Hrev_master Abstract Citalopram intoxications can lead to Serotonin Syndrome (SS) development, characterized by altered mental status, seizures, autonomic instability, hyperthermia and extrapyramidal signs. We review the literature about pediatric acute citalopram intoxications, and we report a case of severe SS in an infant associated to Posterior Reversible Encephalopathy Syndrome (PRES) treated with cyproheptadine as an antidote. An adequate12-month-old girl displayed a sudden global neurological regression with hypotonia, prolonged occipital seizures, right hemiparesis and a progressive wakefulness reduction associated with blindness. Plasmatic con- centration of citalopram was equal to 3225 ng/mL (50-110 ng/mL). MRI revealed a transient bilateral caudate and putamen hyperin- tensity, associated to an occipital cortical and subcortical hyperin- tensity. She was treated with IV cyproheptadine with progressive benefit in few days. Only 4 children with citalopram intoxication are previously described with neurological involvement. Pediatric citalopram intoxication could cause SS leading to PRES, and cyproheptadine could be used with benefit. Introduction Citalopram is a Selective Serotonin Reuptake Inhibitors (SSRIs) used in adults to treat major depressive disorder, obses- sive compulsive disorders, panic disorder, anxiety disorders, post- traumatic stress disorder.1 The daily therapeutic dose of citalopram is 20-60 mg/day and it is used as off-label in pediatric patients.2 The most common side effects include tiredness, confusion, dizzi- ness, stomach pain, sweating, nausea, sinus tachycardia and tremor,3 but it can also cause Serotonin Syndrome (SS) character- ized by altered mental status, anxiety, confusion, agitation, halluci- nations, coma, seizures, autonomic instability and extrapyramidal signs. Among SSRIs, citalopram has a high rate of seizures in over- dose and cardiac toxicity, most of all in doses higher than 400mg/day.4,5 Posterior Reversible Encephalopathy Syndrome (PRES) is described in adult patients with SSRI accidental inges- tions.6-9 When SS occurs in adults, cyproheptadine is used as an antidote (12-32 mg/day).10 Within this context, we review the liter- ature on pediatric citalopram intoxication and we describe the first case of pediatric SS with PRES after accidental ingestion of an unspecified dose of this drug treated with cyproheptadine. The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRIS- MA) guidelines 2021, used in conjunction with the Explanation and Elaboration document and the PRISMA-S extension to the PRISMA Statement for Reporting Literature Searches in Systematic Reviews.11,12 We performed a search using MEDLINE via the PubMed interface for original studies (Figure 1). References were identified from PubMed searches from 1990 to 2023. We combined Emergency Care Journal 2024; volume 20:12574 [Emergency Care Journal 2024; 20:12574] [page 65] Neurotoxicity and PRES after severe citalopram intoxication in a 12-months-old baby Sara Minghetti,¹ Alessandra Lazzerotti,² Debora Sala,² Chiara Vimercati,² Sofia Giudici,2,3 Santa Florio,4 Francesca Formica,5 Stefania Zambrano,6 Nivedita Agarwal,7 Cinzia Peruzzi¹ ¹Pediatric Neurology and Psychiatry Department, Fondazione IRCCS San Gerardo dei Tintori Monza; ²Pediatric Department, Fondazione MBBM, Fondazione IRCCS San Gerardo dei Tintori Monza; ³School of Medicine and Surgery, Milano Bicocca University; 4Neuroimaging Unit, Fondazione IRCCS San Gerardo dei Tintori, Monza; 5Neuropsychiatry and Neurorehabilitation Unit, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco; 6Clinical Neurophysiology Unit, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco; 7Neuroimaging Unit, Scientific Institute IRCCS E. Medea, Bosisio Parini, Lecco, Italy Correspondence: Sara Minghetti, Pediatric Neurology and Psychiatry Department, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, via Pergolesi 33, Italy. E-mail: Sara.minghetti@irccs-sangerardo.it Key words: citalopram intoxication; serotonin syndrome; posterior reversible encephalopathy syndrome; cyproheptadine. Conflict of interest: the authors declare no potential conflict of inter- est, and all authors confirm accuracy. Contributions: SM and SG wrote the paper, CV, AL, DS, FF and CP reviewed the paper. SF and NA reviewed the MRI figure, SZ the EEG figure. No artificial intelligence assisted-tecnologies were used to write this paper. Ethics approval and consent to participate: no ethical committee approval was required for this case report by the Department, because this article does not contain any studies with human partic- ipants or animals. Informed consent was obtained from the patient included in this study. Patient consent for publication: the patient’s guardian/s gave their written consent to use the patient’s personal data for the publication of this case report and any accompanying images. Availability of data and materials: all data underlying the findings are fully available. Received: 15 April 2024. Accepted: 9 August 2024. Early view: 2 September 2024. This work is licensed under a Creative Commons Attribution 4.0 License (by-nc 4.0). ©Copyright: the Author(s), 2024 Licensee PAGEPress, Italy Emergency Care Journal 2024; 20:12574 doi:10.4081/ecj.2024.12574 Publisher's note: all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. Non -co mmerc ial us e o nly the terms “Citalopram” and “Intoxication” or “Ingestion” and or “Pediatric”. Moreover, the reference lists of eligible articles were screened to identify any further relevant articles. We manually select- ed articles related to paediatric patients (≤18 years old). We excluded articles without patient clinical descriptions and/or with multiple intoxications. Finally, we limited our search to original studies pub- lished in the English and French languages. Case Report Here we describe a 12 months female child (10 Kg), with ade- quate psychomotor development, born from blood relatives par- ents (cousins) originating from Africa, with an uneventful birth. The baby was brought to our attention at the age of 12 months in the Emergency Department (ED) because of a first seizure without fever. The mother referred at home an episode last- ing 4-5 minutes, characterized by ocular revulsion and four arms tonic-clonic movements with spontaneous resolution. At the ED, the baby was apyretic and she presented a second similar paroxysmal episode. She was submitted to complete blood chemistry tests (blood gas analysis, electrolyte, carboxyhe- moglobin dosage, ethanol and substance abuse), which resulted negative. Cardiological evaluation did not reveal any involvement: heart rate and pressure remained regular for the entire hospitaliza- tion. In that context, the mother appeared globally numb to clini- cians. She referred to a personal recent history of psychogenic non- epileptic seizures, treated with Citalopram and Delorazepam (the child was not breastfed). Child hospitalization was required and she was submitted to sleep-awake EEG: negative (Figure 2A). The brain MRI was normal (Figure 3A). During the second hospitaliza- tion day, she displayed fever and three paroxysmal episodes with desaturation, loss of consciousness, leg hypertonia, and clonic movements of the left arm, treated with Midazolam IV and Levetiracetam IV bolus with partial seizures control (Figure 2B). In the following days, the baby still displayed frequent occipital focal seizures (Figure 2C) and she started to display a global neu- rological regression, with hypotonia, less of head and trunk con- trol, right hemiparesis and a progressive wakefulness reduction associated to visual impairment and progressive blindness. Phenobarbital infusion was started with seizures resolution, asso- ciated with ceftriaxone, acyclovir and dexamethasone in order to treat a possible infectious pathogenesis. Lumbar puncture with immunological screening, link index and cultural exams was negative. Metabolic discharges (plasmatic amino acid, plasmatic acylcarnitines, urinary organic acid) were excluded. Epilepsy gene panels, and mitochondrial gene panels (Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke- Like Episodes (MELAS), Maternally Inherited Diabetes mellitus and Deafness (MIDD) were negative. In the following days the baby presented an ulterior global worsening with persistent seizures, hypotonia, inconsolable crying and irritability. EEG displayed concomitant left occipital epileptic discharges (Figure 2D). Due to the progressive clinical deteriora- tion, the baby was conducted to the intensive care unit where she remained persistently lethargic but autonomously breathing. In the meanwhile, the mother was found persistently drowsy. Suspecting a voluntary child intoxication, it was hence required a baby plasmatic dosage of citalopram on the blood sample executed in the ED with confirmation of plasmatic concentration equal to 3225 ng/mL (therapeutic interval 50-110 ng/mL), 125 ng/mL after 4 days, 25ng/mL at day 8. We estimated an oral assumption equal to 450 mg (45 mg/kg). The baby was immediately separated from the mother, according to judicial authority indications. After these results (5th hospitalization day), we started therapy with cyprohep- tadine 6 mg/day (0,6 mg/kg/day) per nasogastric tube with pro- gressive seizures resolution and consequent dosage reduction in 5 days. The baby displayed a progressive global improvement with Case Report [page 66] [Emergency Care Journal 2024; 20:12574] Figure 1. PRISMA 2020 flow diagram of study selection about citalopram intoxications in pediatric patients (0-18 y). Non -co mmerc ial us e o nly reduction of somnolence, staying seated alone capability recovery and right hemiparesis resolution. The ERG was negative. Visual evoked potentials and electroretinogram displayed a bilateral ade- quate latency, while a reduced amplitude was observed in the left eye. We opted for a slow reduction of the therapy because, after a rapid reduction attempt, she presented a new seizure (Figure 2F). Repeated EEGs displayed a progressive improvement (Figur 2G- H). Visual impairment and oculo-manual coordination had a slow- er but still partial resolution. A second brain MRI was executed after 18 days hospitalization (Figure 3B) revealing bilateral cau- date and putamen hyperintensity, associated to an occipital cortical and subcortical hyperintensity, with PRES features. The baby was hence transferred to a pediatric rehabilitation center, where she showed a progressive clinical resolution with oculo-manual coor- dination skills recovery. Despite this, PEV FLASH highlights bilateral severe abnormalities of visual conduction. An MRI con- trol after 2 months displayed a global hyperintensities reduction of both basal ganglia, and bilateral subcortical parieto-occipital white matter. A moderate cortical-subcortical thinning of the bilateral parieto-occipital regions was revealed with consequent ex-vacuo ventricular enlargement (Figure 3C). Discussion We reported the first pediatric case of PRES due to severe citalopram intoxication, treated with cyproheptadine. We reviewed the previous pediatric literature and only 4 papers about 3 infants and an adolescent were clinically described (Table 1):13-16 two infants presenting seizures, requiring anti-seizures therapy and with ocular involvement: nystagmus, mydriasis and absence of visual tracking. No precise information about posology assumed was available and none of them displayed brain imaging involve- ment and/or had permanent sequelae. Analyzing literature, these pediatric patients presented acute reversible symptoms, not requir- ing Cyproheptadine. On the contrary, in our patient, seizures occurred suddenly in our patient, and within a few days, she showed a progressive neu- rological impairment and a neuroradiological worsening, requiring antidote treatment with cyproheptadine.4 Her brain MRI dis- played both a vasogenic and cytotoxic edema damage at the poste- rior cortical regions with consequent parieto-occipital neuronal loss and the transient involvement at the level of the basal ganglia, compatible with transient toxic damage due to overstimulation of serotoninergic receptors.6-8 This edemigenous involvement typical of PRES had a sure causative role both in seizures, visual impair- ment occurrence and progressive neurological decay. We could only hypothesize that the progressive occurrence of symptoms could be due to variable protein binding, floating volume of distri- bution and rates of hepatic metabolism and excretion of drugs, typ- ical of infants, that could alter citalopram pharmacodynamics and clinical evolution.13-17 In literature, no evidence of cyproheptadine use as antidote in case of pediatric intoxications and few evidences are available Case Report Figure 2. EEG evolution after acute citalopram intoxication. A) Sleep EEG: regular EEG without paroxysmal discharges observed. Artifacts on right temporal regions (admission); B) Left rhythmical theta activity on the left TO regions during sleep (2nd day hospitaliza- tion); C) Left Temporo-Occipital seizure (4th day Hospitalization); D) Secondary bilateralization of the left TO seizure (4th day Hospitalization); E) Sleep EEG after 2 hours of Cyproheptadine ev infusion (5th day Hospitalization); F) Right Temporo-occipital seizure after Cyproheptadine iv infusion dosage reduction (6th day Hospitalization); G) Sleep EEG without paroxysmal discharges (22nd day Hospitalization); H) awake EEG with persistent right slow occipital activity without paroxysmal discharges (60th day Hospitalization). [Emergency Care Journal 2024; 20:12574] [page 67] Non -co mmerc ial us e o nly about anti-seizures therapy in SS. Cyproheptadine is an histamine- 1 receptor antagonist, available only in oral form and it has increasing evidences as antidotal therapy in SS. As side effects it could cause hypotension (not observed in our patient) and seda- tion, that could have a secondary positive effect in seizures control: we observe a focal seizures resurgence during a rapid cyprohepta- dine reduction attempt. Antiseizures drugs such as valproic acid, lamotrigine, gabapentin, pregabalin, topiramate and carba- mazepine, phenytoin and oxcarbazepine could have serotoninergic properties and should be avoided in case of SS.18 In conclusion, pediatric citalopram intoxication could represent a severe neurological pediatric emergency with PRES features. Cyproheptadine could be a safe and effective antidote to minimize the side effects of citalopram intoxication. Further studies are required to understand the pharmacokinetics of this drug and the pathophysiology of this cortical and subcortical involvement. Case Report Figure 3. Brain MRI evolution after citalopram intoxication. A) normal second day brain MRI; B) bilateral caudate and putamen hyper- intensity, associated to an occipital cortical and subcortical hyperintensity, similar to PRES at 18th day hospitalization; C) basal ganglia, and bilateral subcortical parieto-occipital white matter hyperintensities reduction without volumetric modifications. Moderate cortical- subcortical bilateral thinning of the parieto-occipital regions with ex-vacuo ventricular enlargement. [page 68] [Emergency Care Journal 2024; 20:12574] Table 1. Literature review of pediatric patients with citalopram intoxication. Paper Pt N Age Sex Dosage Plasma dosage SYMPTOMS Imaging Therapy Outcome Neurological Cardiological Masullo, 2006¹³ 1 10 m F NA 1400 ng/ Horizontal nystagmus, - NA MDZ + PHT + NS ml (1 h), 3 TC seizures PB + 10 g AC 583 ng/mL (6 h), (NG tube) + OTI 416 ng/mL (13 h), + MDZ 296 ng/mL (23 h), Janson, 2020¹ 1 1 m M 20 mg 77 μg/L (2 h)- Jitteriness, ↑SBP CUS: AC, ↑muscle tone, (6 mg/kg) 23 μg/L (50 h) opisthotonos (110/38 mmHg) normal sodium sulfate GER (for w) Weigl, 2020¹ 1 14 y F 800 mg 633 ng/mL Dizziness, drowsiness NA NA AC NS (10.4 mg/kg) Borkar, 2022¹ 1 7 w M NA NA Seizures: Intermittent normal MDZ (0.1 mg/kg) At 2 year FU: intense cry, tachycardia, mild speech delay extension of hypertension both arms, clenching of the fists, facial redness, eye deviation to the left, nystagmus, mydriasis, absence of visual tracking. Neck, arms and legs hypertonic flexion Legend: AC, activated charcoal, CUS, cranial ultrasound, FU, follow-up, GER, gastro-esophageal reflux, MDZ, midazolam, NA, non available, N, number, NS, no sequelae, OTI, orotracheal intubation, PB, phenobarbital, PHT, fosphenytoin, PT, patients; SBP, sistolic blood pressure, TC, tonic-clonic. Non -co mmerc ial us e o nly References 1. Javad Alaghband-Rad MH. A randomized controlled clinical trial of citalopram versus fluoxetine in children and adoles- cents with obsessive-compulsive disorder (OCD). Eur Child Adolesc Psychiatry 2009;183:131–5. 2. Cipriani A, Zhou X, Del Giovane C, et al. Comparative effica- cy and tolerability of antidepressants for major depressive dis- order in children and adolescents: a network meta-analysis. Lancet 2016;388:881-90. 3. Bezchlibnyk-Butler K, Aleksic I, Kennedy SH. Citalopram - A review of pharmacological and clinical effects. J Psychiatry Neurosci 2000;25:241–54. 4. Personne M, Sjöberg G, Persson H. Citalopram overdose - Review of cases treated in swedish hospitals. J Toxicol - Clin Toxicol 1997;35:237–40. 5. Klein-Schwartz W, Benson BE, Lee SC, Litovitz T. Comparison of citalopram and other selective serotonin reup- take inhibitor ingestions in children. Clin Toxicol 2012;50:418–23. 6. Ducros A, Boukobza M, Porcher R, et al. The clinical and radi- ological spectrum of reversible cerebral vasoconstriction syn- drome. A prospective series of 67 patients. Brain 2007;130:3091–101. 7. Prakash S, Rathore C, Kaushikkumar R. Posterior reversible encephalopathy syndrome in a patient with serotonin syn- drome. BMJ Case Rep 2020;13:e236450. 8. Bhutada AS, Kodankandath TV. Delayed presentation of pos- terior reversible encephalopathy syndrome in the setting of serotonin-norepinephrine reuptake inhibitors. Cureus 2022;14:e22454. 9. Malik MT, Majeed MF, Zand R. Serotonin syndrome present- ing as a posterior reversible encephalopathy syndrome. Case Rep Neurol 2020;12:63–8. 10. Tormoehlen LM, Rusyniak DE. Neuroleptic malignant syn- drome and serotonin syndrome. 1st ed. Vol. 157, Handbook of Clinical Neurology. Elsevier B.V.; 2018. 663–675 p. 11. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 2021;372:n71. 12. Rethlefsen ML, Kirtley S, Waffenschmidt S, et al. PRISMA-S: an extension to the PRISMA Statement for Reporting Literature Searches in Systematic Reviews. Syst Rev 2021;10:39. 13. Masullo L, Miller M, Baker SD, et al. Clinical course and tox- icokinetic data following isolated citalopram overdose in an infant. Clin Toxicol 2006;44:165–8. 14. Janson JA, Wasylewicz ATM, Eijkemans M, et al. Citalopram intoxication in four week old infant. BMC Pediatr 2020;20:1– 5. 15. Weigl J, Vloet T, Egberts K, et al. Non-fatal intoxication with a high dose of citalopram in a suicidal 14-year-old girl. Z Kinder Jugendpsychiatr Psychother 2019;47:168–70. 16. Borkar D, Kiragub A W, Arensc A, Montaguec A J. A 7-week- old infant with serotonin syndrome. North American Congress of Clinical Toxicology ( NACCT) 2022. Clin Toxicol 2022;60:1–162. 17. Schult RF, Morris AJ, Picard L, et al. Citalopram overdose and severe serotonin syndrome in an intermediate metabolizing patient. Am J Emerg Med 2019;37:1993.e5-1993.e6. 18. Prakash S, Rathore C, Rana K, Patel H. Antiepileptic drugs and serotonin syndrome - A systematic review of case series and case reports. Seizure 2021;91:117–31. Case Report [Emergency Care Journal 2024; 20:12574] [page 69] Non -co mmerc ial us e o nly