Case: You are seeing a 51 year old female patient transferred to your emergency department from a community hospital with a diagnosis of cerebrovascular accident (CVA) with left-sided weakness. Per the community hospital, the weakness apparently began upon awakening this morning, however you are unable to verify this with the patient because she is so sleepy. The transferring hospital mentioned in their history and physical exam that the patient was a little drowsy, however now she is more sleepy and confused, and you notice that her extremities, particularly her upper extremities, are rigid and her reflexes are brisk. At this point she is tachycardic with a heart rate of 114, afebrile, and all other vital signs are within normal limits. The transferring hospital sent some lab and imaging results, including a complete blood count that is normal except for a white blood cell count of 18.2, a complete metabolic panel that is within normal limits, CPK that is elevated at 490, troponin within normal limits, CK-MB elevated at 19.8, AST and ALT that are both elevated at 460 and 323, respectively, and a head CT that was read as negative. There are no signs of trauma. The patient’s past medical history is significant for depression, for which she is on Celexa (citalopram) and Cymbalta (duloxetine). This could be a routine case of CVA, but is there anything else that you should be considering?

When receiving a patient transferred from another facility, it is important to always perform a complete history and physical exam and to review the tests that were ordered at the transferring facility. Keep an open differential diagnosis, because there is no guarantee that the transferring facility has made the correct diagnosis, as was the case with this patient: the patient was not suffering from a stroke, she was suffering from serotonin syndrome. Serotonin syndrome results from an acute hyperserotonergic state with overstimulation of the 5-HT1A receptors in central grey nuclei and the medulla. It commonly occurs when more than one serotonergic medication has been ingested, and symptoms generally occur within minutes to a few hours. Medications implicated include selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), or other serotonergic agents. Cases of mild serotonin syndrome have been reported in patients who have taken St. John’s wort with SSRIs.

There is no lab test to diagnose serotonin syndrome so suspicion must be high and the physical exam must be thorough. Additionally,other toxidromes must be excluded before a diagnosis of serotonin syndrome can be made. The most common signs and symptoms of serotonin syndrome include myoclonus (57%), hyperreflexia (55%), confusion/disorientation (54%), muscle rigidity (49%), tremor (49%), hyperthermia (46%), and diaphoresis (46%). On lab evaluation, an increase in total CK due to rhabdomyolysis, and an elevation in white blood cell count and transaminases are all possible, as is a decrease in bicarbonate. Diagnostic criteria for serotonin syndrome have been developed (see Box 1).

Diagnoses to keep in the differential when evaluating a patient who may have serotonin syndrome include neuroleptic malignant syndrome, infection, herpetic encephalopathy, heat stroke, myocardial necrosis, delirium tremens, and intoxication by adrenergic or anticholinergic agents. Serotonin syndrome can be difficult to distinguish from neuroleptic malignant syndrome (NMS), however the clinician must determine which entity the patient is suffering from as the treatments and prognosis differ. NMS is most frequently observed when there is a rapid increase in dosage of a neuroleptic medication, so a careful medication history should be obtained; this may be all that is required to distinguish serotonin syndrome from NMS. In our patient, NMS could be ruled out by lack of neuroleptic drug use alone. Signs and symptoms of NMS include alteration in the patient’s level of consciousness, diaphoresis, autonomic instability, and hyperthermia. Signs and symptoms that may help distinguish NMS from serotonin syndrome include the “lead pipe” rigidity, dysphagia, hypersalivation, and incontinence that are seen with NMS versus the agitation, diarrhea, dilated pupils and hyperreflexia seen in serontonin syndrome. Hyperthermia is more common in NMS than serotonin syndrome. Creatine kinase may be elevated in both. Unlike serotonin syndrome, which typically occurs within minutes to hours of medication ingestion, NMS symptoms typically occur within 7 days of medication ingestion, although greater than 7 days is possible. Mortality from NMS is 15-20% whereas it is extremely rare in serotonin syndrome.

Once a diagnosis of serotonin syndrome has been made, the first step in management is discontinuation of the offending serotonergic agents. Supportive management is the mainstay of therapy, including intravenous fluids to maintain a diuresis of 50-100 cc/hr as this reduces this risk of myoglobinuria from rhabdomyolysis. Severe cases are rare however if they occur, the patient may need to be intubated for airway protection, cooled if hyperthermic, given anticonvulsives if seizing, or given antihypertensives if severely hypertensive. Benzodiazepines may be used for muscle rigidity and should be titrated to response. The role of antiserotonergic agents is not clearly defined, and many toxicologists recommend only supportive care and benzodiazepines; serotonin syndrome will resolve in 24 - 48 hours with this alone. The most commonly mentioned antiserotonergics are cyproheptadine and chlorpromazine. Cyproheptadine antagonizes the histamine-1 receptor, causing antiserotonergic and anticholinergic effects; its major adverse effect is drowsiness. Chlorpromazine antagonizes the 5-HT1A and the 5-HT 2 receptors. Adverse effects of chlorpromazine include hypotension, dystonias or neuroleptic malignant syndrome; because of these more serious adverse effects, cyproheptadine is preferred for the treatment of serotonin syndrome if one chooses to use an antiserotonergic agent. If cyproheptadine is given, the dose is 4 to 8 mg po; this can be repeated in 2 hours if there is no response to the initial dose. If the patient responds to cyproheptadine, they should be given 4 mg every 6 hours for 48 hours; if they do not respond, discontinue the cyproheptadine after 16 mg. Antipsychotics, particularly ziprasidone, are also powerful blockers of the 5-HT1A receptors and may play a role in the treatment of serotonin syndrome in the future; more research is necessary before their use can be recommended.

All patients with serotonin syndrome should be admitted to the hospital, at least for observation. Intubated or unstable patients may require intensive care unit monitoring. Most patients will improve completely within 24 hours of admission, however symptoms may last up to 48 hours. The duration of symptoms appears to be related to the half-life of the drug.

This case provides several important learning points. First, remember that transferring facilities may not always make the correct diagnosis; keep an open differential and examine the patient with an open mind. Next, always take a careful history and physical exam, including an accurate medication list; this may help greatly in making a diagnosis. Finally, serotonin syndrome requires a high level of suspicion and a thorough physical exam, so be sure to keep this diagnosis in mind in a patient taking a serotonergic agent presenting with any symptom consistent with serotonin syndrome.

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