Microstructural Damage to the Optic Nerve with Vigabatrin Treatment in West Syndrome: A DTI Study

Microstructural Damage to the Optic Nerve with Vigabatrin Treatment in West Syndrome: A DTI Study | 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 Microstructural Damage to the Optic Nerve with Vigabatrin Treatment in West Syndrome: A DTI Study Junjie Hu, Li Chen, Gongwei Zhang, Yu Fang, Huiting Zhang, Yilian Li, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5833219/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 Objective: This study aimed to assess the side effects of vigabatrin (VGB), focusing on optic nerve fiber damage in children with West syndrome, using DTI imaging parameters. Method: Clinical data and DTI images were analyzed, recording FA and ADC values for both optic nerves. ROC curves were used to determine fractional anisotropy thresholds for optic nerve damage. Results: Thirty-five children with West syndrome (0.3-22 months old, male: female = 19:16) were divided into three groups: (1) VGB and other anti-seizure medications (ASMs) with symmetrical thalamus abnormalities, (2) VGB and ASMs without thalamus abnormalities, and (3) control group with other ASMs. FA values in group 1 were significantly lower than in group 3 (P < 0.05), and FA values increased after VGB discontinuation (P < 0.05). The ROC analysis showed a cut-off score of 304 with 63.6% sensitivity and 100% specificity for detecting optic nerve damage. Conclusion: FA values are effective imaging markers for detecting VGB-induced optic nerve damage in West syndrome, especially when thalamus abnormalities are present. FA values significantly improve after stopping VGB treatment. vigabatrin nuclear magnetic resonance cytotoxic oedema optic nerve integrity Figures Figure 1 Figure 2 Figure 3 What this paper adds It is looking for more sensitive indicators to identify optic nerve injury. It is proved the optic nerve injury caused by VGB is reversible. Introduction Vigabatrin (VGB), an anti-seizure medication (ASM) widely used to treat West syndrome, acts as an irreversible inhibitor of γ-aminobutyric acid (GABA) transaminase 1 . This mechanism increases GABA levels in the brain by preventing its breakdown 2 – 4 , thereby contributing to its established efficacy in controlling epileptic spasms 5 , 6 . However, VGB is associated with visual side effects, occurring in approximately one-third of treated children 7 . These effects, often referred to as VGB-induced retinopathy, involve retinal toxicity that can lead to segmental dysfunction and atrophy. Studies in adults with VGB retinopathy, utilizing electroretinograms (ERG) and optical coherence tomography (OCT), have demonstrated atrophic thinning of the retinal nerve fiber layer and other forms of retinal cell damage 8 , 9 . VGB has an efficacyt of 61.8% to achieve seizure free and is currently used as a first-line treatment for West syndrome 5 .In the clinical evaluation of visual abnormalities in children with West syndrome by VGB therapy, which is older than 9 years and his cognitive ability was adequate to finish the evaluations like perimetry. Flash visual evoked potentials (FVEP) can be utilized in older than 3 years children. However, FVEP has the disadvantages that a large variation in waveform and latency, and a high false negative rate for lesions of the visual pathway 10 . Ocular problems of retinopathy in younger are still difficult to detect. Therefore, finding a convenient and accurate method to monitor ocular impairment during VGB therapy in children is the most important. It is recognized from autopsy reports that in addition to pathological changes appeared in the retina, atrophy or even partial absence of the optic nerve were found after VGB treatment 11 . On the basis of the following two points that the optic nerve and optic tract are retinal fiber layer formation 12 , and the retina and visual pathway (such as lateral geniculate) are distributed with GABA A , GABA B , and GABA C receptors 13 – 18 . Animal studies demonstrated that VGB acts on the retina and visual pathways to decrease GABA degradation, resulting in GABA elevation caused the pathology happened 19 . Therefore, monitoring the pathophysiological changes allows assessment of the retinal and intact visual pathway damage caused by VGB therapy in children with West syndrome. On conventional structural imaging sequences, a small proportion showed symmetrical thalamic hyper-intensity on DWI, whereas those shows no abnormal imaging with or without DWI hyper-intensity in the thalamus. The appearance of symmetrical thalamic hyper-intensity on DWI, probably associated with keep GABA in the thalamus and visual pathway 20 , 21 . There was little concern about alterations in the microstructure of the optic nerve at different cerebral imaging, as well as after discontinuation of VGB. DTI (diffusion tensor imaging) is the imaging technique to study white matter fiber nerve in vivo by the anisotropy of divisional motion of water molecules within the tissue, with parametric FA (fractional anisotropy) values and ADC (apparent diffusion coefficient) values are quite sensitive for assessing the integrity of the nerve microstructure 22 – 24 . Previous studies have utilized the DTI at the image level (the voxel level) to assess white matter damage, including detection of optic radiation lesions 25 – 27 . Additionally, it was utilized in patients with optic neuritis as a method to assess optic nerve fiber tract pathology 28 – 30 . However, few reports assess the extent of damage and recovery of the visual pathway by DTI, which caused by VGB. The aim of this study was to find more sensitive monitoring indicators such as FA and ADC values. ROC curves were used to assess optic nerve damage and guide the treatment scheme for VGB. Method Clinical Data A total of 35 patients with West syndrome were consecutively collected from January 2014 to April 2021 in the Shenzhen Children's Hospital. The selection criteria were patients diagnosed with West syndrome, less than 6 months of age, complete clinical data, and a perfect DTI test. The exclusion criteria were patients with defective clinical data, patients unable to cooperate with the test due to sedation, and patients without family consent. And they were divided into three groups: the first group consists of 11 children showing symmetrical thalamic hyper-intensity on DWI by using VGB and other ASMs, such as adrenocortical hormone, Lamotriazine, Levetiracetam and so on. The second group consists of 11 children by using VGB and other ASMs, who did not present symmetrical thalamic hyper intensity on DWI, and the third group consists of 13 patients with West syndrome without VGB using but using other ASMs, which has a normal DWI scan. In the first group, after the appearance of symmetrical thalamic hyper-intensity on DWI, all children stopped taking VGB 3 months, only six children were evaluated changes in FA and ADC values of DTI. Clinical data were collected including sex, start age of medication, duration of medication, cumulative dosing, daily dosing, were collected for all children. The study was approved by the Shenzhen Children Hospital Ethics Committee (Ethics Approval No. 2021002). Image Acquisitions All patients underwent conventional MRI scan and DTI. Foam cushions were utilized to reduce head movements. Imaging data were gathered using an 8-channel head coil on a 3T Siemens scanner (Skyra, Siemens, Germany) at the Shenzhen Children's Hospital (Shenzhen, China). The localization line was the parallel line at the lower border of the corpus callosum. The parameters for conventional axial T1WI and T2WI:T1WI: section thickness of 5 mm, spacing of 1 mm, TR of 2307 ms, TE of 10.6 ms; T2WI: Fast Spin Echo (FSE) sequence: section thickness of 5 mm, spacing of 1 mm, TR of 4000 ms, TE of 103 ms; sagittal T1WI: section thickness of 5 mm, spacing of 1.5 mm, TR of 200 ms, TE of 2.49 ms. The DTI protocol was using a spin echo planar image sequence with the following parameters: TR/TE = 6800/93 ms, FOV = 220×220 mm2, 40 axial slices, slice thickness = 2.5 mm, and in plane resolution = 1.719×1.719 mm2. Diffusion weighing was isotropically distributed along 30 directions (b = 1000 s/mm2). FVEP was monitored using the MEB-9404C device (Nihon Kohden, Japan). The patient wore an LED flash stimulator (Goggles, Unique Medical, Tokyo, Japan) with 20 red lights covered with a transparent protective film to monitor visual function in real time. The monitoring parameters were set as follows: red light source in stimulation mode, stimulation frequency of 1.0 Hz, filter bandwidth of 1-100 Hz and less than 50 overlaps, FVEP and electroretinography (ERG) were recorded approximately 2–3 times at each time point, and typical waveforms with low interference were used to analyze the data. In this study, the vertical distance between N75 and P100 was defined as the FVEP amplitude, the time to P100 onset was defined as the FVEP latency, and the vertical distance between a and B waves was defined as the ERG amplitude. Imaging Processing Image post-processing was performed in a blinded fashion by an experienced radiologist at the post-processing workstation of Siemens syngo, and measurements were repeated three times, and the mean values of the evaluated parameters were recorded. Selection methods for ROI (Region of Interest): the largest diameter of which occupied only 3 pixel points on the transection site, and volume effects of pixel points on the side edges, to ensure the reproducibility and accuracy of the study. The ROI was selected as the middle pixel point of each slice of the image and the starting point of each patient's optic tract with a fixed position on the side. The minimum delineation area (voxel of interest) in the workstation was utilized as the delineation tool (Fig. 1 ). Data Analyses SPSS software version 25.0 (IBM Corporation, Armonk, NY, USA) was used to analyze data. It is made use of Shapiro Wilks test to check the distribution of variables and the Levene test to assess homogeneity of variances. Data that had non-normal distribution were presented as medians with interrogative ranges. Comparisons between groups were evaluated with the One-way analysis of variance and Bonferroni’s post-hoc test for multiple correction. All tests were two-sided, and P values that smaller than 0.05 were examined statistically significant. ROC curves are used to predict the cut-off score for optic nerve damage. Statistical Graph drawing was performed using the software Graphpad Prism 9.5 version. Results Clinical Manifestations None of the patients developed new epileptic symptoms during VGB treatment. In the first group, 11 children were initiated on medication at the age from 0.3 months to 15 months. The duration of medication was from 9.5months to 17.0months.The maximum doses used ranged from 67.0 mg/kg per day to 108.0 mg/kg per day, and the cumulative amount of drug administered ranged from 2.2 grams to 615.0 grams. While in the second group, 11 children were initiated on medication at the age of 3 months to 19 months. The duration of medication was from 7.0months to 19.0 months.The maximum dosage of drugs was between 35.7 mg/kg per day and 194.0 mg/kg per day, and the cumulative amount of drugs ranged from 30.0 grams to 300.00 grams. 13 children in the third group used other ASMs to control seizure, the duration of medication was from 9.5months to 18.0months. (Table 1 ). Table 1 Clinical Manifestations of Participants Group The first group (VGB&Abnormal imaging) The second group (VGB&Normal imaging) The third group (Control) P-value Number of The Patients 11 11 13 Sex(Male/Female) 7/4 5/6 7/6 0.865 Start Age of Medecation(Months)(Median (IQR)) 6.0 (1.0–15.0) 5.0 (3.0–19.0) 6.0 (2.0–20.0) 0.998 Duration of Medication(Months)(Median (IQR)) 11.0 (10.5–16.0) 11.0 (7.0- 18.5) 11.0 (10.0–17.0) 0.999 Maximum of Daily Dose(mg/kg/d)(Median (IQR)) 93 (67.0-100.0) 83 (68.0- 138.0) None 1.000 Drug Cumulation(g)(Median (IQR)) 127.5 (44.6- 158.5) 52.5 (30.0-93.8) None 0.335 Conventional Imaging Features The thalamus, anterior commissure, globus pallidum, substantial nigra, red nucleus, dentate nucleus, and the dorsal aspect of the brainstem of patients in group one showed symmetric hyper-intensity on DWI (Fig. 2 A and B). Medial geniculate and lateral geniculate hyper-intensity on DWI was seen in 8/11 cases (72.7%), with conventional sequences showing no abnormal signal. Additionally, on conventional sequences, the thalamus was showed slightly lower T1WI signals and slightly higher T2WI signals in 7/11 (63.64%) patients, and the pallidum was showed slightly lower T1WI signals and slightly higher T2WI signals in 5/11 (45.45%) patients. Anterior commissure and dorsal brainstem and dentate nucleus, substantial nigra and red nucleus were unremarkable on routine imaging. Patients in the second and the third group showed no abnormal signal intracranially on conventional and DWI sequences. The optic nerve of all patients showed no abnormal signal on conventional and DWI imaging. Results of statistical analysis of FA values and ADC values of both lateral optic FA and ADC values of the bilateral optic were presented in Table 2 . FA values in the first group were decreased and significantly different from the third group (P 0.05). After cessation of VGB, the FA values were significantly higher than before (P < 0.05). In order to distinguish that optic tract damaged or not, an ROC curve was plotted and within the confidence interval, area under the curve (AUC) for LOFA is 0.92 and AUC-ROFA is 0.86, indicating excellent accuracy the cut-off value 304 is measured. the sensitivity and specificity were 63.6% and 100%, respectively(Fig. 3 ). Table 2 FA and ADC values of the bilateral optic nerve for Participants Group The first group (VGB&Abnormal imaging) The second group (VGB&Normal imaging) The third group (Control) df F P-value ROADC ( ×10-6mm2/s ) (Median (IQR) ) 1209.0 (1173.5-1692.5) 1125.0 (990.5-1586.5) 1280.0 (1049.0-1579.0) 2 0.480 0.623 LOADC ( ×10-6mm2/s ) (Median (IQR) ) 1427.0 (1271.5–1624.0) 1435.0 (1309.0-1750.0) 1366.0 (1051.0-1734.0) 2 0.667 0.520 ROFA ( ×10 − 3) (Median (IQR) ) 299.0* (270.5-363.5) 463.0 (363.5–518.0) 427.0* (374.0-533.0) 2 6.173 0.005 LOFA ( ×10 − 3) (Median (IQR) ) 297.0* (239.00-326.50) 390.0 (374.5-411.5) 410.0* (371.0-523.0) 2 9.460 0.001 Notes: *Significant difference between the first and third groups:p < 0.05 In the first group, FA values of bilateral optic nerve were marginally significantly higher after discontinuation of VGB for 3 months compared with discontinuation of VGB before,(Table 3 ). Table 3 Comparison of FA and ADC Values in the Optic Tract of Six Patients while Taking VGB and After Discontinuing VGB for 3 Months VGB Stop-VGB statistic P Value FA value ( ×10 − 3) LOFA 273. 2 ± 64.7 367.0 ± 62.5 2.68297 0.044 ROFA ADC value( ×10-6mm2/s ) 286.5 ± 20.9 437.3 ± 128.5 2.56884 0.050 LOADC 1509.5 ± 310.5 1368.5 ± 254.3 -0.88412 0.417 ROADC 1271.0 ± 311.0 1203.3 ± 241.3 -0.74588 0.489 Notes : VGB for children taking VGB; Stop VGB for discontinued VGB children; LOFA for left optic tract FA value; ROFA for right optic tract FA value; LOADC is the right optic tract ADC value; ROADC is the left optic tract ADC value. Flash Visual evoked potentials Flash visual evoked potentials were performed in all children, which showed that all patients had a normal P100 with normal amplitude, resulting suggestive of normal optical conduction. Discussion Vigabatrin (VGB) is a first-line treatment for patients with West syndrome and is effective in achieving seizure control. This study provides novel insights into the impact of VGB on optic nerve integrity and its potential reversibility. Specifically, the fractional anisotropy (FA) values of the optic nerve were found to decrease significantly during VGB treatment, accompanied by symmetrical thalamic hyperintensity on diffusion-weighted imaging (DWI), indicating marked microstructural damage to the optic nerve. However, a key finding of this study is that FA values returned to normal levels within three months after discontinuation of VGB, suggesting that VGB-induced microstructural changes in the optic nerve are reversible. Interestingly, in cases without symmetrical thalamic hyperintensity on DWI, the FA values of the optic nerve did not differ significantly from those of West syndrome patients who had not received VGB, implying that optic nerve damage may be less severe in such cases. This study also highlights that the presence of symmetrical thalamic hyperintensity on DWI may serve as an imaging biomarker for identifying patients at greater risk of optic nerve impairment during VGB treatment. The findings underscore the importance of close monitoring of optic nerve integrity during VGB therapy using advanced imaging techniques such as DWI and FA analysis. Furthermore, the observed reversibility of optic nerve damage supports the continued use of VGB for epilepsy management in patients with West syndrome, provided regular monitoring is conducted. This study distinguishes itself from prior research by demonstrating both the reversibility of microstructural optic nerve changes and the potential use of imaging biomarkers to guide personalized treatment strategies. General clinical features and indicators VGB is a GABA like hydrophilic structure, which does undergo hepatic metabolism and not bind to plasma proteins 27 , It excretes via the kidneys, and is therefore relatively safe 28 . The cumulative amount of drugs used in this study was not changed between the first and second group. The daily VGB dosage was less than the maximum daily dosage that reported, suggesting that the appearance of thalamic symmetric hyper-intensity on DWI had no relevance with the toxicity of VGB excess and unclear relationship with the accumulation volume, this result was different from study of Hussain et al(> 175 mg/kg/day) 29 . The DWI symmetrical abnormal signal was related to the maximum daily dosage and the same view was not related to the total accumulation volume. Significance of imaging features Symmetrical abnormal hyper intensity in the subthalamus and basal ganglia on DWI after drug administration, and disappeared after drug withdrawal. It suggested that the abnormal hyper-intensity caused cytotoxic edema due to the metabolism of VGB. It is in line with literature mentioning that cytotoxic edema appeared in pathological sections of the rats’ brain after treatment of VGB 30 ,as well as appeared in human brain 31 – 33 .It is found that the GABA A , GABA B and GABA C receptors have differential distribution in the CNS, loss of GABA degradation was associated in the thalamus as well as in the above anatomical sites, and the specific mechanisms are not known 3 – 5 , . In this study, it is first found that abnormal signals in gray matter nuclei, such as the substantial nigra, red nucleus, medial geniculate body, and lateral geniculate body. It was proposed that these gray matter lesions and thalamus lesions are similar and the same as cytotoxic edema. DTI in the assessment of fiber tracts in brain tissue has served in lesions of the optic nerve, optic tract, and optic radiation. FA is one characteristic of DTI that closes relative to myelin integrity, nerve fiber density, or orientation of myelin sheath 28 . ADC is an important index in DTI to measure Brown motion of water molecules in vivo 34 , It reflected the patho-physiological alterations in the micro-structure of the fiber tracts 12 , which can be used to evaluate the integrity of the visual fiber tracts. We wanted to monitor the injury of optic nerve by DTI in routine practice, because a few patients were so sensitive to VGB that even though VGB in a less dosage. When the dosage added, although they didn’t have new symptoms, actually the injury of optic nerve happened. DTI can help us early to find out the dosage VGB is suitable or not. In this study, FA values on DTI of the optic nerve fiber tracts in the first group were significantly decreasing compared with other groups, suggesting that the optic nerve was severely damaged with symmetrical thalamic hyper-intensity on DWI after taking VGB. It may be linked to the role of VGB in inhibiting cerebral cortical excitability and suppressing seizures, as well as the reduced degradation of GABA in the retina, visual pathways and thalamus 19 . While FA values returned to normal levels after 3 months of VGB withdrawal and were not significantly different from the first group, suggesting that this cytotoxic damage of the nerve fiber is reversible and somewhat separate from the irreversible visual damage 15 . Therefore, this study suggested that when symmetric thalamic hyper-intensity appeared on DWI, it could be properly discontinued. The integrity of the micro-structure would be restored after about 3 months and the medication could be expected to continue. It is also observed that some patients discontinue VGB after the appearance of aberrant signals on DWI, and continue to use VGB when imaging disappeared. The anti-seizure effect of VGB remains significant, but its mechanism in optic nerve remains unclear. FA values of some patients without symmetrical thalamic hyper-intensity on DWI were slightly reduced, suggesting that it is possible to maintain the medication if the VGB treatment for seizure free. In this study, it is found that cut-off score that FA value less than 304, the optic nerve might damaged. DTI is widely used to evaluate nerve fiber damage in multiple sclerosis and neuromyelitis optica, but has not been used to evaluate permanent visual field damage caused by VGB 35 . In this study, ADC values of bilateral optic nerve elevated, suggesting that the movement of water molecules in the optic nerve was limited. The results of both optic nerve were only partially significantly different, and both sides were inconsistent, suggesting that the ADC values in response to the diffusion restriction of water molecules in the optic tract were not sensitive enough to response pathological changes in micro-structure earlier 35 .The reasons why optic tract involvement may be seen and why it might be reversible in some patients after VGB is stopped, it is considered that VGBAM is individual difference, just as a few patients were so sensitive to VGB that even though VGB in a less dosage. VGB would keep GABA raised in our bodies until stopping it. Once GABA metabolism in the optic nerve is completed, the abnormal signal disappeared. But there also seem to be individual differences in the timing of complete GABA metabolism. VEP is essentially normal in all groups of patients in this study, which could not determine the location of optic nerve damage and has shortcomings 36 . Therefore, it is not superior to the FA value in DTI, which has monitoring optic nerve fiber damage. Deficiency This is a single center study, and VGBAM is rare to find out as Hussain et.al reported 29 , so that we cannot have a large number of patients to study. DTI imaging follow-up was performed in only 6 patients owing to patient partial compliance. Summary The damage caused by VGB on the optic nerve of children with West syndrome can be monitored by using the FA values of DTI, and it is found that the damage is the most severe with symmetrical thalamic hyper intensity on DWI. The patients have not developed further clinical symptoms, and its mechanism is unclear. When the FA values back to the previous level after stopping VGB, continuing medication might be attempted. This study provided evidence for monitoring optic nerve safety during VGB treatment in patients with West syndrome, and a basis for clinicians to manage drugs safely. Declarations Author Contributions JH designed the study, drafted the initial manuscript, and reviewed and revised the manuscript. GZ,CZ,YF and HZ designed the data collection instruments, collected the data, and reviewed and revised the manuscript. JL and CZ designed the study, coordinated, and supervised data collection, and critically reviewed the manuscript for important intellectual content,they have the exact same contribution to this article. All authors approved the final manuscript as submitted and like to be accountable for all aspects of the work. Consent statement The patients involved in this study, their guardians and carers all signed the informed consent form of clinical research and agreed to publish the inspection results. Disclosure Neither of the authors has any conflict of interest to communicate. Funding This study was financed by Sanming Project of Medicine in Shenzhen(SZSM201812005). 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Hospital","correspondingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Chen","suffix":""},{"id":403001661,"identity":"bcab4f9d-4b6f-46db-85e2-693a7bc22ba6","order_by":2,"name":"Gongwei Zhang","email":"","orcid":"","institution":"Shenzhen Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Gongwei","middleName":"","lastName":"Zhang","suffix":""},{"id":403001662,"identity":"08017723-d69b-45b3-bf79-841d157015ec","order_by":3,"name":"Yu Fang","email":"","orcid":"","institution":"China Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yu","middleName":"","lastName":"Fang","suffix":""},{"id":403001663,"identity":"abbe9ce3-6ff0-4b9c-9286-c4f65c6a3d81","order_by":4,"name":"Huiting Zhang","email":"","orcid":"","institution":"China Medical University","correspondingAuthor":false,"prefix":"","firstName":"Huiting","middleName":"","lastName":"Zhang","suffix":""},{"id":403001664,"identity":"5b4506ab-9fe8-490e-a035-88d5b43ad8c6","order_by":5,"name":"Yilian Li","email":"","orcid":"","institution":"Shenzhen Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yilian","middleName":"","lastName":"Li","suffix":""},{"id":403001665,"identity":"88c4c318-3309-4819-82ec-009bc664bb78","order_by":6,"name":"Jianxiang Liao","email":"","orcid":"","institution":"Shenzhen Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jianxiang","middleName":"","lastName":"Liao","suffix":""},{"id":403001666,"identity":"e0874364-466e-41e0-8b49-0df37c6fe95b","order_by":7,"name":"Cailei Zhao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEElEQVRIie3RMUvDQBTA8XccpMurWV+ItH6EK4HQIeAHcbku6VJdunQIkngQF7WroB9C8QtUH8Ql4OrgkFJwdiodRIy4CYl1c7j/8Kb7De8dgM32H6PvuQtSZKv3WdRzpeRqG4IgpVFYxoF36sRqCwII0Mmpmz+M1BPuUZvoX5lltUmG6HZETlQudMAICpLooImI6yIYnBWEnhFmqGYvRyF3FxUU8WHaQCTp0AeHULHInnX5Og15RyuRciNxaLz24YNwn0VK9zmP7gwqaiNIk9Cvt0AlxYmX1eRG/kKIJtPB+QUhsTAB1Ecmro+sW3bpX45vq836uOfOH5cr+PrKOXP1lkSNpCH9t+c2m81m+9EnBTJV80bxUbMAAAAASUVORK5CYII=","orcid":"","institution":"Shenzhen Children's Hospital","correspondingAuthor":true,"prefix":"","firstName":"Cailei","middleName":"","lastName":"Zhao","suffix":""}],"badges":[],"createdAt":"2025-01-15 09:38:42","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5833219/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5833219/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":74410159,"identity":"3e1bc01e-261c-4a0a-bc44-7b66a9eae471","added_by":"auto","created_at":"2025-01-22 05:29:12","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":74025,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5833219/v1/e24555d345cadbd77f97a08f.jpg"},{"id":74410582,"identity":"b9a82885-ded3-4720-a0b0-d87f8eff5c01","added_by":"auto","created_at":"2025-01-22 05:37:12","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":231176,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5833219/v1/d747ebf51104c033768e1d76.jpg"},{"id":74410166,"identity":"ca7c0171-f1e0-44d1-bc82-0eca16317847","added_by":"auto","created_at":"2025-01-22 05:29:12","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":171001,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5833219/v1/7c4b72e2f33ea324715fc3f3.jpg"},{"id":76596739,"identity":"cf6ced07-450a-40e2-8f93-162dfcf28eff","added_by":"auto","created_at":"2025-02-18 18:46:40","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1219176,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5833219/v1/0f7105f2-c483-45d3-8b93-88206a6a14b9.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Microstructural Damage to the Optic Nerve with Vigabatrin Treatment in West Syndrome: A DTI Study","fulltext":[{"header":"What this paper adds","content":"\u003cp\u003eIt is looking for more sensitive indicators to identify optic nerve injury. It is proved the optic nerve injury caused by VGB is reversible.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eVigabatrin (VGB), an anti-seizure medication (ASM) widely used to treat West syndrome, acts as an irreversible inhibitor of γ-aminobutyric acid (GABA) transaminase \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. This mechanism increases GABA levels in the brain by preventing its breakdown \u003csup\u003e\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e, thereby contributing to its established efficacy in controlling epileptic spasms \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. However, VGB is associated with visual side effects, occurring in approximately one-third of treated children \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. These effects, often referred to as VGB-induced retinopathy, involve retinal toxicity that can lead to segmental dysfunction and atrophy. Studies in adults with VGB retinopathy, utilizing electroretinograms (ERG) and optical coherence tomography (OCT), have demonstrated atrophic thinning of the retinal nerve fiber layer and other forms of retinal cell damage \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eVGB has an efficacyt of 61.8% to achieve seizure free and is currently used as a first-line treatment for West syndrome\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.In the clinical evaluation of visual abnormalities in children with West syndrome by VGB therapy, which is older than 9 years and his cognitive ability was adequate to finish the evaluations like perimetry. Flash visual evoked potentials (FVEP) can be utilized in older than 3 years children. However, FVEP has the disadvantages that a large variation in waveform and latency, and a high false negative rate for lesions of the visual pathway\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Ocular problems of retinopathy in younger are still difficult to detect. Therefore, finding a convenient and accurate method to monitor ocular impairment during VGB therapy in children is the most important.\u003c/p\u003e \u003cp\u003eIt is recognized from autopsy reports that in addition to pathological changes appeared in the retina, atrophy or even partial absence of the optic nerve were found after VGB treatment\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. On the basis of the following two points that the optic nerve and optic tract are retinal fiber layer formation\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e, and the retina and visual pathway (such as lateral geniculate) are distributed with GABA\u003csub\u003eA\u003c/sub\u003e, GABA\u003csub\u003eB\u003c/sub\u003e, and GABA\u003csub\u003eC\u003c/sub\u003e receptors\u003csup\u003e\u003cspan additionalcitationids=\"CR14 CR15 CR16 CR17\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Animal studies demonstrated that VGB acts on the retina and visual pathways to decrease GABA degradation, resulting in GABA elevation caused the pathology happened\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Therefore, monitoring the pathophysiological changes allows assessment of the retinal and intact visual pathway damage caused by VGB therapy in children with West syndrome.\u003c/p\u003e \u003cp\u003eOn conventional structural imaging sequences, a small proportion showed symmetrical thalamic hyper-intensity on DWI, whereas those shows no abnormal imaging with or without DWI hyper-intensity in the thalamus. The appearance of symmetrical thalamic hyper-intensity on DWI, probably associated with keep GABA in the thalamus and visual pathway\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. There was little concern about alterations in the microstructure of the optic nerve at different cerebral imaging, as well as after discontinuation of VGB.\u003c/p\u003e \u003cp\u003eDTI (diffusion tensor imaging) is the imaging technique to study white matter fiber nerve in vivo by the anisotropy of divisional motion of water molecules within the tissue, with parametric FA (fractional anisotropy) values and ADC (apparent diffusion coefficient) values are quite sensitive for assessing the integrity of the nerve microstructure\u003csup\u003e\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. Previous studies have utilized the DTI at the image level (the voxel level) to assess white matter damage, including detection of optic radiation lesions\u003csup\u003e\u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. Additionally, it was utilized in patients with optic neuritis as a method to assess optic nerve fiber tract pathology\u003csup\u003e\u003cspan additionalcitationids=\"CR29\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. However, few reports assess the extent of damage and recovery of the visual pathway by DTI, which caused by VGB. The aim of this study was to find more sensitive monitoring indicators such as FA and ADC values. ROC curves were used to assess optic nerve damage and guide the treatment scheme for VGB.\u003c/p\u003e"},{"header":"Method","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eClinical Data\u003c/h2\u003e \u003cp\u003eA total of 35 patients with West syndrome were consecutively collected from January 2014 to April 2021 in the Shenzhen Children's Hospital. The selection criteria were patients diagnosed with West syndrome, less than 6 months of age, complete clinical data, and a perfect DTI test. The exclusion criteria were patients with defective clinical data, patients unable to cooperate with the test due to sedation, and patients without family consent. And they were divided into three groups: the first group consists of 11 children showing symmetrical thalamic hyper-intensity on DWI by using VGB and other ASMs, such as adrenocortical hormone, Lamotriazine, Levetiracetam and so on. The second group consists of 11 children by using VGB and other ASMs, who did not present symmetrical thalamic hyper intensity on DWI, and the third group consists of 13 patients with West syndrome without VGB using but using other ASMs, which has a normal DWI scan.\u003c/p\u003e \u003cp\u003eIn the first group, after the appearance of symmetrical thalamic hyper-intensity on DWI, all children stopped taking VGB 3 months, only six children were evaluated changes in FA and ADC values of DTI.\u003c/p\u003e \u003cp\u003eClinical data were collected including sex, start age of medication, duration of medication, cumulative dosing, daily dosing, were collected for all children. The study was approved by the Shenzhen Children Hospital Ethics Committee (Ethics Approval No. 2021002).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eImage Acquisitions\u003c/h3\u003e\n\u003cp\u003eAll patients underwent conventional MRI scan and DTI. Foam cushions were utilized to reduce head movements. Imaging data were gathered using an 8-channel head coil on a 3T Siemens scanner (Skyra, Siemens, Germany) at the Shenzhen Children's Hospital (Shenzhen, China). The localization line was the parallel line at the lower border of the corpus callosum. The parameters for conventional axial T1WI and T2WI:T1WI: section thickness of 5 mm, spacing of 1 mm, TR of 2307 ms, TE of 10.6 ms; T2WI: Fast Spin Echo (FSE) sequence: section thickness of 5 mm, spacing of 1 mm, TR of 4000 ms, TE of 103 ms; sagittal T1WI: section thickness of 5 mm, spacing of 1.5 mm, TR of 200 ms, TE of 2.49 ms. The DTI protocol was using a spin echo planar image sequence with the following parameters: TR/TE\u0026thinsp;=\u0026thinsp;6800/93 ms, FOV\u0026thinsp;=\u0026thinsp;220\u0026times;220 mm2, 40 axial slices, slice thickness\u0026thinsp;=\u0026thinsp;2.5 mm, and in plane resolution\u0026thinsp;=\u0026thinsp;1.719\u0026times;1.719 mm2. Diffusion weighing was isotropically distributed along 30 directions (b\u0026thinsp;=\u0026thinsp;1000 s/mm2).\u003c/p\u003e \u003cp\u003eFVEP was monitored using the MEB-9404C device (Nihon Kohden, Japan). The patient wore an LED flash stimulator (Goggles, Unique Medical, Tokyo, Japan) with 20 red lights covered with a transparent protective film to monitor visual function in real time. The monitoring parameters were set as follows: red light source in stimulation mode, stimulation frequency of 1.0 Hz, filter bandwidth of 1-100 Hz and less than 50 overlaps, FVEP and electroretinography (ERG) were recorded approximately 2\u0026ndash;3 times at each time point, and typical waveforms with low interference were used to analyze the data. In this study, the vertical distance between N75 and P100 was defined as the FVEP amplitude, the time to P100 onset was defined as the FVEP latency, and the vertical distance between a and B waves was defined as the ERG amplitude.\u003c/p\u003e\n\u003ch3\u003eImaging Processing\u003c/h3\u003e\n\u003cp\u003eImage post-processing was performed in a blinded fashion by an experienced radiologist at the post-processing workstation of Siemens syngo, and measurements were repeated three times, and the mean values of the evaluated parameters were recorded.\u003c/p\u003e \u003cp\u003eSelection methods for ROI (Region of Interest): the largest diameter of which occupied only 3 pixel points on the transection site, and volume effects of pixel points on the side edges, to ensure the reproducibility and accuracy of the study. The ROI was selected as the middle pixel point of each slice of the image and the starting point of each patient's optic tract with a fixed position on the side. The minimum delineation area (voxel of interest) in the workstation was utilized as the delineation tool (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eData Analyses\u003c/h3\u003e\n\u003cp\u003eSPSS software version 25.0 (IBM Corporation, Armonk, NY, USA) was used to analyze data. It is made use of Shapiro Wilks test to check the distribution of variables and the Levene test to assess homogeneity of variances. Data that had non-normal distribution were presented as medians with interrogative ranges. Comparisons between groups were evaluated with the One-way analysis of variance and Bonferroni\u0026rsquo;s post-hoc test for multiple correction. All tests were two-sided, and P values that smaller than 0.05 were examined statistically significant. ROC curves are used to predict the cut-off score for optic nerve damage. Statistical Graph drawing was performed using the software Graphpad Prism 9.5 version.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eClinical Manifestations\u003c/h2\u003e \u003cp\u003eNone of the patients developed new epileptic symptoms during VGB treatment. In the first group, 11 children were initiated on medication at the age from 0.3 months to 15 months. The duration of medication was from 9.5months to 17.0months.The maximum doses used ranged from 67.0 mg/kg per day to 108.0 mg/kg per day, and the cumulative amount of drug administered ranged from 2.2 grams to 615.0 grams. While in the second group, 11 children were initiated on medication at the age of 3 months to 19 months. The duration of medication was from 7.0months to 19.0 months.The maximum dosage of drugs was between 35.7 mg/kg per day and 194.0 mg/kg per day, and the cumulative amount of drugs ranged from 30.0 grams to 300.00 grams. 13 children in the third group used other ASMs to control seizure, the duration of medication was from 9.5months to 18.0months. (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\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\u003eClinical Manifestations of Participants\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\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 \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eThe first group\u003c/p\u003e \u003cp\u003e(VGB\u0026amp;Abnormal imaging)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eThe second group\u003c/p\u003e \u003cp\u003e(VGB\u0026amp;Normal imaging)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eThe third group\u003c/p\u003e \u003cp\u003e(Control)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of The Patients\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex(Male/Female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5/6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7/6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.865\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStart Age of Medecation(Months)(Median (IQR))\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.0\u003c/p\u003e \u003cp\u003e(1.0\u0026ndash;15.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.0\u003c/p\u003e \u003cp\u003e(3.0\u0026ndash;19.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.0\u003c/p\u003e \u003cp\u003e(2.0\u0026ndash;20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.998\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of Medication(Months)(Median (IQR))\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.0\u003c/p\u003e \u003cp\u003e(10.5\u0026ndash;16.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.0\u003c/p\u003e \u003cp\u003e(7.0- 18.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11.0\u003c/p\u003e \u003cp\u003e(10.0\u0026ndash;17.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaximum of Daily\u003c/p\u003e \u003cp\u003eDose(mg/kg/d)(Median (IQR))\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e93\u003c/p\u003e \u003cp\u003e(67.0-100.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e83\u003c/p\u003e \u003cp\u003e(68.0- 138.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDrug Cumulation(g)(Median (IQR))\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e127.5\u003c/p\u003e \u003cp\u003e(44.6- 158.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e52.5\u003c/p\u003e \u003cp\u003e(30.0-93.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.335\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eConventional Imaging Features\u003c/h3\u003e\n\u003cp\u003eThe thalamus, anterior commissure, globus pallidum, substantial nigra, red nucleus, dentate nucleus, and the dorsal aspect of the brainstem of patients in group one showed symmetric hyper-intensity on DWI (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA and B). Medial geniculate and lateral geniculate hyper-intensity on DWI was seen in 8/11 cases (72.7%), with conventional sequences showing no abnormal signal. Additionally, on conventional sequences, the thalamus was showed slightly lower T1WI signals and slightly higher T2WI signals in 7/11 (63.64%) patients, and the pallidum was showed slightly lower T1WI signals and slightly higher T2WI signals in 5/11 (45.45%) patients. Anterior commissure and dorsal brainstem and dentate nucleus, substantial nigra and red nucleus were unremarkable on routine imaging. Patients in the second and the third group showed no abnormal signal intracranially on conventional and DWI sequences. The optic nerve of all patients showed no abnormal signal on conventional and DWI imaging.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eResults of statistical analysis of FA values and ADC values of both lateral optic\u003c/b\u003e FA and ADC values of the bilateral optic were presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. FA values in the first group were decreased and significantly different from the third group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). ADC values in the first group were enlarged and not statistically different from each other group(P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). After cessation of VGB, the FA values were significantly higher than before (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). In order to distinguish that optic tract damaged or not, an ROC curve was plotted and within the confidence interval, area under the curve (AUC) for LOFA is 0.92 and AUC-ROFA is 0.86, indicating excellent accuracy the cut-off value 304 is measured. the sensitivity and specificity were 63.6% and 100%, respectively(Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eFA and ADC values of the bilateral optic nerve for Participants\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\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 \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eThe first group\u003c/p\u003e \u003cp\u003e(VGB\u0026amp;Abnormal imaging)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eThe second group\u003c/p\u003e \u003cp\u003e(VGB\u0026amp;Normal imaging)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eThe third group\u003c/p\u003e \u003cp\u003e(Control)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003edf\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eROADC ( \u003cb\u003e\u0026times;10-6mm2/s\u003c/b\u003e)\u003c/p\u003e \u003cp\u003e(Median (IQR) )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1209.0\u003c/p\u003e \u003cp\u003e(1173.5-1692.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1125.0\u003c/p\u003e \u003cp\u003e(990.5-1586.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1280.0\u003c/p\u003e \u003cp\u003e(1049.0-1579.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.480\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.623\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLOADC ( \u003cb\u003e\u0026times;10-6mm2/s\u003c/b\u003e)\u003c/p\u003e \u003cp\u003e(Median (IQR) )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1427.0\u003c/p\u003e \u003cp\u003e(1271.5\u0026ndash;1624.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1435.0\u003c/p\u003e \u003cp\u003e(1309.0-1750.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1366.0\u003c/p\u003e \u003cp\u003e(1051.0-1734.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.667\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.520\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eROFA ( \u003cb\u003e\u0026times;10\u0026thinsp;\u0026minus;\u0026thinsp;3)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(Median (IQR) )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e299.0*\u003c/p\u003e \u003cp\u003e(270.5-363.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e463.0\u003c/p\u003e \u003cp\u003e(363.5\u0026ndash;518.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e427.0*\u003c/p\u003e \u003cp\u003e(374.0-533.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e6.173\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLOFA ( \u003cb\u003e\u0026times;10\u0026thinsp;\u0026minus;\u0026thinsp;3)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(Median (IQR) )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e297.0*\u003c/p\u003e \u003cp\u003e(239.00-326.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e390.0\u003c/p\u003e \u003cp\u003e(374.5-411.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e410.0*\u003c/p\u003e \u003cp\u003e(371.0-523.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e9.460\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eNotes: *Significant difference between the first and third groups:p\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn the first group, FA values of bilateral optic nerve were marginally significantly\u003c/p\u003e \u003cp\u003ehigher after discontinuation of VGB for 3 months compared with discontinuation of VGB before,(Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of FA and ADC Values in the Optic Tract of Six Patients while Taking VGB and After Discontinuing VGB for 3 Months\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVGB\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eStop-VGB\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003estatistic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP Value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003eFA value ( \u003cb\u003e\u0026times;10\u0026thinsp;\u0026minus;\u0026thinsp;3)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLOFA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e273. 2\u0026thinsp;\u0026plusmn;\u0026thinsp;64.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e367.0\u0026thinsp;\u0026plusmn;\u0026thinsp;62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.68297\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.044\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eROFA\u003c/p\u003e \u003cp\u003eADC value( \u003cb\u003e\u0026times;10-6mm2/s\u003c/b\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e286.5\u0026thinsp;\u0026plusmn;\u0026thinsp;20.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e437.3\u0026thinsp;\u0026plusmn;\u0026thinsp;128.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.56884\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.050\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLOADC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1509.5\u0026thinsp;\u0026plusmn;\u0026thinsp;310.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1368.5\u0026thinsp;\u0026plusmn;\u0026thinsp;254.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.88412\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.417\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eROADC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1271.0\u0026thinsp;\u0026plusmn;\u0026thinsp;311.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1203.3\u0026thinsp;\u0026plusmn;\u0026thinsp;241.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.74588\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.489\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNotes\u003c/b\u003e: VGB for children taking VGB; Stop VGB for discontinued VGB children; LOFA for left optic tract FA value; ROFA for right optic tract FA value; LOADC is the right optic tract ADC value; ROADC is the left optic tract ADC value.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eFlash Visual evoked potentials\u003c/h3\u003e\n\u003cp\u003eFlash visual evoked potentials were performed in all children, which showed that all patients had a normal P100 with normal amplitude, resulting suggestive of normal optical conduction.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eVigabatrin (VGB) is a first-line treatment for patients with West syndrome and is effective in achieving seizure control. This study provides novel insights into the impact of VGB on optic nerve integrity and its potential reversibility. Specifically, the fractional anisotropy (FA) values of the optic nerve were found to decrease significantly during VGB treatment, accompanied by symmetrical thalamic hyperintensity on diffusion-weighted imaging (DWI), indicating marked microstructural damage to the optic nerve. However, a key finding of this study is that FA values returned to normal levels within three months after discontinuation of VGB, suggesting that VGB-induced microstructural changes in the optic nerve are reversible.\u003c/p\u003e \u003cp\u003eInterestingly, in cases without symmetrical thalamic hyperintensity on DWI, the FA values of the optic nerve did not differ significantly from those of West syndrome patients who had not received VGB, implying that optic nerve damage may be less severe in such cases. This study also highlights that the presence of symmetrical thalamic hyperintensity on DWI may serve as an imaging biomarker for identifying patients at greater risk of optic nerve impairment during VGB treatment.\u003c/p\u003e \u003cp\u003eThe findings underscore the importance of close monitoring of optic nerve integrity during VGB therapy using advanced imaging techniques such as DWI and FA analysis. Furthermore, the observed reversibility of optic nerve damage supports the continued use of VGB for epilepsy management in patients with West syndrome, provided regular monitoring is conducted. This study distinguishes itself from prior research by demonstrating both the reversibility of microstructural optic nerve changes and the potential use of imaging biomarkers to guide personalized treatment strategies.\u003c/p\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eGeneral clinical features and indicators\u003c/h2\u003e \u003cp\u003eVGB is a GABA like hydrophilic structure, which does undergo hepatic metabolism and not bind to plasma proteins\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e, It excretes via the kidneys, and is therefore relatively safe\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. The cumulative amount of drugs used in this study was not changed between the first and second group. The daily VGB dosage was less than the maximum daily dosage that reported, suggesting that the appearance of thalamic symmetric hyper-intensity on DWI had no relevance with the toxicity of VGB excess and unclear relationship with the accumulation volume, this result was different from study of Hussain et al(\u0026gt;\u0026thinsp;175 mg/kg/day)\u003csup\u003e29\u003c/sup\u003e. The DWI symmetrical abnormal signal was related to the maximum daily dosage and the same view was not related to the total accumulation volume.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSignificance of imaging features\u003c/h2\u003e \u003cp\u003eSymmetrical abnormal hyper intensity in the subthalamus and basal ganglia on DWI after drug administration, and disappeared after drug withdrawal. It suggested that the abnormal hyper-intensity caused cytotoxic edema due to the metabolism of VGB. It is in line with literature mentioning that cytotoxic edema appeared in pathological sections of the rats\u0026rsquo; brain after treatment of VGB\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e,as well as appeared in human brain\u003csup\u003e\u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e.It is found that the GABA\u003csub\u003eA\u003c/sub\u003e, GABA\u003csub\u003eB\u003c/sub\u003e and GABA\u003csub\u003eC\u003c/sub\u003e receptors have differential distribution in the CNS, loss of GABA degradation was associated in the thalamus as well as in the above anatomical sites, and the specific mechanisms are not known\u003csup\u003e\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn this study, it is first found that abnormal signals in gray matter nuclei, such as the substantial nigra, red nucleus, medial geniculate body, and lateral geniculate body. It was proposed that these gray matter lesions and thalamus lesions are similar and the same as cytotoxic edema.\u003c/p\u003e \u003cp\u003eDTI in the assessment of fiber tracts in brain tissue has served in lesions of the optic nerve, optic tract, and optic radiation. FA is one characteristic of DTI that closes relative to myelin integrity, nerve fiber density, or orientation of myelin sheath\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. ADC is an important index in DTI to measure Brown motion of water molecules in vivo\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e, It reflected the patho-physiological alterations in the micro-structure of the fiber tracts\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e, which can be used to evaluate the integrity of the visual fiber tracts. We wanted to monitor the injury of optic nerve by DTI in routine practice, because a few patients were so sensitive to VGB that even though VGB in a less dosage. When the dosage added, although they didn\u0026rsquo;t have new symptoms, actually the injury of optic nerve happened. DTI can help us early to find out the dosage VGB is suitable or not. In this study, FA values on DTI of the optic nerve fiber tracts in the first group were significantly decreasing compared with other groups, suggesting that the optic nerve was severely damaged with symmetrical thalamic hyper-intensity on DWI after taking VGB. It may be linked to the role of VGB in inhibiting cerebral cortical excitability and suppressing seizures, as well as the reduced degradation of GABA in the retina, visual pathways and thalamus\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. While FA values returned to normal levels after 3 months of VGB withdrawal and were not significantly different from the first group, suggesting that this cytotoxic damage of the nerve fiber is reversible and somewhat separate from the irreversible visual damage\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Therefore, this study suggested that when symmetric thalamic hyper-intensity appeared on DWI, it could be properly discontinued. The integrity of the micro-structure would be restored after about 3 months and the medication could be expected to continue. It is also observed that some patients discontinue VGB after the appearance of aberrant signals on DWI, and continue to use VGB when imaging disappeared. The anti-seizure effect of VGB remains significant, but its mechanism in optic nerve remains unclear. FA values of some patients without symmetrical thalamic hyper-intensity on DWI were slightly reduced, suggesting that it is possible to maintain the medication if the VGB treatment for seizure free. In this study, it is found that cut-off score that FA value less than 304, the optic nerve might damaged. DTI is widely used to evaluate nerve fiber damage in multiple sclerosis and neuromyelitis optica, but has not been used to evaluate permanent visual field damage caused by VGB\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn this study, ADC values of bilateral optic nerve elevated, suggesting that the movement of water molecules in the optic nerve was limited. The results of both optic nerve were only partially significantly different, and both sides were inconsistent, suggesting that the ADC values in response to the diffusion restriction of water molecules in the optic tract were not sensitive enough to response pathological changes in micro-structure earlier\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e.The reasons why optic tract involvement may be seen and why it might be reversible in some patients after VGB is stopped, it is considered that VGBAM is individual difference, just as a few patients were so sensitive to VGB that even though VGB in a less dosage. VGB would keep GABA raised in our bodies until stopping it. Once GABA metabolism in the optic nerve is completed, the abnormal signal disappeared. But there also seem to be individual differences in the timing of complete GABA metabolism.\u003c/p\u003e \u003cp\u003eVEP is essentially normal in all groups of patients in this study, which could not determine the location of optic nerve damage and has shortcomings\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. Therefore, it is not superior to the FA value in DTI, which has monitoring optic nerve fiber damage.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eDeficiency\u003c/h2\u003e \u003cp\u003eThis is a single center study, and VGBAM is rare to find out as Hussain et.al reported\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e, so that we cannot have a large number of patients to study. DTI imaging follow-up was performed in only 6 patients owing to patient partial compliance.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eSummary\u003c/h2\u003e \u003cp\u003eThe damage caused by VGB on the optic nerve of children with West syndrome can be monitored by using the FA values of DTI, and it is found that the damage is the most severe with symmetrical thalamic hyper intensity on DWI. The patients have not developed further clinical symptoms, and its mechanism is unclear. When the FA values back to the previous level after stopping VGB, continuing medication might be attempted. This study provided evidence for monitoring optic nerve safety during VGB treatment in patients with West syndrome, and a basis for clinicians to manage drugs safely.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eJH\u003c/strong\u003e designed the study, drafted the initial manuscript, and reviewed and revised the manuscript. \u003cstrong\u003eGZ,CZ,YF\u003c/strong\u003e and\u003cstrong\u003e\u0026nbsp;HZ\u003c/strong\u003e designed the data collection instruments, collected the data, and reviewed and revised the manuscript. \u003cstrong\u003eJL\u003c/strong\u003e and \u003cstrong\u003eCZ\u003c/strong\u003e designed the study, coordinated, and supervised data collection, and critically reviewed the manuscript for important intellectual content,they have the exact same contribution to this article. All authors approved the final manuscript as submitted and like to be accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe patients involved in this study, their guardians and carers all signed the informed consent form of clinical research and agreed to publish the inspection results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNeither of the authors has any conflict of interest to communicate.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study was financed by Sanming Project of Medicine in Shenzhen(SZSM201812005).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBen-Menachem EV (1995) \u003cem\u003eEpilepsia\u003c/em\u003e.36(Suppl 2): S95\u0026ndash;S\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e104.6.https://doi.org/10.1111/j.1528-1157.1995.tb06003.x\u003c/span\u003e\u003cspan address=\"104.6.10.1111/j.1528-1157.1995.tb06003.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCubells JF, Blanchard JS, Smith DM et al (1986) In vivo action of enzyme-activated irreversible inhibitors of glutamic acid decarboxylase and gammaaminobutyric acid transaminase in retina vs.brain. 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J Magn Reson Imaging 06(6). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/jmri.25528\u003c/span\u003e\u003cspan address=\"10.1002/jmri.25528\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCammann R (1985) Use of visual evoked potentials in neurology\u0026ndash;a review.II.Zentralblatt fur. \u003cem\u003eNeurochirurgie.\u003c/em\u003e\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":"vigabatrin, nuclear magnetic resonance, cytotoxic oedema, optic nerve integrity","lastPublishedDoi":"10.21203/rs.3.rs-5833219/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5833219/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective:\u003c/strong\u003e This study aimed to assess the side effects of vigabatrin (VGB), focusing on optic nerve fiber damage in children with West syndrome, using DTI imaging parameters.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethod: \u003c/strong\u003eClinical data and DTI images were analyzed, recording FA and ADC values for both optic nerves. ROC curves were used to determine fractional anisotropy thresholds for optic nerve damage.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThirty-five children with West syndrome (0.3-22 months old, male: female = 19:16) were divided into three groups: (1) VGB and other anti-seizure medications (ASMs) with symmetrical thalamus abnormalities, (2) VGB and ASMs without thalamus abnormalities, and (3) control group with other ASMs. FA values in group 1 were significantly lower than in group 3 (P \u0026lt; 0.05), and FA values increased after VGB discontinuation (P \u0026lt; 0.05). The ROC analysis showed a cut-off score of 304 with 63.6% sensitivity and 100% specificity for detecting optic nerve damage.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e FA values are effective imaging markers for detecting VGB-induced optic nerve damage in West syndrome, especially when thalamus abnormalities are present. FA values significantly improve after stopping VGB treatment.\u003c/p\u003e","manuscriptTitle":"Microstructural Damage to the Optic Nerve with Vigabatrin Treatment in West Syndrome: A DTI Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-22 05:29:07","doi":"10.21203/rs.3.rs-5833219/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":"6eb9c9ff-2987-4630-865d-d89b64348db3","owner":[],"postedDate":"January 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-02-27T05:38:26+00:00","versionOfRecord":[],"versionCreatedAt":"2025-01-22 05:29:07","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5833219","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5833219","identity":"rs-5833219","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}