Long term analysis of the epileptic outcome in a consecutive series of 50 patients with "non-enhancing" IDH-mutated gliomas with a mean follow-up of 70 months

Long term analysis of the epileptic outcome in a consecutive series of 50 patients with "non-enhancing" IDH-mutated gliomas with a mean follow-up of 70 months | 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 Long term analysis of the epileptic outcome in a consecutive series of 50 patients with "non-enhancing" IDH-mutated gliomas with a mean follow-up of 70 months Francesco Salomi, Francesco Guerrini, Viola Marta Custodi, Pasquale De Bonis, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9031484/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Patients with low-grade gliomas tipically experience seizures at the onset and are generally treated with surgery that, especially when radical and uncomplicated, can ensure good post operative seizure control. There is very little data available to understand the evolution of seizures throughout the history of these patients. This retrospective study aims to analyze long-term epileptic data of 50 consecutive patients who underwent resection of non-enhancing IDH-mutated glioma between 2006 and 2020. Several factors were analyzed with a mean follow-up of 70 months. During the follow-up, 28 patients experienced seizures (56%), of which 11 were uncontrolled (39.3%), while 22 patients did not experienced seizures (44%). The average time of first postoperative seizure was 30 months. The only significant variables in the univariate analyses were GTR ( p = 0.019), preoperative seizures control ( p = 0.029) and radiological progression during the follow up ( p = 0.002). The only independent predictor in a multivariate logistic regression was the progression of the disease (OR 5.145, 95% CI 0.188–3.162, p = 0.03). A ROC curve based on recurrence or absence of seizures was computed and the optimal threshold of residual tumor volume was 0.5 cm 3 . Kaplan-Meier approach showed no significant differences between the two groups in terms of overall survival ( p = 0.76) and progression free survival ( p = 0.054). Our data show that, in the long term, the only risk factor for the recurrence of epilepsy may be the recurrence of the disease itself. Conversely, the presence or absence of seizure control does not seem to be significantly correlated with overall survival and progression free survival epilepsy seizures IDH mutated glioma surgery antiepileptic drugs prognosis Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Low-grade gliomas (LGG) account for 15–20% of all gliomas and 9–45% of non enhancing tumors are histologically high grade [ 1 ]. Up to 80–90% of patients with low-grade glioma experience seizures before tumor diagnosis [ 2 ], while approximately 25% of cases have seizures onset in the postoperative period [ 3 , 4 ], negatively impacting the quality of life for both the patient and their family. The literature is consistent in stating that the likelihood of tumor-related epilepsy onset depends on several factors, including the location (frontal, insular, temporal) [ 5 , 6 ], histology, and volume. The IDH1/2 mutation, overexpression of p53, and the presence of the 1p19q co-deletion, combined with the pathophysiology of epileptic seizures, represent additional factors that increase the likelihood of epileptogenesis. These tumors are generally treated with surgery and any necessary adjuvant therapies. Various evidence shows that surgery, especially when radical and without complications, can ensure good seizure control in the postoperative period [ 7 ]. Additionally, radiotherapy and chemotherapy may also help reduce the risk of seizures [ 8 ]. There is very little data available to help understand the evolution of seizures throughout the complex and often long history of these patients in relation to various therapeutic phases. The purpose of this study was to analyze these still unclear aspects by providing long-term follow-up data. Materials and methods This retrospective study analyzed a database of patients who underwent resection of non-enhancing glioma between 2006 and 2020. The study protocol was approved by the local Ethics Committee and has been performed in accordance with Declaration of Helsinki for human rights. Informed consent was not required due to the study's retrospective design and the anonymization of patients’ data. The inclusion criteria consisted of age between 16 and 80 years old, non-enhancing IDH-mutated gliomas, and first diagnosis of the disease. All patients who had been previously treated or had a follow-up of less than 12 months were excluded, as well as all cases of biopsy. Several factors were analyzed, including tumor location, KPS, tumor volume, duration, frequency and type of preoperative seizures, degree of surgical resection, residual volume, histology (according to WHO 2007 and 2016), and adjuvant treatments. A surgical resection of 90% or more of the total volume was considered a subtotal resection (STR). Two authors (F.G., V.M.C.) blinded to patient outcome data measured volumetric extent of resection (EOR) through manual segmentation using BrainLab Elements software (BrainLAB Inc., Feldkirchen, Germany) by comparing regions of interest (ROI) on the basis of hyperintensity signal on FLAIR MRI scans obtaind pre-operatively and between 1 and 3 months after surgery, to minimize effects of surgically induced changes like oedema, calculating the post operative residual volume. All patients were also evaluated from a neurological standpoint, and the antiepileptic therapy was progressively reduced at intervals of at least six months in the absence of epileptic seizures. During the follow up, every occurrence of seizures were recorded, evaluating the time interval between the date of the seizure and the radiological evidence of disease progression. A recurrence of epilepsy was considered if it occurred at least 12 months after surgery. Statistical analysis The primary clinical outcome was the onset of seizures during the follow up and an univariate analysis was performed using the chi-square test for categorical variables and the Mann-Withney-U test for continuous variables. A multivariate analysis using a model of logistic regression was then performed to assess the predictive impact of multiple indipendent variables on the onset of seizures. P value < 0.05 was considered statistically significant. To evaluate the residual tumor volume as a predictor, a ROC curve was plotted to determine the value of higher sensitivity and specificity. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method and log rank test was used to assess differences in the seizures outcome. A probability value < 0.05 was consider significative. For the statistical analysis, the SPSS v26.0 and the software R version 4.1.0 were used. Results 50 consecutive patients were included in the study, with a mean age of 42.5 years old (min 18 - max 77). There was a predominance of male patients, with 33 males and 17 females. The mean follow-up was 70 months (min 34-max 192). The demographic, clinical, histological, radiological and molecular data are summarized in the table 1. The diagnosis was astrocytoma in 28 cases (56%) and oligodendroglioma in 22 cases (44%), of which 6 and 3 respectively were grade III. The tumor was revealed by epileptic seizures in 38 patients (76%), while, in the 12 remaining patients, the tumor was diagnosed incidentally in 8 patients (16%) and because of neurological deficits in 4 patients (8%). Preoperative anticonvulsant treatment was administered to 36 patients, of whom 5 patients had seizures that were still uncontrolled (13.1%). No anticonvulsant prophylaxis was undertaken. The most commonly used medication, in 31 patients, was Levetiracetam (86.1%). Preoperative epileptic data are shown in table 2. The preoperative tumor volume was highly variable, with a minimum of 7.3 cm³, a maximum of 276.7 cm³, and a mean volume of 95.7 cm³. The residual tumor volume ranged from 0 to 50.2 cm³, with a median residual volume of 4,1 cm³. After the surgical procedure, 26 patients (52%) underwent adjuvant treatment, of which 11 received chemotherapy with temozolomide and radiotherapy (42.3%), and 15 received only radiotherapy (57.7%). A radiological evidence of progression of disease was observed in 34 patients (68%), with a median PFS of 48 months (min 6-max 90), and a different time to progression between astrocytomas (40 months) and oligodendrogliomas (68 months). A second surgery for tumor recurrence/progression was performed in 7 patients (14%), of whom 5 had previously undergone STR and 2 had a gross total resection (GTR). The mean time between the first and second surgery was 25 months (min 12-max 48). Currently, 25 patients are still alive (50%), of whom 15 (60%) have tumor presence and 10 (40%) show no evidence of disease, while 25 patients have passed away (50%), with only one (4%) due to other causes. The median OS was 84 months, with a different survival between oligodendroglioma and astrocytoma of respectively 90 and 82 months, and between grade II and III of respectively 90 and 78 months. Post operative seizures control analysis . During the follow-up, 28 patients experienced seizures (56%), of which 11 had uncontrolled seizures (39.3%) despite multiple pharmacological changes. In contrast, 22 patients (44%) did not experienced seizure episodes during the follow up. Among the 12 patients who did not have epilepsy before surgery, 7 remained seizure-free during the follow-up (58.3%), 3 developed pharmacologically controlled epilepsy (25%), and 2 had intractable epilepsy (16.7%). These last two patients underwent a partial resection respectively of an astrocytoma and an oligodendroglioma, both grade III, and adjuvant chemotherapy and radiotherapy. Epileptic data are synthetized in Fig. 1 . Among the 16 patients with temporal lobe gliomas, 10 patients (62,5%) experienced postoperative seizures, of whom only one patient had intractable epilepsy following the onset of disease progression. In the 7 cases of precentral glioma, two patients (28,6%) experienced intractable epilepsy during the follow-up, in both cases concomitant with disease progression. The mean interval between surgery and the first postoperative seizure was 30 months. Among the variables reported in tables, the only ones found to be significant in the univariate analyses were GTR ( p = 0.019), preoperative seizures control ( p = 0.029) and radiological evidence of relapse or progression within three months after the epilepsy recurrence ( p = 0.002). These variables were than included in a multivariate analysis using a model of logistic regression and the only independent predictor of epileptic outcome was the radiological progression of the disease (OR 5.145, 95% CI 0.188–3.162, p = 0.03). A ROC curve was constructed to determine a predictive residual volume cutoff, based on the occurrence or absence of epileptic seizures following surgery (Fig. 2 ). The optimal threshold was a residual tumor volume of 0.5 cm 3 , which corresponded to the point of highest sensitivity (0,826) and specificity (0.568). Using the Kaplan-Meier method, we evaluated OS and PFS based on the presence or absence of seizures during follow-up. Patients without seizures showed a progressively decreasing survival, with a survival rate of 60.3% at 73 months and 59.1% at 95 months, Patients with seizures showed similar results with a survival rate of 43.6% at 90 months. Log-rank test showed no significant differences between the two groups ( p = 0.76) (Fig. 3 ). In patients without seizures, PFS progressively decreases to 62.9% at 48 months, while in patients with seizures, PFS declines rapidly after 24 months, reaching 32.9% at 48 months. Log-rank test suggested a possible difference between the two groups, but not strong enough to be considered significant ( p = 0.054) (Fig. 4 ). Discussion Epilepsy often represents the manifestation of a brain tumors, especially LGGs, due to their infiltrative nature and slower growth rate. To consider a patient disease-free, a 12-month cutoff is generally used because, after this period, any recurrence of seizures is more likely to be attributed to a neoplastic recurrence rather than to poor seizure control [ 9 ]. In this retrospective study, we analyzed the long-term and very long-term epileptological outcome of 50 consecutive patients who underwent resection of a non-enhancing IDH-mutated glioma, in relation to various pre- and postoperative variables. Most studies in the literature report results obtained in the short term (generally with 6–18 months of follow-up), while our study is based on data collected with a mean follow-up of 70 months. The location of the tumor is an important prognostic factor in patients with brain glioma, because it influences surgical resectability, seizure control following treatment and survival. Tumors located in the temporal and in the precentral frontal region are associated with a more unfavorable outcome in terms of seizure control [ 6 , 10 ]. A worse epileptic outcome in primary motor area locations is believed to stem from its localization itself, as being an eloquent area, making often impossible to achieve a radical resection [ 7 ]. However, in our study, no localization or lateralization of the tumor was significantly correlated with the epileptic outcome. Several studies have reported that a time interval of more than 12 months between seizure onset and surgery or preoperative intractable seizures are negative prognostic factors for epileptic outcome [ 7 , 11 ]. In our case series, however, no patient underwent surgery more than a year after the onset of the disease. Therefore, we divided the onset of epilepsy into less than one month, less than three months, and more than three months before surgery, and no significant differences were observed. Similarly, pharmacological control of epilepsy before surgery was significant in univariate analyses but not in a multivariate model. Tumors with particularly large volumes cause more disabling neurological impairment, both organically and functionally, and are often associated with more challenging resections due to the involvement of eloquent areas. The literature consistently highlights the prognostic role of tumor volume; however, there is no consensus on the threshold defining a patient with a worse outcome [ 12 ]. Regarding epileptological outcome, rather than the initial tumor volume, other variables appear to be more significant for better epilepsy control. The EOR, as radical as possible, is considered the gold standard in glioma therapy. Several studies demonstrate that the EOR is a factor correlated with both seizure freedom and survival [ 7 , 8 , 12 , 13 ]. Various tumor resection cut-offs have been described as significant for better postoperative seizure control. These range from 80% [ 13 ], to 85% [ 8 ], to 91% [ 15 ]. We divided the types of resection into three categories: gross total, subtotal, and partial, using a cut-off of values lower than 90% to define a resection as partial. Only a GTR was found to have an impact on seizure control but only in univariate analysis. Similarly, the residual volume is considered an independent variable for both survival and seizure control. However, there is no consensus on the cut-off to be considered [ 14 , 15 ], and significant results have been reported with post-surgical residual tumor volumes even higher than 10cc [ 8 , 15 ]. We found a significant cut-off corresponding to 0.5cc. This can be explained by the fact that, in the long term, even smaller residues inevitably lead to disease progression, and therefore to a progressive higher probability of developing epilepsy. The same applies to EOR, but obviously, it is often not possible to achieve a GTR in cases of tumors located in deep sites or in eloquent areas. The use of adjuvant radiotherapy is also considered one of the factors positively impacting patient outcomes, both in terms of PFS and seizure control, with an effectiveness ranging from 72–100% [ 16 , 17 , 18 ]. In addition to its antitumor effect, it seems to reduce epileptic activity by damaging epileptogenic neurons and altering the microenvironment of the peritumoral tissue. Moreover, the use of concomitant adjuvant chemotherapy is also considered a favorable prognostic factor for increased survival and symptom control, with effectiveness in 48–100% of cases [ 13 , 19 ]. However, in our study no adjuvant treatment has been found to be protective in seizure control after surgery in long term. This may also be explained by the fact that adjuvant therapy is indicated in cases of tumors with more aggressive characteristics, so the epileptic outcome is inevitably influenced by other tumor-related factors (EOR, histotype, residual volume, etc.). Our results suggest that the factors generally described as protective against the development of seizures after surgery are likely relevant in the short term. However, the long history of these patients is usually marked by a disease progression, and, in the long term, the only risk factor for the recurrence of epilepsy is the recurrence of the disease itself. Recent studies seem to highlight the oncogenic role of epilepsy as a factor that may promote neoplastic progression so that some antiepileptic drugs have shown promising results regarding their mechanism of action, even in an anti-tumor mechanism [ 20 ]. It seems that the control of tumor-related epilepsy may influence survival [ 21 , 22 ]. The reciprocal relationship between epilepsy and tumor progression can therefore explain the correlation with improved OS, not so much due to pharmacological control, but rather because the absence of seizures is a sign of a disease that is currently inactive. Several studies have highlighted that a worsening of the epileptic condition may be a warning sign of disease progression, with a neuroradiological evidence of disease progression up to 3 months after the onset of new seizure symptoms [ 23 , 24 ]. Our results have indeed shown a possible correlation between the absence of seizures during follow-up and PFS, but no correlation with survival. Currently, with the new WHO 2021 classification, molecular alterations have gained greater importance both as determinants of disease prognosis and as potential targets for therapies. Several studies demonstrated that IDH mutations are more commonly linked to tumor-related seizures [ 25 , 26 , 27 ]. One suggested explanation is that D-2-hydroxyglutarate (D2HG), a byproduct of mutant IDH, shares structural similarities with glutamate, a key excitatory neurotransmitter in the central nervous system. As a result, D2HG may disrupt the balance between excitatory and inhibitory regions in the brain, potentially leading to epilepsy. Conversely, 1p19q status is not univocally considered a significant predictor of epilepsy [ 11 , 28 , 29 , 30 , 31 ]. In our study, we analyzed the cases according to the 2007 and 2016 WHO classifications, as the patients studied underwent surgery up to 2019, but no difference in epileptic outcomes was found between astrocytomas and oligodendrogliomas and between grade II and III. However, molecular findings should be interpreted with caution, given the low statistical power and potential bias resulting from the missing data in our database. Among the limitations of this study, the retrospective nature of the analysis certainly stands out, which may lead to potential errors in data collection. Additionally, while the sample size is reasonably representative, it may not be large enough to yield statistically significant results. Further long-term multicentric studies are needed to confirm our findings. Furthermore, ROI tracking in imaging analysis software was performed using a semi-automatic freehand drawing tool and is therefore susceptible to potential bias. Conclusions Seizures are an important symptom associated with brain gliomas that significantly impact patients’ quality of life. Surgical resection is an effective treatment in reducing seizures; however, given the long course of the disease, in the long term our data showed that recurrence/progression of the disease appears to be the only risk factor associated with the recurrence of epilepsy. Lastly, the presence or absence of seizure control does not seem to be significantly correlated with overall survival and progression free survival. Declarations Acknowledgements . Thanks to Marco Viganò for his support with statistical analysis Competing interests. The authors have no personal, financial, or institutional interest in any of the materials or devices described in this article. Funding. The authors declare that no funds, grants, or other support were received during the preparation of this manuscript Clinical trial number. Not applicable Author contributions. G.S. conceptualization; F.S., F.G. and V. M. C. data curation, formal analysis; F.S. Writing – review & editing; G.S., F.S., P.D.B. and F.G. supervision. All authors have read and approved the final manuscript. Ethics approval. This study was conducted in accordance with the Declaration of Helsinki, and approved by the local Ethics Committee of Fondazione IRCCS Policlinico San Matteo (code 2023-3.11-43) Consent to participate. Not applicable. As this was a retrospective study, the requirement for informed consent to participate and/or publish was waived by the IRB. References Eichberg DG, Di L, Morell AA et al (2020) Incidence of high grade gliomas presenting as radiographically non-enhancing lesions: experience in 111 surgically treated non-enhancing gliomas with tissue diagnosis. J Neurooncol 147(3):671–679. 10.1007/s11060-020-03474-z Berntsson SG, Malmer B, Bondy ML, Qu M, Smits A (2009) Tumor-associated epilepsy and glioma: are there common genetic pathways? Acta Oncol 48(7):955–963. 10.1080/02841860903104145 Manaka S, Ishijima B, Mayanagi Y (2003) Postoperative seizures: epidemiology, pathology, and prophylaxis. 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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-9031484","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":605130414,"identity":"43661a85-3345-4931-ac39-5d20439a1af1","order_by":0,"name":"Francesco Salomi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6UlEQVRIie3RsQrCMBAG4IOCWSJdIy0+QyFQOhT7KilCt+4dddFF8FUEoXOgoxXXQheLL6C4ZNNUEVT00E0k/5DhuI+7IwAmJj8YMtLPFoDaD2WBECqvDbTXWnlrFYi5EfDkPcHGUCDNXmS5yzer+HhQYR+cmQeNwgjlTJQ19at0yaRIOLilhy4WacTiSUu6C02KeMQSgd8CZKdawufrpZLi9AkB/zLFgzTXU6QmQ4kTi/pBewur0jwokyHvuIXUNyGETHfVPqsjWy9WZeGgbzvjcaPC9wSs50KH6f9BwKuwL/tNTExM/j5nSw1QaQlKjlYAAAAASUVORK5CYII=","orcid":"","institution":"Fondazione IRCCS Policlinico San Matteo","correspondingAuthor":true,"prefix":"","firstName":"Francesco","middleName":"","lastName":"Salomi","suffix":""},{"id":605130415,"identity":"a7e97c2f-0d21-496a-94ee-8870b507a594","order_by":1,"name":"Francesco Guerrini","email":"","orcid":"","institution":"Fondazione IRCCS Policlinico San Matteo","correspondingAuthor":false,"prefix":"","firstName":"Francesco","middleName":"","lastName":"Guerrini","suffix":""},{"id":605130416,"identity":"93fdf042-33a0-4fea-bb43-b3232969d4e4","order_by":2,"name":"Viola Marta Custodi","email":"","orcid":"","institution":"Fondazione IRCCS Policlinico San Matteo","correspondingAuthor":false,"prefix":"","firstName":"Viola","middleName":"Marta","lastName":"Custodi","suffix":""},{"id":605130425,"identity":"5de1feb2-8375-4121-8f55-1cae61f3fe23","order_by":3,"name":"Pasquale De Bonis","email":"","orcid":"","institution":"Sant'Anna University Hospital of Ferrara","correspondingAuthor":false,"prefix":"","firstName":"Pasquale","middleName":"","lastName":"De Bonis","suffix":""},{"id":605130426,"identity":"040ec971-8e6c-4072-b5eb-883be3404732","order_by":4,"name":"Giannantonio Spena","email":"","orcid":"","institution":"Fondazione IRCCS Policlinico San Matteo","correspondingAuthor":false,"prefix":"","firstName":"Giannantonio","middleName":"","lastName":"Spena","suffix":""}],"badges":[],"createdAt":"2026-03-04 14:39:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9031484/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9031484/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104835613,"identity":"b347c20c-1eb4-4f74-9c0b-fa6ce6a506d3","added_by":"auto","created_at":"2026-03-17 17:46:47","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":229179,"visible":true,"origin":"","legend":"\u003cp\u003eSummary of epileptic data of non enhancing IDH mutated gliomas\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9031484/v1/f1ac94171b99f8a1d5576961.png"},{"id":104668010,"identity":"f60695e9-dc9c-4846-9fea-6d33e20008cb","added_by":"auto","created_at":"2026-03-15 16:50:51","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":67475,"visible":true,"origin":"","legend":"\u003cp\u003eROC curve for residual volume on FLAIR images, to predict post operative seizures recurrence. The optimal threshold corresponded to a residual volume of 0,5 cm\u003csup\u003e3\u003c/sup\u003e, which was the point with the highest sensitivity (0.826 and specificity (0.568), with a resulting area under the curve of 0.698 (CI 95% 0.547-0.849)\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-9031484/v1/0441240af520ac348203be15.png"},{"id":104668012,"identity":"c34b8498-44ca-4410-8ddd-7c5bfc94c261","added_by":"auto","created_at":"2026-03-15 16:50:51","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":129278,"visible":true,"origin":"","legend":"\u003cp\u003eOverall survival stratified according to presence or absence of seizures during follow up, approached with a kaplan-Meier method. Log rank test (\u003cem\u003ep\u003c/em\u003e=0.76)\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-9031484/v1/4c554425276770944cd44240.png"},{"id":104782886,"identity":"b6dd7c73-a898-49a6-b9e3-c23a54c03cd9","added_by":"auto","created_at":"2026-03-17 07:57:54","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":115605,"visible":true,"origin":"","legend":"\u003cp\u003eProgression-free survival stratified according to presence or absence of seizures during follow up, approached with a kaplan-Meier method. Log rank test (\u003cem\u003ep\u003c/em\u003e=0.054)\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-9031484/v1/cd5c3a82f4c5c73e544321eb.png"},{"id":104836096,"identity":"b6580efc-1420-4023-915f-ad8e440065d7","added_by":"auto","created_at":"2026-03-17 17:51:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":988022,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9031484/v1/d9e7ba82-493e-4811-bdc0-9d5188527489.pdf"},{"id":104668008,"identity":"6631de84-b50c-4bf4-ab54-5d8693e6370b","added_by":"auto","created_at":"2026-03-15 16:50:51","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":18602,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-9031484/v1/bb9a6ccf8aab958ce5417e8a.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eLong term analysis of the epileptic outcome in a consecutive series of 50 patients with \"non-enhancing\" IDH-mutated gliomas with a mean follow-up of 70 months\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLow-grade gliomas (LGG) account for 15\u0026ndash;20% of all gliomas and 9\u0026ndash;45% of non enhancing tumors are histologically high grade [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Up to 80\u0026ndash;90% of patients with low-grade glioma experience seizures before tumor diagnosis [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], while approximately 25% of cases have seizures onset in the postoperative period [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], negatively impacting the quality of life for both the patient and their family. The literature is consistent in stating that the likelihood of tumor-related epilepsy onset depends on several factors, including the location (frontal, insular, temporal) [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], histology, and volume. The IDH1/2 mutation, overexpression of p53, and the presence of the 1p19q co-deletion, combined with the pathophysiology of epileptic seizures, represent additional factors that increase the likelihood of epileptogenesis. These tumors are generally treated with surgery and any necessary adjuvant therapies. Various evidence shows that surgery, especially when radical and without complications, can ensure good seizure control in the postoperative period [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Additionally, radiotherapy and chemotherapy may also help reduce the risk of seizures [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. There is very little data available to help understand the evolution of seizures throughout the complex and often long history of these patients in relation to various therapeutic phases. The purpose of this study was to analyze these still unclear aspects by providing long-term follow-up data.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003eThis retrospective study analyzed a database of patients who underwent resection of non-enhancing glioma between 2006 and 2020. The study protocol was approved by the local Ethics Committee and has been performed in accordance with Declaration of Helsinki for human rights. Informed consent was not required due to the study's retrospective design and the anonymization of patients\u0026rsquo; data. The inclusion criteria consisted of age between 16 and 80 years old, non-enhancing IDH-mutated gliomas, and first diagnosis of the disease. All patients who had been previously treated or had a follow-up of less than 12 months were excluded, as well as all cases of biopsy. Several factors were analyzed, including tumor location, KPS, tumor volume, duration, frequency and type of preoperative seizures, degree of surgical resection, residual volume, histology (according to WHO 2007 and 2016), and adjuvant treatments. A surgical resection of 90% or more of the total volume was considered a subtotal resection (STR). Two authors (F.G., V.M.C.) blinded to patient outcome data measured volumetric extent of resection (EOR) through manual segmentation using BrainLab Elements software (BrainLAB Inc., Feldkirchen, Germany) by comparing regions of interest (ROI) on the basis of hyperintensity signal on FLAIR MRI scans obtaind pre-operatively and between 1 and 3 months after surgery, to minimize effects of surgically induced changes like oedema, calculating the post operative residual volume. All patients were also evaluated from a neurological standpoint, and the antiepileptic therapy was progressively reduced at intervals of at least six months in the absence of epileptic seizures. During the follow up, every occurrence of seizures were recorded, evaluating the time interval between the date of the seizure and the radiological evidence of disease progression. A recurrence of epilepsy was considered if it occurred at least 12 months after surgery.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe primary clinical outcome was the onset of seizures during the follow up and an univariate analysis was performed using the chi-square test for categorical variables and the Mann-Withney-U test for continuous variables. A multivariate analysis using a model of logistic regression was then performed to assess the predictive impact of multiple indipendent variables on the onset of seizures. P value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. To evaluate the residual tumor volume as a predictor, a ROC curve was plotted to determine the value of higher sensitivity and specificity. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method and log rank test was used to assess differences in the seizures outcome. A probability value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was consider significative. For the statistical analysis, the SPSS v26.0 and the software \u003cb\u003eR\u003c/b\u003e version 4.1.0 were used.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e50 consecutive patients were included in the study, with a mean age of 42.5 years old (min 18 - max 77). There was a predominance of male patients, with 33 males and 17 females. The mean follow-up was 70 months (min 34-max 192). The demographic, clinical, histological, radiological and molecular data are summarized in the table 1.\u003c/p\u003e\n\u003cdiv\u003eThe diagnosis was astrocytoma in 28 cases (56%) and oligodendroglioma in 22 cases (44%), of which 6 and 3 respectively were grade III. The tumor was revealed by epileptic seizures in 38 patients (76%), while, in the 12 remaining patients, the tumor was diagnosed incidentally in 8 patients (16%) and because of neurological deficits in 4 patients (8%). Preoperative anticonvulsant treatment was administered to 36 patients, of whom 5 patients had seizures that were still uncontrolled (13.1%). No anticonvulsant prophylaxis was undertaken. The most commonly used medication, in 31 patients, was Levetiracetam (86.1%). Preoperative epileptic data are shown in table 2.\u003c/div\u003e\n\u003cdiv\u003eThe preoperative tumor volume was highly variable, with a minimum of 7.3 cm\u0026sup3;, a maximum of 276.7 cm\u0026sup3;, and a mean volume of 95.7 cm\u0026sup3;. The residual tumor volume ranged from 0 to 50.2 cm\u0026sup3;, with a median residual volume of 4,1 cm\u0026sup3;. After the surgical procedure, 26 patients (52%) underwent adjuvant treatment, of which 11 received chemotherapy with temozolomide and radiotherapy (42.3%), and 15 received only radiotherapy (57.7%). A radiological evidence of progression of disease was observed in 34 patients (68%), with a median PFS of 48 months (min 6-max 90), and a different time to progression between astrocytomas (40 months) and oligodendrogliomas (68 months). A second surgery for tumor recurrence/progression was performed in 7 patients (14%), of whom 5 had previously undergone STR and 2 had a gross total resection (GTR). The mean time between the first and second surgery was 25 months (min 12-max 48). Currently, 25 patients are still alive (50%), of whom 15 (60%) have tumor presence and 10 (40%) show no evidence of disease, while 25 patients have passed away (50%), with only one (4%) due to other causes. The median OS was 84 months, with a different survival between oligodendroglioma and astrocytoma of respectively 90 and 82 months, and between grade II and III of respectively 90 and 78 months.\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003ePost operative seizures control analysis\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eDuring the follow-up, 28 patients experienced seizures (56%), of which 11 had uncontrolled seizures (39.3%) despite multiple pharmacological changes. In contrast, 22 patients (44%) did not experienced seizure episodes during the follow up. Among the 12 patients who did not have epilepsy before surgery, 7 remained seizure-free during the follow-up (58.3%), 3 developed pharmacologically controlled epilepsy (25%), and 2 had intractable epilepsy (16.7%). These last two patients underwent a partial resection respectively of an astrocytoma and an oligodendroglioma, both grade III, and adjuvant chemotherapy and radiotherapy. Epileptic data are synthetized in Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n\u003cdiv class=\"Drawing\" id=\"4\" name=\"Immagine 4\"\u003eAmong the 16 patients with temporal lobe gliomas, 10 patients (62,5%) experienced postoperative seizures, of whom only one patient had intractable epilepsy following the onset of disease progression. In the 7 cases of precentral glioma, two patients (28,6%) experienced intractable epilepsy during the follow-up, in both cases concomitant with disease progression. The mean interval between surgery and the first postoperative seizure was 30 months. Among the variables reported in tables, the only ones found to be significant in the univariate analyses were GTR (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.019), preoperative seizures control (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.029) and radiological evidence of relapse or progression within three months after the epilepsy recurrence (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002). These variables were than included in a multivariate analysis using a model of logistic regression and the only independent predictor of epileptic outcome was the radiological progression of the disease (OR 5.145, 95% CI 0.188\u0026ndash;3.162, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03).\u003c/div\u003e\n\u003cp\u003eA ROC curve was constructed to determine a predictive residual volume cutoff, based on the occurrence or absence of epileptic seizures following surgery (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"Drawing\" id=\"3\" name=\"Immagine 3\"\u003eThe optimal threshold was a residual tumor volume of 0.5 cm\u003csup\u003e3\u003c/sup\u003e, which corresponded to the point of highest sensitivity (0,826) and specificity (0.568).\u003c/div\u003e\n\u003cp\u003eUsing the Kaplan-Meier method, we evaluated OS and PFS based on the presence or absence of seizures during follow-up. Patients without seizures showed a progressively decreasing survival, with a survival rate of 60.3% at 73 months and 59.1% at 95 months, Patients with seizures showed similar results with a survival rate of 43.6% at 90 months. Log-rank test showed no significant differences between the two groups (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.76) (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"Drawing\" id=\"1\" name=\"Immagine 1\"\u003eIn patients without seizures, PFS progressively decreases to 62.9% at 48 months, while in patients with seizures, PFS declines rapidly after 24 months, reaching 32.9% at 48 months. Log-rank test suggested a possible difference between the two groups, but not strong enough to be considered significant (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.054) (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eEpilepsy often represents the manifestation of a brain tumors, especially LGGs, due to their infiltrative nature and slower growth rate. To consider a patient disease-free, a 12-month cutoff is generally used because, after this period, any recurrence of seizures is more likely to be attributed to a neoplastic recurrence rather than to poor seizure control [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In this retrospective study, we analyzed the long-term and very long-term epileptological outcome of 50 consecutive patients who underwent resection of a non-enhancing IDH-mutated glioma, in relation to various pre- and postoperative variables. Most studies in the literature report results obtained in the short term (generally with 6\u0026ndash;18 months of follow-up), while our study is based on data collected with a mean follow-up of 70 months.\u003c/p\u003e \u003cp\u003eThe location of the tumor is an important prognostic factor in patients with brain glioma, because it influences surgical resectability, seizure control following treatment and survival. Tumors located in the temporal and in the precentral frontal region are associated with a more unfavorable outcome in terms of seizure control [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. A worse epileptic outcome in primary motor area locations is believed to stem from its localization itself, as being an eloquent area, making often impossible to achieve a radical resection [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, in our study, no localization or lateralization of the tumor was significantly correlated with the epileptic outcome.\u003c/p\u003e \u003cp\u003eSeveral studies have reported that a time interval of more than 12 months between seizure onset and surgery or preoperative intractable seizures are negative prognostic factors for epileptic outcome [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In our case series, however, no patient underwent surgery more than a year after the onset of the disease. Therefore, we divided the onset of epilepsy into less than one month, less than three months, and more than three months before surgery, and no significant differences were observed. Similarly, pharmacological control of epilepsy before surgery was significant in univariate analyses but not in a multivariate model.\u003c/p\u003e \u003cp\u003eTumors with particularly large volumes cause more disabling neurological impairment, both organically and functionally, and are often associated with more challenging resections due to the involvement of eloquent areas.\u003c/p\u003e \u003cp\u003eThe literature consistently highlights the prognostic role of tumor volume; however, there is no consensus on the threshold defining a patient with a worse outcome [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Regarding epileptological outcome, rather than the initial tumor volume, other variables appear to be more significant for better epilepsy control.\u003c/p\u003e \u003cp\u003eThe EOR, as radical as possible, is considered the gold standard in glioma therapy. Several studies demonstrate that the EOR is a factor correlated with both seizure freedom and survival [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Various tumor resection cut-offs have been described as significant for better postoperative seizure control. These range from 80% [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], to 85% [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], to 91% [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. We divided the types of resection into three categories: gross total, subtotal, and partial, using a cut-off of values lower than 90% to define a resection as partial. Only a GTR was found to have an impact on seizure control but only in univariate analysis. Similarly, the residual volume is considered an independent variable for both survival and seizure control. However, there is no consensus on the cut-off to be considered [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], and significant results have been reported with post-surgical residual tumor volumes even higher than 10cc [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. We found a significant cut-off corresponding to 0.5cc. This can be explained by the fact that, in the long term, even smaller residues inevitably lead to disease progression, and therefore to a progressive higher probability of developing epilepsy. The same applies to EOR, but obviously, it is often not possible to achieve a GTR in cases of tumors located in deep sites or in eloquent areas.\u003c/p\u003e \u003cp\u003eThe use of adjuvant radiotherapy is also considered one of the factors positively impacting patient outcomes, both in terms of PFS and seizure control, with an effectiveness ranging from 72\u0026ndash;100% [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In addition to its antitumor effect, it seems to reduce epileptic activity by damaging epileptogenic neurons and altering the microenvironment of the peritumoral tissue. Moreover, the use of concomitant adjuvant chemotherapy is also considered a favorable prognostic factor for increased survival and symptom control, with effectiveness in 48\u0026ndash;100% of cases [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. However, in our study no adjuvant treatment has been found to be protective in seizure control after surgery in long term. This may also be explained by the fact that adjuvant therapy is indicated in cases of tumors with more aggressive characteristics, so the epileptic outcome is inevitably influenced by other tumor-related factors (EOR, histotype, residual volume, etc.).\u003c/p\u003e \u003cp\u003eOur results suggest that the factors generally described as protective against the development of seizures after surgery are likely relevant in the short term. However, the long history of these patients is usually marked by a disease progression, and, in the long term, the only risk factor for the recurrence of epilepsy is the recurrence of the disease itself. Recent studies seem to highlight the oncogenic role of epilepsy as a factor that may promote neoplastic progression so that some antiepileptic drugs have shown promising results regarding their mechanism of action, even in an anti-tumor mechanism [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. It seems that the control of tumor-related epilepsy may influence survival [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The reciprocal relationship between epilepsy and tumor progression can therefore explain the correlation with improved OS, not so much due to pharmacological control, but rather because the absence of seizures is a sign of a disease that is currently inactive. Several studies have highlighted that a worsening of the epileptic condition may be a warning sign of disease progression, with a neuroradiological evidence of disease progression up to 3 months after the onset of new seizure symptoms [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Our results have indeed shown a possible correlation between the absence of seizures during follow-up and PFS, but no correlation with survival.\u003c/p\u003e \u003cp\u003eCurrently, with the new WHO 2021 classification, molecular alterations have gained greater importance both as determinants of disease prognosis and as potential targets for therapies. Several studies demonstrated that IDH mutations are more commonly linked to tumor-related seizures [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. One suggested explanation is that D-2-hydroxyglutarate (D2HG), a byproduct of mutant IDH, shares structural similarities with glutamate, a key excitatory neurotransmitter in the central nervous system. As a result, D2HG may disrupt the balance between excitatory and inhibitory regions in the brain, potentially leading to epilepsy. Conversely, 1p19q status is not univocally considered a significant predictor of epilepsy [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. In our study, we analyzed the cases according to the 2007 and 2016 WHO classifications, as the patients studied underwent surgery up to 2019, but no difference in epileptic outcomes was found between astrocytomas and oligodendrogliomas and between grade II and III. However, molecular findings should be interpreted with caution, given the low statistical power and potential bias resulting from the missing data in our database.\u003c/p\u003e \u003cp\u003eAmong the limitations of this study, the retrospective nature of the analysis certainly stands out, which may lead to potential errors in data collection. Additionally, while the sample size is reasonably representative, it may not be large enough to yield statistically significant results. Further long-term multicentric studies are needed to confirm our findings. Furthermore, ROI tracking in imaging analysis software was performed using a semi-automatic freehand drawing tool and is therefore susceptible to potential bias.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eSeizures are an important symptom associated with brain gliomas that significantly impact patients\u0026rsquo; quality of life. Surgical resection is an effective treatment in reducing seizures; however, given the long course of the disease, in the long term our data showed that recurrence/progression of the disease appears to be the only risk factor associated with the recurrence of epilepsy. Lastly, the presence or absence of seizure control does not seem to be significantly correlated with overall survival and progression free survival.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e. Thanks to Marco Vigan\u0026ograve; for his support with statistical analysis\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eCompeting interests.\u0026nbsp;\u003c/strong\u003eThe authors have no personal, financial, or institutional interest in any of the materials or devices described in this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding.\u0026nbsp;\u003c/strong\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number.\u003c/strong\u003e Not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions. G.S.\u0026nbsp;\u003c/strong\u003econceptualization; \u003cstrong\u003eF.S., F.G.\u0026nbsp;\u003c/strong\u003eand \u003cstrong\u003eV. M. C.\u0026nbsp;\u003c/strong\u003edata curation, formal analysis; \u003cstrong\u003eF.S.\u0026nbsp;\u003c/strong\u003eWriting \u0026ndash; review \u0026amp; editing; \u003cstrong\u003eG.S., F.S., P.D.B. and F.G.\u003c/strong\u003e supervision. All authors have read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval.\u0026nbsp;\u003c/strong\u003eThis study was conducted in accordance with the Declaration of Helsinki, and approved by the local Ethics Committee of Fondazione IRCCS Policlinico San Matteo (code 2023-3.11-43)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate.\u0026nbsp;\u003c/strong\u003eNot applicable. As this was a retrospective study, the requirement for informed consent to participate and/or publish was waived by the IRB.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eEichberg DG, Di L, Morell AA et al (2020) Incidence of high grade gliomas presenting as radiographically non-enhancing lesions: experience in 111 surgically treated non-enhancing gliomas with tissue diagnosis. J Neurooncol 147(3):671\u0026ndash;679. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s11060-020-03474-z\u003c/span\u003e\u003cspan address=\"10.1007/s11060-020-03474-z\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBerntsson SG, Malmer B, Bondy ML, Qu M, Smits A (2009) Tumor-associated epilepsy and glioma: are there common genetic pathways? 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PMID: 24374407\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"neurosurgical-review","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nrev","sideBox":"Learn more about [Neurosurgical Review](https://www.springer.com/journal/10143)","snPcode":"10143","submissionUrl":"https://submission.nature.com/new-submission/10143/3","title":"Neurosurgical Review","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"epilepsy, seizures, IDH mutated glioma, surgery, antiepileptic drugs, prognosis","lastPublishedDoi":"10.21203/rs.3.rs-9031484/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9031484/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePatients with low-grade gliomas tipically experience seizures at the onset and are generally treated with surgery that, especially when radical and uncomplicated, can ensure good post operative seizure control. There is very little data available to understand the evolution of seizures throughout the history of these patients. This retrospective study aims to analyze long-term epileptic data of 50 consecutive patients who underwent resection of non-enhancing IDH-mutated glioma between 2006 and 2020. Several factors were analyzed with a mean follow-up of 70 months. During the follow-up, 28 patients experienced seizures (56%), of which 11 were uncontrolled (39.3%), while 22 patients did not experienced seizures (44%). The average time of first postoperative seizure was 30 months. The only significant variables in the univariate analyses were GTR (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.019), preoperative seizures control (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.029) and radiological progression during the follow up (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002). The only independent predictor in a multivariate logistic regression was the progression of the disease (OR 5.145, 95% CI 0.188\u0026ndash;3.162, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03). A ROC curve based on recurrence or absence of seizures was computed and the optimal threshold of residual tumor volume was 0.5 cm\u003csup\u003e3\u003c/sup\u003e. Kaplan-Meier approach showed no significant differences between the two groups in terms of overall survival (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.76) and progression free survival (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.054). Our data show that, in the long term, the only risk factor for the recurrence of epilepsy may be the recurrence of the disease itself. Conversely, the presence or absence of seizure control does not seem to be significantly correlated with overall survival and progression free survival\u003c/p\u003e","manuscriptTitle":"Long term analysis of the epileptic outcome in a consecutive series of 50 patients with \"non-enhancing\" IDH-mutated gliomas with a mean follow-up of 70 months","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-15 16:50:41","doi":"10.21203/rs.3.rs-9031484/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-20T23:15:37+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-19T11:05:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"117443536165326663091235558649956667557","date":"2026-03-15T07:41:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"97723642438465549976929105013266008475","date":"2026-03-12T05:31:58+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-10T06:29:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"141196852809443840904840342661219269925","date":"2026-03-10T06:20:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"269643759022362802864803764076376798467","date":"2026-03-10T05:20:10+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-10T04:29:18+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-10T04:28:09+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-09T17:47:51+00:00","index":"","fulltext":""},{"type":"submitted","content":"Neurosurgical Review","date":"2026-03-04T14:25:09+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"neurosurgical-review","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nrev","sideBox":"Learn more about [Neurosurgical Review](https://www.springer.com/journal/10143)","snPcode":"10143","submissionUrl":"https://submission.nature.com/new-submission/10143/3","title":"Neurosurgical Review","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"c196fea7-f82f-4d54-970e-e0544032cb2e","owner":[],"postedDate":"March 15th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-01T14:23:54+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-15 16:50:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9031484","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9031484","identity":"rs-9031484","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}