Accepted Manuscript Serotonin syndrome and hippocampal infarction S. French , C. Wray PII: DOI: Reference: S0887-8994(18)30823-3 https://doi.org/10.1016/j.pediatrneurol.2018.10.004 PNU 9435 To appear in: Pediatric Neurology Please cite this article as: S. French , C. Wray , Serotonin syndrome and hippocampal infarction, Pediatric Neurology (2018), doi: https://doi.org/10.1016/j.pediatrneurol.2018.10.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT Serotonin syndrome and hippocampal infarction French S, Wray C AN US CR IP T Oregon Health and Science University, Pediatric Neurology, Portland (OR) USA * Corresponding author. Oregon Health and Science University, Pediatric Fellowship Program, Mail Code: CDRCP Rm 3214, 707 SW Gaines St, Portland, OR 97239-2998. Tel.: (505)412-5716; Fax: 503-494-6868 CASE REPORT The patient is a 15-year-old boy who presented with serotonin syndrome after an intentional overdose by ingestion of 60 tablets of bupropion (300mg) and 30 tablets of vilazodone (20mg). Prior to the ingestion he was taking several advanced classes and received good grades in school. At presentation, the patient had hallucinations, fever, and intermittent tremor without seizures. He became hypotensive and hypoxic with SpO2 in the 80s for roughly 1 minute, prompting immediate intubation. He was treated with vasopressors and cyproheptidine. He also received lorazepam and fosphenytoin because of his tremors, but video electroencephalogram (EEG) demonstrated that these were not epileptic. EEG showed a single right central 17 second focal subclinical seizure. Head magnetic resonance imaging (MRI) demonstrated acute isolated bilateral hippocampal anoxic injury (Fig 1). Memory testing at two weeks post-ingestion showed poor short term memory that improved at the 3-month reevaluation (Tab 1). Because of his memory deficits, the patient required new provisions at school that allowed him access to notes during exams. He also developed focal epilepsy. Fig. 1. MRI brain without contrast on hospital day 15 showing acute diffusion restriction within the hippocampus bilaterally with corresponding T2 hyperintensity and increased FLAIR signal, consistent with cytotoxic injury, likely postischemic. Table 1. Wide Range Assessment of Memory and Learning, second edition (WRAML-II) at 2 weeks and 3 months post ingestion showing improving memory deficits. AC CE PT ED M WRAML-II Classification at 2 weeks Classification at 3 months Story Memory Immediate Recall Borderline Low Average/Age-Typical Delayed Recall Low Average/Age-Typical Delayed Recognition Borderline Low Average/Age-Typical Verbal Learning Immediate Recall Low Average Average/Age-Typical Delayed Recognition Low Average/Age-Typical Delayed Recall Low Average/Age-Typical Picture Memory Immediate Recall -Low Average Delayed Recognition -Average/Age-Typical DISCUSSION The etiology of infarction in this patient is likely multifactorial with serotonin syndrome being the strongest contributor. He was hypotensive and hypoxic with possible transient hypoperfusion, though the brevity of this state makes it unlikely to fully explain his infarcts. His subclinical seizure would have increased cerebral metabolic demand and may have made his brain more susceptible to ischemic injury. While status epilepticus alone in the 1 setting of hypoxia can cause bilateral hippocampal infarcts, this patient’s seizure was too short and focal to explain his injury. 2 Serotonin syndrome can cause stroke, and patients on selective serotonin reuptake inhibitors (SSRIs) have been 3 reported to develop reversible segmental vasoconstriction of cerebral arteries. Parallels in mechanism of injury may be drawn between cocaine abuse and serotonin syndrome because SSRIs and cocaine inhibit the serotonin receptor SERT, and, similar to bupropion, cocaine inhibits reuptake of norepinephrine and dopamine. Isolated 4 bilateral hippocampal infarcts have been reported in the setting of cocaine abuse. The mechanism of injury is 5 thought to be cerebral vasospasm and vascular thrombosis. ACCEPTED MANUSCRIPT CR IP T This case identifies a novel association between serotonin syndrome and bilateral hippocampal infarctions with a potential causative explanation and provides prognostic guidance that resulting memory deficits may improve. It adds to our knowledge of potential complications of serotonin syndrome that should be evaluated for and treated. STATEMENT OF EHTICS The authors have no ethical conflicts to disclose DISCLOSURE STATEMENT The authors have no conflicts of interest to declare FUNDING SOURCES The authors did not receive funding related to this report AUTHOR CONTRIBUTIONS Sophia French, MD: Wrote, revised, and approved work Carter Wray, MD: Revised and approved work References Kartsounis LD, Rudge P, Stevens JM . Bilateral lesions of CAl and CA2 fields of the hippocampus are sufficient to cause severe amnesic syndrome in humans. J Neurol, Neurosurg and Psychiatry. 1995 Jul; 59(1):95-98. 2. Molaie M1.Serotonin syndrome presenting with migrainelike stroke. Headache. 1997 Sep;37(8):519-21. 3. Noskin O, Elham Jafarimojarrad, Richard B. Libman and Jeffrey L. Nelson. Diffuse cerebral vasoconstriction (Call–Fleming syndrome) and stroke associated with antidepressants. Neurology. 2006 Jul; 67(1)159-160. 4. Connelly KL, Chen X, Kwan PF. Bilateral hippocampal stroke secondary to acute cocaine intoxication. Oxf Med Case Reports. 2015 Mar; (3): 215–217. 5. Johnson BA, Devous MD, Ruiz P, Ait-Daoud N. Treatment advances for cocaine-induced ischemic stroke: focus on dihydropyridine-class calcium channel blockers. Am J Psychiatry. 2001 Aug; 158(8):1191–1198 AC CE PT ED M AN US 1.