Can unexplained fever be caused by serotonin syndrome?

Unexplained Fever Can Be Caused by Serotonin Syndrome

Yes, unexplained fever is a common manifestation of serotonin syndrome and can be a key diagnostic feature when evaluating patients with fever of unknown origin who are taking serotonergic medications. 1

Clinical Features of Serotonin Syndrome

Serotonin syndrome presents with a clinical triad of:

1. Mental status changes - confusion, agitation
2. Autonomic hyperactivity - including fever, diaphoresis, tachycardia
3. Neuromuscular abnormalities - tremor, hyperreflexia, clonus, rigidity 1

Fever is a significant component of the autonomic hyperactivity seen in serotonin syndrome. According to the Hunter criteria, which are the most sensitive (84%) and specific (97%) diagnostic criteria, a temperature above 38°C (100.4°F) is one of the key features that can help establish the diagnosis when combined with other symptoms 1, 2.

Diagnostic Criteria

The modified Dunkley criteria (Hunter criteria) state that serotonin syndrome can be diagnosed if the patient has taken a serotonergic drug within the last 5 weeks and presents with any of the following:

• Muscle rigidity, temperature >38°C, and either ocular clonus or inducible clonus
• Other combinations of symptoms including tremor, hyperreflexia, and clonus 3, 1

Common Culprits

Serotonin syndrome can be caused by a wide range of medications:

• SSRIs, SNRIs, TCAs
• MAOIs
• Opioids (particularly tramadol, meperidine)
• Over-the-counter products (dextromethorphan, St. John's wort)
• Antibiotics, antiemetics, antimigraine drugs 3, 1

Differentiating from Other Causes of Fever

When evaluating unexplained fever, it's crucial to differentiate serotonin syndrome from other conditions:

• Neuroleptic malignant syndrome (NMS): Typically has more prominent rigidity, develops more slowly (days rather than hours), and is associated with dopamine antagonists rather than serotonergic agents 1
• Infectious causes: Negative workup for infectious, toxic, metabolic, or neurologic causes supports serotonin syndrome diagnosis 3
• Malignant hyperthermia: Associated with anesthetic agents rather than psychiatric medications 1

Management of Serotonin Syndrome with Fever

1. Immediate discontinuation of all serotonergic agents - this is the most critical first step 1
2. Supportive care:
   • IV fluids for hydration
   • Benzodiazepines for agitation and muscle hyperactivity
   • External cooling measures for hyperthermia 1, 2
3. Pharmacological intervention:
   • Cyproheptadine (a serotonin antagonist) may be administered in moderate to severe cases (initial dose 12 mg orally, maximum 32 mg daily) 1, 4
4. For severe cases with high fever (>41°C):
   • Consider neuromuscular paralysis with non-depolarizing agents
   • Intubation and mechanical ventilation may be necessary 1

Prognosis and Timeline

• Fever typically takes 1-3 days to return to normal after removing the offending agent but can take up to 7 days 1
• With prompt recognition and appropriate management, most mild to moderate cases resolve within 24-72 hours 2
• The mortality rate is approximately 11% when not promptly treated, highlighting the importance of early recognition 1

Common Pitfalls

• Misdiagnosis: Serotonin syndrome is often misdiagnosed as infection, NMS, or other conditions 1
• Delayed recognition: Failure to associate fever with medication use can lead to delayed diagnosis 1
• Medication errors: Adding another serotonergic agent to treat symptoms can worsen the condition 1
• Physical restraints: Should be avoided as they may worsen hyperthermia and lactic acidosis 1

When evaluating a patient with unexplained fever, always review the medication list for serotonergic agents, especially if there are accompanying symptoms of altered mental status, autonomic instability, or neuromuscular abnormalities.