Early Amantadine Treatment in Children with Severe Traumatic Brain Injury: A Dual-Center Cohort Study and Brief Review

Early Amantadine Treatment in Children with Severe Traumatic Brain Injury: A Dual-Center Cohort Study and Brief Review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Early Amantadine Treatment in Children with Severe Traumatic Brain Injury: A Dual-Center Cohort Study and Brief Review Hüseyin Bahadır Şenol, Kaan Furkan Bıyık, Çağatay Günay, Gökay Gedik, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6610737/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose Traumatic brain injury (TBI) is a major public health concern and a leading cause of disability and mortality worldwide. While the acute phase of TBI is characterized by increased dopamine release, long-term alterations in the dopaminergic system often lead to dopamine deficiency. Amantadine, a dopamine agonist and NMDA antagonist, has been suggested as a potential therapeutic agent for cognitive and behavioral impairments in TBI. In pediatric populations, amantadine has been primarily used in the rehabilitation phase; however, its effects during the acute phase remain unclear. This study aimed to evaluate the neurological and systemic outcomes of early amantadine treatment in children with severe TBI. Methods This retrospective study analyzed data from pediatric patients with severe TBI admitted to two centers between 2020 and 2025. Patients were divided into two groups based on whether they received amantadine treatment. The treatment protocol was initiated during the acute phase. Functional outcomes were assessed at intensive care unit discharge (ICU) and six months post-injury. Results A total of 60 patients were included, with 32 receiving amantadine. The median ICU stay was 11 days, and the hospital stay was 20 days. At the six-month follow-up, there was a significant improvement in functional status scores compared to ICU discharge (p < 0.001*), but no significant difference was observed between the amantadine and non-amantadine groups in functional recovery. A strong positive correlation was observed between functional scores and length of hospitalization. Conclusion Early administration of amantadine in pediatric patients with severe TBI did not provide a significant functional benefit. However, it was well tolerated and demonstrated a favorable safety profile. neurorehabilitation dopaminergic therapy pediatric trauma management pediatric intensive care pediatric brain injury Figures Figure 1 1/Introduction Traumatic brain injury (TBI) is a significant public health concern as the most common cause of disability and mortality [ 1 ]. Annual incidence of TBI is approximately 69 million cases worldwide [ 2 ]. Moderate and severe TBI are correlated with poorer clinical outcomes [ 3 ]. Moderate TBI is characterized by a Glasgow Coma Scale (GCS) score ranging from greater than eight to less than twelve, whereas severe TBI is defined by a GCS score of eight or below [ 4 ], [ 5 ]. Given the widespread impact of TBI as a leading cause of disability, continuous efforts are being made to develop effective treatments [ 6 ]. While the acute phase of TBI is associated with increased dopamine release, long-term alterations in the dopaminergic system ultimately lead to dopamine deficiency [ 7 ]. Consequently, the dopaminergic system has become a target for the development of pharmacological treatment options [ 8 ]. Amantadine is a dopamine agonist and N-methyl-d-aspartate is an antagonist [ 9 ]. Because of these dual mechanisms of action, amantadine has been widely reported as a therapeutic agent for managing TBI-related cognitive and behavioral impairments [ 10 ]. In 2018, the American Academy of Neurology recommended the use of amantadine for cognitive recovery in adults with TBI [ 11 ]. Yet, during the same period, two randomized controlled trials conducted in Iran, showed no efficacy in improving cognitive function [ 12 ], [ 13 ]. Therefore, its use in adults remains controversial. Amantadine is an FDA-approved drug for Influenza A prophylaxis in the pediatric population [ 14 ]. In the pediatric age group, studies have suggested that amantadine may be a potential solution for behavioral problems such as agitation during the late rehabilitation phase [ 15 ]. Nevertheless, to the best of our knowledge, the effects of early amantadine treatment during the acute phase have not been investigated in pediatric population. Hence, this study aimed to evaluate the neurological and systemic outcomes of early amantadine treatment in children with TBI. 2/Methods 2.1/ Study design and participants A retrospective analysis was conducted on patient records retrieved from the Department of Pediatric Neurology, Dokuz Eylul University Faculty of Medicine, and Siirt Training and Research Hospital for the period between January 2020 and January 2025. Patients with severe TBI according to GCS who were admitted to the intensive care unit (ICU) were included in the study. The demographic characteristics, trauma mechanisms, laboratory and imaging findings, Rotterdam computed tomography (CT) score [ 16 ], neurological examinations of the patients in the intensive care unit were evaluated. Participants were divided into two groups based on amantadine treatment. 2.2/ Amantadine Treatment Protocol Since 2022, amantadine treatment has been initiated for pediatric patients aged two years and older with severe traumatic brain injury at two centers. The treatment is started on the third day of admission, with a dosage of 6 mg/kg/day for young children and 100 mg twice daily for older children. The treatment is administered for approximately six weeks, with the last two weeks involving a weaning phase. 2.3/ Assesment of the Outcomes Clinical outcomes were assessed using the Functional Status Scale (FSS), which evaluates five domains: mental status, vision and hearing status, communication skills, motor functions, respiration, and feeding. Scores were evaluated at two key time points: at ICU discharge and upon presentation to the Pediatric Neurology Clinic six months post-injury. 2.4/ Statistical evaluation Statistical analysis was conducted using IBM SPSS Statistics version 27.0 (SPSS Inc., Chicago, IL, USA). Frequency distributions of categorical data were reported as counts and percentages, while continuous variables were presented as medians and interquartile ranges (IQR). Normality of data distribution was assessed using the Shapiro–Wilk and Kolmogorov-Smirnov tests. Owing to the non-normal distribution of the data, the Mann–Whitney U test was employed for comparisons between groups. The Chi-square test was utilized to compare categorical variables across groups. Friedman tests were conducted to test whether there was a significant change in the FSS score variables. 2.5/ Ethical Publication Statement The present study was approved by the local ethics committee (number of approval: 2024/34 − 26). 3/ Results In this study, a total of 60 patients were included, with a median age of 14.5 years (IQR: 8, range: 2–17 years) and 42 (70%) were male. The most common injury mechanism was pedestrian traffic accidents (n = 33, 55%). This was followed by falls in 14 patients (23.3%) and traffic accidents as vehicle occupants in nine patients (15%). Among the remaining four patients, two (3.3%) sustained injuries due to falling objects, while two (3.3%) were gunshot injuries. Intracranial CT pathologies were observed as follows: subarachnoid hemorrhage in 25 patients (41.7%), subdural hemorrhage in 24 patients (40%), epidural hemorrhage in 17 patients (28.3%), parenchymal hemorrhage in 12 patients (20%), and intraventricular hemorrhage in 2 patients (3.3%). Additionally, hemorrhage involving two or more regions was present in 29 patients (48.3%). The median value of the Rotterdam CT score was 1 (IQR 2). In 45 patients (75%), an additional systemic trauma was present. The median hospital stay was 20 days (IQR 26 days), while the median intensive care unit (ICU) stay was 11 days (IQR 10 days). Invasive mechanical ventilation was required in 56 patients (93.3%), and inotropic drug use was observed in 23 patients (38.3%). Additionally, secondary infections occured in 26 patients (43.3%). The mortality rate was 15%. 32 patients (53.3%) received amantadine treatment. The comparison between patients who received amantadine and those who did not revealed notable differences in injury mechanisms and clinical characteristics. No significant differences were found in the frequency of injury types (Table 1). Intracranial hemorrhage subtypes also varied between groups. Subarachnoid, epidural, and parenchymal hemorrhages were more frequent in the amantadine group. No significant differences were observed in the frequency of subdural hemorrhage. Intraventricular hemorrhage was observed only two patients in the amantadine group. In the assessment of the severity of findings, the Rotterdam CT score did not significantly differ between groups, in addition brain edema and multiple regions of hemorrhages were observed at a similar frequency. However, craniectomy was performed more frequently in the non-amantadine group (Table 1). The number of patients receiving inotropic support and invasive mechanical ventilation during intensive care follow-up was similar in both groups (Table 1). Table 1 Comparison of Clinical and Radiological Characteristics Between Amantadine and Non-Amantadine Groups Amantadine Treatment p -value Yes (n = 32) No (n = 28) Age at trauma (years) 15 (2–17) 12.5 (2–17) 0.073 Male Gender (n/%) 23 (71.8) 19 (67.8) 0.783 Injury Mechanism (n/%) Pedestrian Accidents 21 (65.6) 12 (42.8) 0.118 Fall 4 (12.5) 10 (35.7) 0.064 Vehicle Accidents 5 (15.6) 4 (14.2) > 0.99 Other 2 (6.2) 2 (7.1) > 0.99 Multiple Trauma (n/%) 22 (68.8) 23 (82.1) 0.371 Inotropic Support (n/%) 12 (37.5) 11 (39.2) > 0.99 Invasive MV (n/%) 28 (87.5) 28 (100) 0.116 Intracranial Hemorrhage (n/%) Subarachnoid 18 (56.2) 7 (25.0) 0.019* Subdural 13 (40.6) 11 (39.2) > 0.99 Epidural 13 (40.6) 4 (14.2) 0.043* Parenchymal 10 (31.2) 2 (7.1) 0.025* Intraventricular 2 (6.2) - 0.494 Two or More Region 17 (53.1) 12 (42.8) 0.451 Rotterdam CT Score 1 (0–5) 1.5 (0–4) 0.854 Brain Edema 8 (25.0) 11 (39.2) 0.275 Craniectomy 5 (15.6) 11 (39.2) 0.047* At the 6-month evaluation of the FSS score, significant improvement was observed compared to ICU discharge. The median value decreased from 7 to 6 (p < 0.001*) (Fig. 1). In 22 patients (36.7%), the score had declined. The comparison of clinical outcomes between patients receiving amantadine and those who did not revealed differences in hospitalization duration. The length of hospital and ICU stay was similar between groups. FSS score at ICU discharge, showed no noticeable difference between groups. Likewise, functional status at follow-up remained comparable, indicating that amantadine treatment did not lead to a significant difference in functional recovery by the time of discharge. Mortality was higher in the non-amantadine group compared to those receiving amantadine; however, this difference was not statistically significant (Table 2). Tablo 2: Comparison of Prognostic Outcomes in Amantadine-Treated and Non-Treated Patients Outcomes Amantadine Treatment p -value Yes (n = 32) No (n = 28) Length of Stay (ICU) 12 days (IQR: 22) 10 days (IQR:8) 0.163 Length of Stay (Total) 23.5 days (IQR: 34) 16 days (IQR:24) 0.069 Score of Functional Status Score at ICU Discharge 7 (IQR: 6, range: 6–23) 7 (IQR:4, range: 6–21) 0.485 Functional Status Score at Follow-up 6 (IQR: 4, range: 6–17) 6 (IQR:2, range: 6–20) 0.849 Mortality (n/%) 2 (6.2) 7 (25) 0.069 Spearman’s rank correlation analysis demonstrated a strong positive correlation between FSS at ICU discharge and length of stay (LOS) in the ICU (ρ = 0.710, p < 0.001*). Likewise, another significant positive correlation was observed between FSS at follow-up and LOS in the hospital (ρ = 0.730, p < 0.001*). No adverse effects were observed in any clinical or laboratory parameters in the group receiving amantadine in the study, and no patients required treatment discontinuation. 4/ Discussion Previous pediatric studies have investigated the contribution of amantadine in the rehabilitation process and initiated its use when consciousness impairment persisted after the acute event [ 17 ], [ 18 ]. In this study, we aimed to examine the impact of early administration on prognosis before the development of consciousness impairment. Similarly, studies have investigated early-stage amantadine treatment in adults, examining its impact on neurological recovery in patients with TBI [ 12 ], [ 13 ]. In these two studies, the initiation of treatment varied between 3 to 16 days, whereas in our study, only patients who started treatment on the third day were included as a standard approach. Moreover, the absence of this acute-phase effect in our study may be attributed to the fact that striatal dopamine levels are higher in the pediatric population compared to adults and tend to decrease with age [ 19 ]. The treatment duration in adult studies has been reported with varying intervals, including four weeks, six weeks, and until extubation [ 10 ]. Different approaches have been reported in the pediatric population. In the study by McLaughlin et al., the median duration was 24 days (range: 1–225 days) [ 15 ], whereas Patrick et al. and McMahon et al. used six-week treatment regimens, including a two-week weaning period [ 20 ], [ 21 ]. Similar to the current literature, the treatment duration in our study also consisted of a six-week regimen, with the last two weeks as a weaning period. In pediatric studies, no significant differences were observed in treatments initiated during the rehabilitation period. Patrick et al.[ 20 ] found no significant effect of treatment in children over the age of eight who were in a low-response state. Similarly, McMahon et al.[ 21 ] did not observe distinct findings in patients aged 6 to 18 years with impaired consciousness. McLaughlin et al. [ 17 ], on the other hand, conducted their study in a post-adolescent group and reported longer LOS and rehabilitation duration in the amantadine group, while no other significant differences were noted. In our study, the age range was broader compared to these studies and included younger age groups. Therefore, the findings may be considered more representative of childhood prognosis. However, similar to previous studies, we did not observe a significant change in the FSS score in either the early or late period. On the other hand, in studies conducted on adult groups, a study from the United States, in which the second functional assessment was performed at the sixth week, reported a faster recovery at the fourth week, whereas no difference was observed at the sixth week [ 22 ]. In two studies conducted in Iran, one reported no difference in functional assessment at hospital discharge, while the other found no difference at the sixth month [ 12 ], [ 13 ]. These findings appear to be consistent with our study. Regarding adverse effects, no serious adverse events have been reported in studies on the pediatric age group [ 17 ], [ 21 ]. However, in the study conducted by Patrick et al.[ 20 ], one patient experienced autonomic instability, which persisted even after drug discontinuation and was not attributed to the medication. Our study has some limitations. The first of which is its retrospective design and the small patient cohort. However, the development of our current protocol based on contemporary literature over a defined period partially mitigates this limitation. Larger, randomized controlled prospective studies in the pediatric age group will be valuable in addressing this issue. 5/Conclusion In this study, early administration of amantadine in the pediatric age group did not demonstrate a significant benefit in functional status. Furthermore, amantadine treatment was well tolerated and showed a favorable safety profile. Declarations Author Contribution All authors made substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data. All authors were involved in drafting the work or revising it critically for important intellectual content, approved the version to be published, and agreed to be accountable for all aspects of the work in ensuring the integrity and accuracy of the study.H.B.Ş. conceptualized and coordinated the study, performed the data analysis, interpreted the findings, and drafted the main manuscript text. He also contributed significantly to the literature review, ethics committee submission, and final revisions of the manuscript. K.F.B., Ç.G., G.G., G.A., F.C.S., and A.İ.P. contributed to data collection, patient follow-up, and initial drafting of the methods section. A.A. and A.S.H. participated in data interpretation and critically reviewed the manuscript for intellectual content. U.Y. provided senior supervision, contributed to the design of the study, and critically revised the manuscript.All authors reviewed and approved the final version of the manuscript. References Maas AIR et al (2017) Traumatic brain injury: Integrated approaches to improve prevention, clinical care, and research, Dec. 01, Lancet Publishing Group . 10.1016/S1474-4422(17)30371-X Dewan MC et al (Apr. 2019) Estimating the global incidence of traumatic brain injury. J Neurosurg 130(4):1080–1097. 10.3171/2017.10.JNS17352 Weppner J, Ide W, Tu J, Boomgaardt J, Chang A, Suskauer S Prognostication and Determinants of Outcome in Adults and Children with Moderate-to-Severe Traumatic Brain Injury, 10.1007/s40141-020-00298-w/Published Maas AIR et al (2007) Prognostic value of computerized tomography scan characteristics in traumatic brain injury: Results from the IMPACT study, J Neurotrauma , vol. 24, no. 2, pp. 303–314, Feb. 10.1089/neu.2006.0033 Foulkes MA, Eisenberg HM, Jane JA, Marmarou A, Marshall LF (1991) The Traumatic Coma Data Bank: design, methods, and baseline characteristics DelSignore LA, Tasker RC (2017) Treatment options for severe traumatic brain injuries in children: current therapies, challenges, and future prospects. Expert Rev Neurother 17(12):1145–1155. 10.1080/14737175.2017.1380520 Lan Y-L, Li S, Lou J-C, Ma X-C, Zhang B (2019) The potential roles of dopamine in traumatic brain injury: a preclinical and clinical update, [Online]. Available: www.ajtr.org Mohamed MS, El Sayed I, Zaki A, Abdelmonem S (2022) Assessment of the effect of amantadine in patients with traumatic brain injury: A meta-analysis, Mar. 01, Lippincott Williams and Wilkins . 10.1097/TA.0000000000003363 Kornhuber J, Weller M (1997) Psychotogenicity and N-methyl-D-aspartate Receptor Antagonism. Implications for Neuroprotective Pharmacotherapy Loggini A et al The role of amantadine in cognitive recovery early after traumatic brain injury: A systematic review. Jul 01 2020 Elsevier B V 10.1016/j.clineuro.2020.105815 Giacino JT et al (2018) Sep., Practice guideline update recommendations summary: Disorders of consciousness, Neurology , vol. 91, no. 10, pp. 450–460. 10.1212/wnl.0000000000005926 Ghalaenovi H et al (2018) The effects of amantadine on traumatic brain injury outcome: a double-blind, randomized, controlled, clinical trial, Brain Inj , vol. 32, no. 8, pp. 1050–1055, Jul. 10.1080/02699052.2018.1476733 Abbasivash R, Valizade Hasanloei MA, Kazempour A, Mahdkhah A, Shaaf Ghoreishi MM, Akhavan Masoumi G (Jan. 2019) The Effect of Oral Administration of Amantadine on Neurological Outcome of Patients With Diffuse Axonal Injury in ICU. J Exp Neurosci 13:117906951882485. 10.1177/1179069518824851 Uyeki TM et al (Mar. 2019) Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management of Seasonal Influenzaa. Clin Infect Dis 68(6):e1–e47. 10.1093/cid/ciy866 McLaughlin MJ et al (2022) Prescribing Patterns of Amantadine during Pediatric Inpatient Rehabilitation after Traumatic Brain Injury: A Multicentered Retrospective Review from the Pediatric Brain Injury Consortium, Jul. 01, Lippincott Williams and Wilkins . 10.1097/HTR.0000000000000709 Liesemer K et al (2014) Use of Rotterdam CT scores for mortality risk stratification in children with traumatic brain injury. Pediatr Crit Care Med 15(6):554–562. 10.1097/PCC.0000000000000150 McLaughlin MJ et al (2022) Prescribing Patterns of Amantadine during Pediatric Inpatient Rehabilitation after Traumatic Brain Injury: A Multicentered Retrospective Review from the Pediatric Brain Injury Consortium, Jul. 01, Lippincott Williams and Wilkins . 10.1097/HTR.0000000000000709 Reddy CC, Collins M, Lovell M, Kontos AP (2013) Efficacy of amantadine treatment on symptoms and neurocognitive performance among adolescents following sports-related concussion, Journal of Head Trauma Rehabilitation , vol. 28, no. 4, pp. 260–265, Jul. 10.1097/HTR.0b013e318257fbc6 Pitzer M (2019) The development of monoaminergic neurotransmitter systems in childhood and adolescence, International Journal of Developmental Neuroscience , vol. 74, no. February, pp. 49–55. 10.1016/j.ijdevneu.2019.02.002 Patrick PD, Blackman JA, Mabry JL, Buck ML, Gurka MJ, Conaway MR (2006) Dopamine Agonist Therapy in Low-Response Children Following Traumatic Brain Injury, J Child Neurol , vol. 21, no. 10, pp. 879–885, Oct. 10.1177/08830738060210100901 McMahon MA, Vargus-Adams JN, Michaud LJ, Bean J (2009) Effects of amantadine in children with impaired consciousness caused by acquired brain injury: A pilot study, Am J Phys Med Rehabil , vol. 88, no. 7, pp. 525–532, Jul. 10.1097/PHM.0b013e3181a5ade3 Giacino JT et al (2012) Placebo-Controlled Trial of Amantadine for Severe Traumatic Brain Injury From the JFK Johnson Rehabilitation Insti-tute Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6610737","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":472127314,"identity":"e297a560-91ee-4cbe-b8e4-626950edda9f","order_by":0,"name":"Hüseyin Bahadır 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09:53:31","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6610737/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6610737/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":84860229,"identity":"32f5166b-fd4e-4d51-a562-f6e04ca91143","added_by":"auto","created_at":"2025-06-18 06:48:15","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":67035,"visible":true,"origin":"","legend":"\u003cp\u003eFunctional Status Scores at The Time of Intensive Care Unit Discharge and at Six-month Follow-up\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6610737/v1/4272b0562e4a434bdd2edfb3.jpeg"},{"id":85609954,"identity":"3ba0f244-348f-4f96-9993-2a3659b3ba09","added_by":"auto","created_at":"2025-06-29 10:16:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":684855,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6610737/v1/e6ae9be8-6b8f-48f8-89bb-ba535139d94c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Early Amantadine Treatment in Children with Severe Traumatic Brain Injury: A Dual-Center Cohort Study and Brief Review","fulltext":[{"header":"1/Introduction","content":"\u003cp\u003eTraumatic brain injury (TBI) is a significant public health concern as the most common cause of disability and mortality [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Annual incidence of TBI is approximately 69\u0026nbsp;million cases worldwide [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Moderate and severe TBI are correlated with poorer clinical outcomes [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Moderate TBI is characterized by a Glasgow Coma Scale (GCS) score ranging from greater than eight to less than twelve, whereas severe TBI is defined by a GCS score of eight or below [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGiven the widespread impact of TBI as a leading cause of disability, continuous efforts are being made to develop effective treatments [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. While the acute phase of TBI is associated with increased dopamine release, long-term alterations in the dopaminergic system ultimately lead to dopamine deficiency [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Consequently, the dopaminergic system has become a target for the development of pharmacological treatment options [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Amantadine is a dopamine agonist and N-methyl-d-aspartate is an antagonist [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Because of these dual mechanisms of action, amantadine has been widely reported as a therapeutic agent for managing TBI-related cognitive and behavioral impairments [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn 2018, the American Academy of Neurology recommended the use of amantadine for cognitive recovery in adults with TBI [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Yet, during the same period, two randomized controlled trials conducted in Iran, showed no efficacy in improving cognitive function [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Therefore, its use in adults remains controversial. Amantadine is an FDA-approved drug for Influenza A prophylaxis in the pediatric population [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In the pediatric age group, studies have suggested that amantadine may be a potential solution for behavioral problems such as agitation during the late rehabilitation phase [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Nevertheless, to the best of our knowledge, the effects of early amantadine treatment during the acute phase have not been investigated in pediatric population. Hence, this study aimed to evaluate the neurological and systemic outcomes of early amantadine treatment in children with TBI.\u003c/p\u003e"},{"header":"2/Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1/ Study design and participants\u003c/h2\u003e \u003cp\u003eA retrospective analysis was conducted on patient records retrieved from the Department of Pediatric Neurology, Dokuz Eylul University Faculty of Medicine, and Siirt Training and Research Hospital for the period between January 2020 and January 2025. Patients with severe TBI according to GCS who were admitted to the intensive care unit (ICU) were included in the study. The demographic characteristics, trauma mechanisms, laboratory and imaging findings, Rotterdam computed tomography (CT) score [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], neurological examinations of the patients in the intensive care unit were evaluated. Participants were divided into two groups based on amantadine treatment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2/ Amantadine Treatment Protocol\u003c/h2\u003e \u003cp\u003eSince 2022, amantadine treatment has been initiated for pediatric patients aged two years and older with severe traumatic brain injury at two centers. The treatment is started on the third day of admission, with a dosage of 6 mg/kg/day for young children and 100 mg twice daily for older children. The treatment is administered for approximately six weeks, with the last two weeks involving a weaning phase.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3/ Assesment of the Outcomes\u003c/h2\u003e \u003cp\u003eClinical outcomes were assessed using the Functional Status Scale (FSS), which evaluates five domains: mental status, vision and hearing status, communication skills, motor functions, respiration, and feeding. Scores were evaluated at two key time points: at ICU discharge and upon presentation to the Pediatric Neurology Clinic six months post-injury.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4/ Statistical evaluation\u003c/h2\u003e \u003cp\u003eStatistical analysis was conducted using IBM SPSS Statistics version 27.0 (SPSS Inc., Chicago, IL, USA). Frequency distributions of categorical data were reported as counts and percentages, while continuous variables were presented as medians and interquartile ranges (IQR). Normality of data distribution was assessed using the Shapiro\u0026ndash;Wilk and Kolmogorov-Smirnov tests. Owing to the non-normal distribution of the data, the Mann\u0026ndash;Whitney \u003cem\u003eU\u003c/em\u003e test was employed for comparisons between groups. The Chi-square test was utilized to compare categorical variables across groups. Friedman tests were conducted to test whether there was a significant change in the FSS score variables.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5/ Ethical Publication Statement\u003c/h2\u003e \u003cp\u003e The present study was approved by the local ethics committee (number of approval: 2024/34\u0026thinsp;\u0026minus;\u0026thinsp;26).\u003c/p\u003e \u003c/div\u003e"},{"header":"3/ Results","content":"\u003cp\u003eIn this study, a total of 60 patients were included, with a median age of 14.5 years (IQR: 8, range: 2\u0026ndash;17 years) and 42 (70%) were male. The most common injury mechanism was pedestrian traffic accidents (n\u0026thinsp;=\u0026thinsp;33, 55%). This was followed by falls in 14 patients (23.3%) and traffic accidents as vehicle occupants in nine patients (15%). Among the remaining four patients, two (3.3%) sustained injuries due to falling objects, while two (3.3%) were gunshot injuries.\u003c/p\u003e \u003cp\u003eIntracranial CT pathologies were observed as follows: subarachnoid hemorrhage in 25 patients (41.7%), subdural hemorrhage in 24 patients (40%), epidural hemorrhage in 17 patients (28.3%), parenchymal hemorrhage in 12 patients (20%), and intraventricular hemorrhage in 2 patients (3.3%). Additionally, hemorrhage involving two or more regions was present in 29 patients (48.3%). The median value of the Rotterdam CT score was 1 (IQR 2). In 45 patients (75%), an additional systemic trauma was present.\u003c/p\u003e \u003cp\u003eThe median hospital stay was 20 days (IQR 26 days), while the median intensive care unit (ICU) stay was 11 days (IQR 10 days). Invasive mechanical ventilation was required in 56 patients (93.3%), and inotropic drug use was observed in 23 patients (38.3%). Additionally, secondary infections occured in 26 patients (43.3%). The mortality rate was 15%.\u003c/p\u003e \u003cp\u003e32 patients (53.3%) received amantadine treatment. The comparison between patients who received amantadine and those who did not revealed notable differences in injury mechanisms and clinical characteristics. No significant differences were found in the frequency of injury types (Table\u0026nbsp;1).\u003c/p\u003e \u003cp\u003eIntracranial hemorrhage subtypes also varied between groups. Subarachnoid, epidural, and parenchymal hemorrhages were more frequent in the amantadine group. No significant differences were observed in the frequency of subdural hemorrhage. Intraventricular hemorrhage was observed only two patients in the amantadine group. In the assessment of the severity of findings, the Rotterdam CT score did not significantly differ between groups, in addition brain edema and multiple regions of hemorrhages were observed at a similar frequency. However, craniectomy was performed more frequently in the non-amantadine group (Table\u0026nbsp;1).\u003c/p\u003e \u003cp\u003eThe number of patients receiving inotropic support and invasive mechanical ventilation during intensive care follow-up was similar in both groups (Table\u0026nbsp;1).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of Clinical and Radiological Characteristics Between Amantadine and Non-Amantadine Groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eAmantadine Treatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes (n\u0026thinsp;=\u0026thinsp;32)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo (n\u0026thinsp;=\u0026thinsp;28)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge at trauma (years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (2\u0026ndash;17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.5 (2\u0026ndash;17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.073\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMale Gender (n/%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (71.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (67.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.783\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eInjury Mechanism (n/%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePedestrian Accidents\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (65.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (42.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.118\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFall\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (12.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (35.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.064\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVehicle Accidents\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (15.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (14.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (6.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (7.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultiple Trauma (n/%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (68.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (82.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.371\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInotropic Support (n/%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (37.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (39.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInvasive MV (n/%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (87.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.116\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIntracranial Hemorrhage (n/%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubarachnoid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (56.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (25.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.019*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubdural\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (40.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (39.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEpidural\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (40.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (14.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.043*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParenchymal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (31.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (7.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.025*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntraventricular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (6.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.494\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTwo or More Region\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (53.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (42.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.451\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRotterdam CT Score\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0\u0026ndash;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.5 (0\u0026ndash;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.854\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBrain Edema\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (25.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (39.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.275\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCraniectomy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (15.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (39.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.047*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAt the 6-month evaluation of the FSS score, significant improvement was observed compared to ICU discharge. The median value decreased from 7 to 6 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001*) (Fig.\u0026nbsp;1). In 22 patients (36.7%), the score had declined. The comparison of clinical outcomes between patients receiving amantadine and those who did not revealed differences in hospitalization duration. The length of hospital and ICU stay was similar between groups. FSS score at ICU discharge, showed no noticeable difference between groups. Likewise, functional status at follow-up remained comparable, indicating that amantadine treatment did not lead to a significant difference in functional recovery by the time of discharge. Mortality was higher in the non-amantadine group compared to those receiving amantadine; however, this difference was not statistically significant (Table\u0026nbsp;2).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTablo 2: Comparison of Prognostic Outcomes in Amantadine-Treated and Non-Treated Patients\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eOutcomes\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eAmantadine Treatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes (n\u0026thinsp;=\u0026thinsp;32)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo (n\u0026thinsp;=\u0026thinsp;28)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLength of Stay (ICU)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 days (IQR: 22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 days (IQR:8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.163\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLength of Stay (Total)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23.5 days (IQR: 34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 days (IQR:24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.069\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eScore of Functional Status Score at ICU Discharge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (IQR: 6, range: 6\u0026ndash;23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (IQR:4, range: 6\u0026ndash;21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.485\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFunctional Status Score at Follow-up\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (IQR: 4, range: 6\u0026ndash;17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (IQR:2, range: 6\u0026ndash;20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.849\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMortality (n/%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (6.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.069\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eSpearman\u0026rsquo;s rank correlation analysis demonstrated a strong positive correlation between FSS at ICU discharge and length of stay (LOS) in the ICU (ρ\u0026thinsp;=\u0026thinsp;0.710, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001*). Likewise, another significant positive correlation was observed between FSS at follow-up and LOS in the hospital (ρ\u0026thinsp;=\u0026thinsp;0.730, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001*).\u003c/p\u003e \u003cp\u003eNo adverse effects were observed in any clinical or laboratory parameters in the group receiving amantadine in the study, and no patients required treatment discontinuation.\u003c/p\u003e"},{"header":"4/ Discussion","content":"\u003cp\u003ePrevious pediatric studies have investigated the contribution of amantadine in the rehabilitation process and initiated its use when consciousness impairment persisted after the acute event [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In this study, we aimed to examine the impact of early administration on prognosis before the development of consciousness impairment. Similarly, studies have investigated early-stage amantadine treatment in adults, examining its impact on neurological recovery in patients with TBI [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In these two studies, the initiation of treatment varied between 3 to 16 days, whereas in our study, only patients who started treatment on the third day were included as a standard approach. Moreover, the absence of this acute-phase effect in our study may be attributed to the fact that striatal dopamine levels are higher in the pediatric population compared to adults and tend to decrease with age [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe treatment duration in adult studies has been reported with varying intervals, including four weeks, six weeks, and until extubation [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Different approaches have been reported in the pediatric population. In the study by McLaughlin et al., the median duration was 24 days (range: 1\u0026ndash;225 days) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], whereas Patrick et al. and McMahon et al. used six-week treatment regimens, including a two-week weaning period [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Similar to the current literature, the treatment duration in our study also consisted of a six-week regimen, with the last two weeks as a weaning period.\u003c/p\u003e \u003cp\u003eIn pediatric studies, no significant differences were observed in treatments initiated during the rehabilitation period. Patrick et al.[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] found no significant effect of treatment in children over the age of eight who were in a low-response state. Similarly, McMahon et al.[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] did not observe distinct findings in patients aged 6 to 18 years with impaired consciousness. McLaughlin et al. [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], on the other hand, conducted their study in a post-adolescent group and reported longer LOS and rehabilitation duration in the amantadine group, while no other significant differences were noted. In our study, the age range was broader compared to these studies and included younger age groups. Therefore, the findings may be considered more representative of childhood prognosis. However, similar to previous studies, we did not observe a significant change in the FSS score in either the early or late period. On the other hand, in studies conducted on adult groups, a study from the United States, in which the second functional assessment was performed at the sixth week, reported a faster recovery at the fourth week, whereas no difference was observed at the sixth week [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. In two studies conducted in Iran, one reported no difference in functional assessment at hospital discharge, while the other found no difference at the sixth month [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. These findings appear to be consistent with our study.\u003c/p\u003e \u003cp\u003eRegarding adverse effects, no serious adverse events have been reported in studies on the pediatric age group [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. However, in the study conducted by Patrick et al.[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], one patient experienced autonomic instability, which persisted even after drug discontinuation and was not attributed to the medication.\u003c/p\u003e \u003cp\u003eOur study has some limitations. The first of which is its retrospective design and the small patient cohort. However, the development of our current protocol based on contemporary literature over a defined period partially mitigates this limitation. Larger, randomized controlled prospective studies in the pediatric age group will be valuable in addressing this issue.\u003c/p\u003e"},{"header":"5/Conclusion","content":"\u003cp\u003eIn this study, early administration of amantadine in the pediatric age group did not demonstrate a significant benefit in functional status. Furthermore, amantadine treatment was well tolerated and showed a favorable safety profile.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAll authors made substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data. All authors were involved in drafting the work or revising it critically for important intellectual content, approved the version to be published, and agreed to be accountable for all aspects of the work in ensuring the integrity and accuracy of the study.H.B.Ş. conceptualized and coordinated the study, performed the data analysis, interpreted the findings, and drafted the main manuscript text. He also contributed significantly to the literature review, ethics committee submission, and final revisions of the manuscript. K.F.B., \u0026Ccedil;.G., G.G., G.A., F.C.S., and A.İ.P. contributed to data collection, patient follow-up, and initial drafting of the methods section. A.A. and A.S.H. participated in data interpretation and critically reviewed the manuscript for intellectual content. U.Y. provided senior supervision, contributed to the design of the study, and critically revised the manuscript.All authors reviewed and approved the final version of the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMaas AIR et al (2017) Traumatic brain injury: Integrated approaches to improve prevention, clinical care, and research, Dec. 01, \u003cem\u003eLancet Publishing Group\u003c/em\u003e. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S1474-4422(17)30371-X\u003c/span\u003e\u003cspan address=\"10.1016/S1474-4422(17)30371-X\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDewan MC et al (Apr. 2019) Estimating the global incidence of traumatic brain injury. J Neurosurg 130(4):1080\u0026ndash;1097. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3171/2017.10.JNS17352\u003c/span\u003e\u003cspan address=\"10.3171/2017.10.JNS17352\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWeppner J, Ide W, Tu J, Boomgaardt J, Chang A, Suskauer S Prognostication and Determinants of Outcome in Adults and Children with Moderate-to-Severe Traumatic Brain Injury, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s40141-020-00298-w/Published\u003c/span\u003e\u003cspan address=\"10.1007/s40141-020-00298-w/Published\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaas AIR et al (2007) Prognostic value of computerized tomography scan characteristics in traumatic brain injury: Results from the IMPACT study, \u003cem\u003eJ Neurotrauma\u003c/em\u003e, vol. 24, no. 2, pp. 303\u0026ndash;314, Feb. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1089/neu.2006.0033\u003c/span\u003e\u003cspan address=\"10.1089/neu.2006.0033\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFoulkes MA, Eisenberg HM, Jane JA, Marmarou A, Marshall LF (1991) The Traumatic Coma Data Bank: design, methods, and baseline characteristics\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDelSignore LA, Tasker RC (2017) Treatment options for severe traumatic brain injuries in children: current therapies, challenges, and future prospects. Expert Rev Neurother 17(12):1145\u0026ndash;1155. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1080/14737175.2017.1380520\u003c/span\u003e\u003cspan address=\"10.1080/14737175.2017.1380520\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLan Y-L, Li S, Lou J-C, Ma X-C, Zhang B (2019) The potential roles of dopamine in traumatic brain injury: a preclinical and clinical update, [Online]. Available: www.ajtr.org\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMohamed MS, El Sayed I, Zaki A, Abdelmonem S (2022) Assessment of the effect of amantadine in patients with traumatic brain injury: A meta-analysis, Mar. 01, \u003cem\u003eLippincott Williams and Wilkins\u003c/em\u003e. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/TA.0000000000003363\u003c/span\u003e\u003cspan address=\"10.1097/TA.0000000000003363\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKornhuber J, Weller M (1997) Psychotogenicity and N-methyl-D-aspartate Receptor Antagonism. Implications for Neuroprotective Pharmacotherapy\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLoggini A et al The role of amantadine in cognitive recovery early after traumatic brain injury: A systematic review. Jul 01 2020 Elsevier B V \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.clineuro.2020.105815\u003c/span\u003e\u003cspan address=\"10.1016/j.clineuro.2020.105815\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGiacino JT et al (2018) Sep., Practice guideline update recommendations summary: Disorders of consciousness, \u003cem\u003eNeurology\u003c/em\u003e, vol. 91, no. 10, pp. 450\u0026ndash;460. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1212/wnl.0000000000005926\u003c/span\u003e\u003cspan address=\"10.1212/wnl.0000000000005926\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGhalaenovi H et al (2018) The effects of amantadine on traumatic brain injury outcome: a double-blind, randomized, controlled, clinical trial, \u003cem\u003eBrain Inj\u003c/em\u003e, vol. 32, no. 8, pp. 1050\u0026ndash;1055, Jul. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1080/02699052.2018.1476733\u003c/span\u003e\u003cspan address=\"10.1080/02699052.2018.1476733\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbbasivash R, Valizade Hasanloei MA, Kazempour A, Mahdkhah A, Shaaf Ghoreishi MM, Akhavan Masoumi G (Jan. 2019) The Effect of Oral Administration of Amantadine on Neurological Outcome of Patients With Diffuse Axonal Injury in ICU. J Exp Neurosci 13:117906951882485. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1177/1179069518824851\u003c/span\u003e\u003cspan address=\"10.1177/1179069518824851\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUyeki TM et al (Mar. 2019) Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management of Seasonal Influenzaa. Clin Infect Dis 68(6):e1\u0026ndash;e47. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/cid/ciy866\u003c/span\u003e\u003cspan address=\"10.1093/cid/ciy866\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcLaughlin MJ et al (2022) Prescribing Patterns of Amantadine during Pediatric Inpatient Rehabilitation after Traumatic Brain Injury: A Multicentered Retrospective Review from the Pediatric Brain Injury Consortium, Jul. 01, \u003cem\u003eLippincott Williams and Wilkins\u003c/em\u003e. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/HTR.0000000000000709\u003c/span\u003e\u003cspan address=\"10.1097/HTR.0000000000000709\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiesemer K et al (2014) Use of Rotterdam CT scores for mortality risk stratification in children with traumatic brain injury. Pediatr Crit Care Med 15(6):554\u0026ndash;562. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/PCC.0000000000000150\u003c/span\u003e\u003cspan address=\"10.1097/PCC.0000000000000150\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcLaughlin MJ et al (2022) Prescribing Patterns of Amantadine during Pediatric Inpatient Rehabilitation after Traumatic Brain Injury: A Multicentered Retrospective Review from the Pediatric Brain Injury Consortium, Jul. 01, \u003cem\u003eLippincott Williams and Wilkins\u003c/em\u003e. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/HTR.0000000000000709\u003c/span\u003e\u003cspan address=\"10.1097/HTR.0000000000000709\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eReddy CC, Collins M, Lovell M, Kontos AP (2013) Efficacy of amantadine treatment on symptoms and neurocognitive performance among adolescents following sports-related concussion, \u003cem\u003eJournal of Head Trauma Rehabilitation\u003c/em\u003e, vol. 28, no. 4, pp. 260\u0026ndash;265, Jul. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/HTR.0b013e318257fbc6\u003c/span\u003e\u003cspan address=\"10.1097/HTR.0b013e318257fbc6\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePitzer M (2019) The development of monoaminergic neurotransmitter systems in childhood and adolescence, \u003cem\u003eInternational Journal of Developmental Neuroscience\u003c/em\u003e, vol. 74, no. February, pp. 49\u0026ndash;55. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ijdevneu.2019.02.002\u003c/span\u003e\u003cspan address=\"10.1016/j.ijdevneu.2019.02.002\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePatrick PD, Blackman JA, Mabry JL, Buck ML, Gurka MJ, Conaway MR (2006) Dopamine Agonist Therapy in Low-Response Children Following Traumatic Brain Injury, \u003cem\u003eJ Child Neurol\u003c/em\u003e, vol. 21, no. 10, pp. 879\u0026ndash;885, Oct. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1177/08830738060210100901\u003c/span\u003e\u003cspan address=\"10.1177/08830738060210100901\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcMahon MA, Vargus-Adams JN, Michaud LJ, Bean J (2009) Effects of amantadine in children with impaired consciousness caused by acquired brain injury: A pilot study, \u003cem\u003eAm J Phys Med Rehabil\u003c/em\u003e, vol. 88, no. 7, pp. 525\u0026ndash;532, Jul. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/PHM.0b013e3181a5ade3\u003c/span\u003e\u003cspan address=\"10.1097/PHM.0b013e3181a5ade3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGiacino JT et al (2012) Placebo-Controlled Trial of Amantadine for Severe Traumatic Brain Injury From the JFK Johnson Rehabilitation Insti-tute\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"neurorehabilitation, dopaminergic therapy, pediatric trauma management, pediatric intensive care, pediatric brain injury","lastPublishedDoi":"10.21203/rs.3.rs-6610737/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6610737/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eTraumatic brain injury (TBI) is a major public health concern and a leading cause of disability and mortality worldwide. While the acute phase of TBI is characterized by increased dopamine release, long-term alterations in the dopaminergic system often lead to dopamine deficiency. Amantadine, a dopamine agonist and NMDA antagonist, has been suggested as a potential therapeutic agent for cognitive and behavioral impairments in TBI. In pediatric populations, amantadine has been primarily used in the rehabilitation phase; however, its effects during the acute phase remain unclear. This study aimed to evaluate the neurological and systemic outcomes of early amantadine treatment in children with severe TBI.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis retrospective study analyzed data from pediatric patients with severe TBI admitted to two centers between 2020 and 2025. Patients were divided into two groups based on whether they received amantadine treatment. The treatment protocol was initiated during the acute phase. Functional outcomes were assessed at intensive care unit discharge (ICU) and six months post-injury.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 60 patients were included, with 32 receiving amantadine. The median ICU stay was 11 days, and the hospital stay was 20 days. At the six-month follow-up, there was a significant improvement in functional status scores compared to ICU discharge (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001*), but no significant difference was observed between the amantadine and non-amantadine groups in functional recovery. A strong positive correlation was observed between functional scores and length of hospitalization.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eEarly administration of amantadine in pediatric patients with severe TBI did not provide a significant functional benefit. However, it was well tolerated and demonstrated a favorable safety profile.\u003c/p\u003e","manuscriptTitle":"Early Amantadine Treatment in Children with Severe Traumatic Brain Injury: A Dual-Center Cohort Study and Brief Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-18 06:48:10","doi":"10.21203/rs.3.rs-6610737/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"be3e1453-af86-4f66-a9a0-4c9cff8b5e05","owner":[],"postedDate":"June 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-06-29T10:08:33+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-18 06:48:10","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6610737","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6610737","identity":"rs-6610737","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}