Authors: Sanjay Prakash, Chetsi Shah
Categories: Letters to the Editor
Source: Annals of Indian Academy of Neurology
Dear Editor,
Serotonin syndrome (SS) is a drug-induced clinical syndrome caused by excess intrasynaptic serotonin.[1] We describe a case where we treated the patient as SS, even though we were unable to obtain a history of serotonergic agent ingestion.
A 34-year-old man was brought to the emergency with a 4-day history of fever and abnormal behavior in the form of irritability, easily being annoyed, and restlessness. On arrival, the patient had fever (101.3°F), tachycardia (118 beats/minute), and hypertension (168/98 mmHg). He had no past history of any significant illnesses, including hypertension. A syndromic diagnosis of febrile encephalopathy was made, and tests were performed to determine the cause. The initial workup, which included biochemical parameters, a cerebrospinal fluid (CSF) test, and brain magnetic resonance imaging, was normal. Serological tests for human immunodeficiency virus, hepatitis B virus, dengue virus, Salmonella typhi, malaria parasite, and Mycobacterium tuberculosis were negative. Biomarkers for autoimmune encephalitis were negative. CSF examinations revealed the 2 cells/µL, protein 40 mg/dL, glucose 82 mg/dL, and CSF/serum glucose ratio of 0.78. No growth was identified in blood and urine cultures. The initial creatine phosphokinase level was raised (546 IU/L) (normal 40–160 IU/L).
Initially, he received antibiotics (ceftriaxone), atenolol, pantoprazole, and clonazepam. However, the patient did not improve and he gradually became drowsy and less communicative. In addition, he started experiencing myoclonus, tremulousness, and limb incoordination. At this point, a neurology consultation was requested. We noted fever (102.8°F), hypertension (154/96 mmHg), diaphoresis, and hyperactive bowel sound. A motor examination showed incoordination, generalized hyperreflexia, ankle clonus, rigidity in the limbs, tremors, myoclonus, and mydriasis. The clinical picture was consistent with the description of SS. We checked to see if the patient had recently used serotonergic medicines. However, the patient and his family denied using any drugs before the current condition started. With the exception of recent serotonergic medication usage, the patient satisfied both the Hunter and Sternbach criteria for SS. Since SS is a potentially fatal syndrome and there was no other better diagnosis, a 12 mg loading dose of cyproheptadine was administered. Then, 2 mg of cyproheptadine was administered every 2 h. His symptoms began to improve within 14–16 h of initiating cyproheptadine; the level of consciousness improved, and speech became comprehensible. The fever decreased to 100.0°F in 12 h. Blood pressure (128/86 mmHg) and fever (98.4°F) progressively returned to normal in 24 h. Diaphoresis, tremors, incoordination, rigidity, clonus, myoclonus, and bowel sounds all decreased substantially over 20–24 h. After 24 h, the dosage of cyproheptadine was lowered to 6 mg eight hourly. Unfortunately, the symptoms worsened or returned 16–20 h after reducing the dose. The temperature increased to 100.2°F. In addition, the blood pressure increased to 148/92 mmHg; there was an increase in incoordination, clonus, diaphoresis, and tremors. Cyproheptadine was reintroduced in the same regimen as before (12 mg loading dose followed by 2 mg every 2 h). Again, the symptoms began to improve within 12 h. Most of the symptoms subsided within 48 h. There was no fever, diaphoresis, hypertension, tremors, incoordination, clonus, and rigidity. The dosage of cyproheptadine was rescheduled to 8 mg four times a day after 48 h. This dosage was continued for 7 days. When he returned to normalcy, we asked him again if he had taken any medicines in the past few weeks. However, he strongly denied using any medications in the previous 4 months. No symptoms reappeared over the course of the 9-month follow-up.
According to the diagnosis and treatment algorithm for SS, there will be no SS if there is no history of serotonergic agent ingestion.[2,3] However, getting a history of serotonergic drug administration may be challenging for several reasons. The patient may not remember taking any medicines due to cognitive impairment. In one study on SS in the intensive care unit (ICU) setting, only 50% of the patients reported having taken serotonergic medications at the time of admission.[4] Over 70 drugs have been identified in the literature with serotonergic properties.[1] Several foods, dietary-supplements, and herbal products may induce SS.[1,5] Salimnia et al.[6] reported a patient in whom excess ingestion of pineapple juice precipitated SS. Patel and Marzella described a case of SS precipitated by ingestion of food products.[5] Warner et al.[7] reported a case of SS in which they believed turmeric enhanced the serotonergic properties of other serotonergic drugs. Tryptophan is the precursor to serotonin and is abundant in many foods.[7] Therefore, the identification of serotonergic agents may not be easy for physicians. Table 1 lists the drugs or products that may cause SS.[1,8,9]
Recently, Keith et al.[10] reported SS-like presentation in two patients with severe acute respiratory syndrome coronavirus 2 infection. Both patients responded to cyproheptadine. Both patients did not receive any serotonergic agent. The authors suggested that a raised serotonin level in patients with coronavirus disease infections has probably induced SS. One patient in the series of Prakash et al.[4] in the ICU setting did not have a history of serotonergic agent ingestion.[4] Geedigunta et al.[11] also reported a case of SS in which there was no history of ingestion of serotonergic agents.
Despite not having a history of serotonergic agent ingestion, our patient met the criteria for SS and responded to cyproheptadine. The recurrence of symptoms upon dosage reduction and the response with cyproheptadine reinstitution indicate a temporal relationship between the administration of cyproheptadine and response in different symptoms. However, there are inconsistent reports on the responsiveness to cyproheptadine in SS. The difference in response could be attributed to different dosages. According to a study, 30 mg of cyproheptadine is needed to block 85%–95% of 5-hydroxytryptamine 2A (5-HT2A) receptors in the brain.[12] Therefore, the case series which administered a higher initial dose (12–32 mg) in the first 24 h showed a positive response. Alternatively, no beneficial response was shown in the case series where patients were given a lower dose.[1,12] So, a response to therapeutic dose of cyproheptadine may be supportive of SS.
We are confident that our patient had SS. We presume that this patient had taken some serotonergic agents unknowingly. It may include dietary supplements or herbal products. The likelihood of other unusual or atypical causes cannot be ruled out because a complete evaluation for febrile encephalopathy was not performed. However, the absence of a history of serotonergic drug use in our patient, as well as in other cases reported in the literature, raises the question of whether SS can occur without the administration of serotonergic medications. It raises the question if there is any other way to induce SS. More such case reports from throughout the world are needed to answer this question.
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Nil.
There are no conflicts of interest.