but also tachycardia, hypertension, diaphoresis, mydriasis) 1
Importantly, autonomic hyperactivity can manifest without hyperthermia - patients may present with blood pressure fluctuations, tachycardia, or diaphoresis alone 1.
Diagnostic Criteria and Temperature Requirements
Hunter Criteria (Preferred)
The Hunter Criteria, which have higher sensitivity (84%) and specificity (97%) than older criteria 3, require a serotonergic agent plus one of the following 1, 3:
- Spontaneous clonus
- Inducible clonus with agitation or diaphoresis
- Ocular clonus with agitation or diaphoresis
- Tremor and hyperreflexia
- Hypertonia, temperature >38°C, and ocular or inducible clonus
Note that only the last criterion requires fever - the first four diagnostic pathways do not require any temperature elevation whatsoever 1, 3.
Modified Dunkley Criteria
Similarly, the modified Dunkley criteria allow diagnosis with tremor and hyperreflexia, spontaneous clonus, or muscle rigidity - none of which require fever 1.
Evidence of Atypical Temperature Presentations
Case Evidence
- A 70-year-old woman developed serotonin syndrome from paroxetine and quetiapine with fever initially, but the case emphasizes that diagnosis requires high clinical suspicion and can occur without medication changes 4
- A case report documented hypothermia (not hyperthermia) as a presenting symptom of serotonin syndrome, with complete resolution after discontinuing fluoxetine and trazodone 5
- This hypothermia case highlights critical gaps in current diagnostic criteria, which all list fever but not hypothermia, despite both being possible manifestations of dysregulated thermoregulation 5
Key Diagnostic Features (Temperature-Independent)
Clonus and hyperreflexia are considered highly diagnostic for serotonin syndrome when occurring with serotonergic drug use 1, 3, 2. These neuromuscular findings are far more specific than temperature changes and should be actively sought in any patient on serotonergic agents presenting with altered mental status.
What to Look For in Your Elderly Patient on Quetiapine:
- Inducible clonus (rapid rhythmic muscle contractions when passively stretching the muscle) - most specific finding 1, 6
- Hyperreflexia (exaggerated deep tendon reflexes) 1, 2
- Myoclonus (present in 57% of cases) 2
- Tremor 1, 6
- Confusion or agitated delirium 1
- Diaphoresis 1, 6
- Tachycardia or blood pressure fluctuations (≥20 mm Hg diastolic or ≥25 mm Hg systolic change within 24 hours) 1
Severity Spectrum Without Fever
Serotonin toxicity exists on a spectrum 6:
- Mild: Serotonergic features causing concern but not distress - may have no fever 6, 7
- Moderate: Significant distress requiring treatment - may or may not have fever 6, 7
- Severe: Medical emergency with rapid onset of severe hyperthermia (>41.1°C), muscle rigidity, and multiple organ failure 1, 2
Only severe cases consistently demonstrate hyperthermia 1. Mild to moderate cases frequently present without significant temperature elevation 6, 7.
Critical Pitfall to Avoid
Do not wait for fever to diagnose serotonin syndrome. The condition can deteriorate rapidly, and the mortality rate is approximately 11% 1, 3, 2. Symptoms typically develop within 6-24 hours of medication changes, but can occur without any dosage adjustments in susceptible individuals 1, 4, 7.
Management Regardless of Temperature
If serotonin syndrome is suspected based on neuromuscular and mental status findings:
- Immediately discontinue all serotonergic agents (including quetiapine if implicated) 3, 2
- Administer benzodiazepines as first-line treatment for agitation and neuromuscular symptoms 3, 2
- Provide IV fluids for autonomic instability 3, 2
- Consider cyproheptadine (12 mg initially, then 2 mg every 2 hours) for moderate to severe cases 1, 3
- Avoid physical restraints as they worsen muscle rigidity and can precipitate complications even without hyperthermia 3, 2