Some diagnoses may be distinguished from serotonin syndrome by the clinical features, medication usage, and time course. The many differential diagnoses to consider when diagnosing serotonin syndrome include neuroleptic malignant syndrome (NMS), malignant hyperthermia, anticholinergic toxicity, serotonergic discontinuation syndrome, sympathomimetic drug intoxication, meningitis, encephalitis, heat stroke, and central hyperthermia. Serum serotonin concentrations do not correlate with the severity of this syndrome. 3 Some nonspecific laboratory abnormalities may be seen in serotonin syndrome: leukocytosis, low bicarbonate level, elevated creatinine level, and elevated transaminases. Prominent features of life-threatening cases include hyperthermia (>38.5☌), peripheral hypertonicity, and truncal rigidity because of the high risk of progression to respiratory failure. 3 Clonus and hyperreflexia are most important for the diagnosis however, severe muscle rigidity may mask these symptoms.
The HSTC include the use of a serotonergic agent plus 1 of the 5 following criteria: spontaneous clonus, inducible clonus plus agitation or diaphoresis, ocular clonus plus agitation or diaphoresis, tremor and hyperreflexia, hypertonia and a temperature above 38☌ plus ocular or inducible clonus. When compared to the gold standard of diagnosis by a medical toxicologist, the HSTC are more sensitive (84% versus 75%) and specific (97% versus 96%) than the Sternbach criteria. The most recent diagnostic criteria are the Hunter Serotonin Toxicity Criteria (HSTC) that have replaced the older Sternbach Criteria in an attempt to simplify the diagnosis. Several diagnostic criteria have been proposed for serotonin syndrome. 5 An integral part of the physical examination for diagnosing serotonin syndrome is the neurological examination. These patients are prone to developing serotonin toxicity, suggesting that this increased toxicity could be related to a decrease in renal functioning. Also, a higher incidence of serotonin syndrome has been reported in patients with end-stage renal disease who are on selective serotonin reuptake inhibitors (SSRIs) and hemodialysis. Certain comorbidities, such as depression and chronic pain, may alert the clinician to the use of drugs that can precipitate serotonin syndrome.
The onset and description of symptoms and the presence of any comorbidities are of utmost importance. Important components of the history include prescription drug use, over-the-counter medication and dietary supplement use, illicit substance use, any recent changes in dosing, or the addition of new drugs to a drug regimen. Therefore, a diagnosis of serotonin syndrome is entirely clinical and is based on the history and physical examination along with history of the patient's use of a serotonergic drug. 3 In a clinical setting, however, the suspicion of serotonin syndrome and diagnosis must occur rapidly so treatment can prevent the morbidity and mortality associated with this condition. 2, 4 The diagnostic gold standard for serotonin syndrome is diagnosis by a medical toxicologist. No single diagnostic test can confirm this syndrome. Serotonin syndrome is a diagnosis of exclusion. 1, 2 The symptoms of hyperreflexia, rigidity, and clonus tend to be more prominent in the lower extremities. Severe cases may result in complications, such as seizures, rhabdomyolysis, myoglobinuria, metabolic acidosis, renal failure, acute respiratory distress syndrome, respiratory failure, diffuse intravascular clotting, coma, and death. In severe cases, patients have all of the above symptoms plus hyperthermia greater than 41.1☌, dramatic swings in pulse rate and blood pressure, delirium, and muscle rigidity. Patients with a moderate syndrome usually have the above symptoms plus hyperthermia (40☌), hyperactive bowel sounds, horizontal ocular clonus, mild agitation, hypervigilance, and pressured speech. Patients with a mild syndrome are usually afebrile. In mild cases, the predominating features are mild hypertension and tachycardia, mydriasis, diaphoresis, shivering, tremor, myoclonus, and hyperreflexia. Patients will present with a triad of symptoms that range in severity ( Table 1). Most patients will seek help at a hospital within 6 hours however, patients with mild symptoms may have a more subacute or chronic presentation, as in the case by Houlihan.
3 Symptoms usually begin within 24 hours of an increased dose of a serotonergic agent, the addition of another serotonergic agent to a drug regimen, or overdosing. Many reports prefer to call this serotonin toxicity rather than syndrome due to its wide range of symptoms and toxicity. The presentation of serotonin syndrome is extremely variable, ranging from mild symptoms to a life-threatening syndrome.