Intrinsic and extrinsic risk factors in tumor-related epilepsy

Intrinsic and extrinsic risk factors in tumor-related epilepsy | 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 Intrinsic and extrinsic risk factors in tumor-related epilepsy Omar Rafi, Alessandro Carretta, Luca Zanuttini, Victor Staartjes, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6403995/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose: This study consolidated evidence on the association of tumor-intrinsic and investigated the underexplored association of tumor-extrinsic factors with tumor-related epilepsy, aiming to contribute to the overall risk assessment for clinical management in tumor-related epilepsy. Methods: Over a period of one year (2020), we prospectively collected imaging and clinical data of 373 patients with histopathologically confirmed brain tumors. Assessed tumor-intrinsic factors included histopathology, diameter and anatomical location, with the central lobe comprising the precentral, postcentral and subcentral gyrus and paracentral lobule. Tumor-extrinsic factors comprised sex, age, BMI, smoking, alcohol abuse, and Na + /K + imbalances. We applied univariable and multivariable binary logistic regression to characterize the associations between tumor-intrinsic and tumor-extrinsic factors with tumor-related epilepsy. Results: Preoperative seizures occurred in 29.5% (n = 110) of patients, with cortical locations — particularly the central lobe (91.3%, n = 21) — posing the highest seizure incidence among all factors. In univariable analysis, compared to WHO grade 3/4 gliomas, WHO grade 1/2 neuroepithelial tumors exhibited moderately higher, whereas pituitary adenomas/ craniopharyngiomas and schwannomas showed lower incidences of preoperative seizures. In multivariable analysis, the central lobe (OR 58.15), other cortical locations (OR 3.47–3.76), male sex (OR 1.77), low BMI (OR 4.61) and smoking (OR 1.013 per pack-year), revealed significant associations (p = < 0.05). Conclusion: Cortical location, especially in the central lobe, male sex, low BMI and smoking, are independently associated with tumor-related epilepsy. Our findings support the importance of considering both tumor-intrinsic and tumor-extrinsic factors to develop a holistic seizure-risk assessment and highlight the need for larger, prospective studies to refine clinical management and potentially pharmacological seizure prophylaxis. Anatomy Glioma Metastases Seizure Topography Figures Figure 1 Figure 2 Figure 3 Introduction Tumor-related epilepsy (TRE) represents a frequent and debilitating neurological complication, further exacerbating the clinical burden and quality-of-life impairment in patients with brain tumors [ 1 ]. Nevertheless, due to well-known side effects of antiseizure medication and an incomplete understanding of TRE’s pathophysiology and seizure risk stratification, the prophylactic use of antiseizure medication is generally not recommended [ 2 – 5 ]. Further insights into all seizure risk factors, including less-studied tumor-extrinsic factors (TEFs), are needed. These insights could enhance clinical management and reveal potential benefits through lifestyle changes [ 2 , 3 , 6 , 7 ]. The most prominent known tumor-intrinsic factor (TIF) is anatomical location, with particularly the temporal and frontal lobes associated with higher risks [ 1 , 7 – 14 ]. However, the anatomical distinction of a central lobe [ 15 , 16 ], as opposed to the traditional frontal-parietal lobe concept, appears especially relevant in the context of TRE, given its strong observed association with seizure incidence [ 11 , 12 ]. Other TIFs such as histopathology have also exhibit associations with higher incidences of 60–100% in patients with WHO grade 1/2 neuroepithelial tumors and rather low incidences in patients with WHO grade 3/4 gliomas between 30–50 % [ 8 , 11 , 12 , 17 ]. In contrast, associaions of seizure risk with tumor size remain controversial [ 18 – 20 ]. Certain TEFs like sex, age, lifestyle, and pathological laboratory levels may also be related to TRE. However, current data on this is limited, with only some indications that younger age and male sex might be associated with higher seizure risks [ 20 – 22 ]. Further investigation into these factors is particularly important, as they could serve for initial risk stratification in clinical practice and are potentially modifiable. The objective of this study was to deepen our insights into the relevance of competitive or synergistic TIFs and TEFs. Therefore, we aimed to screen for factors with the strongest associations, emphasize anatomical predispositions linked to TRE, identify clinically relevant and early detectable TEFs, and thus contribute to a more comprehensive framework for risk stratification. Methods 5.1 Study population During 2020, we conducted a weekly standardized approach to collect epidemiologic, clinical, imaging, and histopathological data for all patients undergoing brain tumor surgery. The final inclusion criteria were: (I) histopathological diagnosis of a primary or secondary brain tumor after resection or biopsy; (II) no use of prophylactic antiseizure medication; (III) availability of a standardized preoperative MRI (for technical details, see Supplementary Methods ). Patients with inconclusive histopathological results, secondary intracranial pathology such as vascular or infectious diseases, or a history of previous structural lesions or cranial surgery were excluded. 5.2 Data collection Ethics board approval was obtained prior to data gathering from the Cantonal Ethics Committee of Zurich (KEK-ZH-Nr. 01120). Informed general consent for scientific use of all medical data was obtained from all patients upon admission to the hospital. The definitive histopathological diagnosis was made after biopsy or surgery by independent analysis from our Neuropathology department and categorized according to the 2021 WHO Classification of Tumors of the Central Nervous System [ 23 ]. Two neurosurgeons (CS, AC) independently collected and analyzed topographical data using standard morphological MR sequences (T1, T1 with contrast, T2, FLAIR), being blinded to the histopathological and tumor-extrinsic data. The standard approach was to describe infiltrated, but not displaced or edematous structures. Imaging data were analyzed for following tumor features: (I) diameter; (II) intraparenchymal uni- vs. multifocality (included larger tumors encompassing multiple regions), and if unifocal; (III) exact lobar location; or (IV) extraparenchymal location. We applied the concept of a central lobe on a lobar level, composed of the precentral, postcentral and subcentral gyrus and paracentral lobule [ 15 , 16 ], excluding these areas in the frontal and parietal lobes. TRE was defined as seizures occurring preoperatively without prior antiseizure medication. The presence or absence of TRE was collected as a binary categorical variable (yes vs. no). The collected TEFs included demographic characteristics (sex and age), lifestyle factors (BMI, smoking behavior [in pack-years] and alcohol abuse) and electrolyte disturbances, particularly pathological Na + /K + levels. While age and pack-years were recorded as continuous data, sex (male vs. female), BMI categories (underweight [BMI < 18.5], normal weight [BMI 18.5–24.9], overweight [BMI 25–29.9], obese [BMI ≥ 30]), alcohol abuse (yes vs. no) or pathological Na + /K + levels (yes vs. no) were collected as categorical variables. Normal Na + /K + levels were defined as 135–145 mmol/L and 3.5–5.0 mmol/L. The most recent result before a seizure was used; if unavailable, the pre-surgery blood result was selected. 5.3 Statistical Analysis The primary objective of our study was to describe the association of the incidence of preoperative TRE (dependent variable) with independent variables including TIFs (histopathology, tumor diameter, anatomical location) and TEFs (sex, age, BMI, smoking, alcohol abuse, pathological Na + /K + levels). The following statistical approach was applied to assess the association of TIFs and TEFs with TRE: (I) crosstabs provided a descriptive overview of the quantitative distribution of subgroups within each variable. If counts were < 10, expressions were combined or merged with an existing group; (II) seizure risk was calculated, and univariable binary logistic regression assessed the isolated effect size (odds ratio [OR], 95% confidence intervals [CI], p value); (III) for variables with multiple expressions, the most frequent was generally chosen as the reference level, unless subgroup sizes were similar, in which case a content-related reference was selected; (IV) only statistically significant TIFs and TEFs (p < 0.05) were included in the multivariable binary logistic regression model to assess the real effect size and interactions, but also to prevent overfitting and to improve model stability by reducing noise and unnecessary predictors. Significant factors in this analysis were interpreted having independent associations with TRE; (V) to prepare for combining relevant TEFs in a heatmap, interaction effects were tested using hierarchical logistic regression. A model with main effects was compared to one including all two- and three-way interactions via chi-square deviance tests. This methodological prerequisite showed no significant improvement (p > 0.05), indicating no significant interactions. Continuous variables were displayed as means ± standard deviations and categorical data as absolute numbers and percentages with CIs. Analyses were conducted using R 4.4.1 and RStudio 2024.04.2 + 764. Results All descriptive data and the results from univariable analysis are displayed in Supplementary Table 1. Of 373 patients, most patients suffered from WHO grade 3/4 gliomas (n = 98, 26.3%), meningioma (n = 81, 21.7%), or metastasis (n = 80, 21.5%), while fewer patients had WHO grade 1/2 neuroepithelial tumors (n = 16, 4.3%), schwannoma (n = 14, 3.6%), or primary CNS lymphoma (n = 13, 3.5%). The average tumor diameter was 36 mm, with most tumors located intraparenchymally, particularly in the temporal lobe (n = 48, 12.9%), frontal lobe (n = 36, 9.7%), or were multifocal (n = 41, 11%). The cerebellum (n = 18, 4.8%) and occipital lobe (n = 14, 3.8%) were least affected. Among extraparenchymal tumors, a location over the convexity was most common (n = 39, 10.5%), while the anterior cranial fossa was the least common location (n = 15, 4%). 194 patients (52%) were female, mean age was 55 years, 176 patients were of normal weight (47.2%) and 126 patients (33.8%) were overweight. Patients had an average of 11.5 smoking pack-years (SD 20.9), while 5.7% had a history of alcohol abuse, and 19.9% presented with pathological Na + /K + levels either during hospitalization or near a seizure event. 6.1 Univariable analysis While differences in seizure incidence were minor across histopathological subgroups, anatomical location revealed pronounced associations with TRE in the univariable analysis of TIFs. WHO grade 3/4 gliomas served as the reference histopathological category with a seizure incidence of 32.7% (CI 31.7–33.6). WHO grade 1/2 neuroepithelial tumors counted the highest incidence at 43.6% (CI 41.3–46.2), while only pituitary adenomas/craniopharyngiomas showed a significantly lower incidence of 6.3% (CI 5.4–7.1) with an OR of 0.14 (CI 0.02–0.5, p = 0.0092) compared to WHO grade 3/4 gliomas. Tumor diameter showed no association with TRE (OR 1.00, CI 0.987–1.014, p = 0.9425). For location, compared to the “other” reference group (14% incidence, CI 4.4–23.6), multifocal intraparenchymal tumors and those in the frontal, parietal, and temporal lobes had increased seizure incidences of 35–42% with ORs of 3.47–4.35. The central lobe had the highest incidence at 91.3% (CI 79.8–100) and an OR of 64.5 (CI 14.88–466.3, p < 0.0001). The low incidence (3.6%–9,5%) of extraparenchymal tumors in the cranial base were similar to the low seizure incidence (14%) of the reference group. Among TEFs, male sex, underweight or normal BMI, increasing pack-years, and abnormal Na + /K + levels were associated with an increased seizure incidence, whereas different ages and alcohol abuse demonstrated little to no isolated effects. Males had a higher seizure incidence with 35.8% (CI 35.1–36.5) than females (23.7%, CI 23.1–24.3), resulting in a OR of 1.79 (CI 1.14–2.82, p = 0.0113) for males. Among weight categories, obese patients showed the lowest seizure incidence (14%, CI 13–15) compared to overweight (25.4%, CI 24.6–26.2), normal weight (35.2%, CI 34.5–35.9), and underweight (42.9%, CI 40.7–45). Using obesity as the reference, normal weight and underweight patients had ORs of 3.34 (CI 1.5–8.52, p = 0.0058) and 4.61 (CI 1.44–15.54, p = 0.011). Smoking was linked to an increased risk (OR 1.015 per pack-year, CI 1.005–1.026, p = 0.003). Patients with pathological Na + /K + levels had a seizure incidence of 39.2% (CI 38.1–40.3) versus 27.1% (CI 26.6–27.6) in patients with normal Na + /K + levels (OR 1.73, CI 1.01–2.94, p = 0.0424). 6.2 Multivariable analysis In contrast to the univariable model, the combined testing in the multivariable analysis (Fig. 1 ) revealed strong associations with TRE for the subgroups male sex (ref. female), underweight (ref. obese), increasing pack-years, most cortical regions, especially the central lobe, and multifocality (ref. "other") compared to their reference categories. Notably, normal BMI and abnormal Na + /K + levels showed no, while extraparenchymal location in the osseous/meningeal convexity demonstrated secondarily significant associations, which could indicate existing multicollinearity or confounding among the tested independent variables. Given the absence of relevant differences in seizure incidence and nonsignificant ORs within the subcategories of histopathology and tumor diameter in the univariable analysis, the multivariable analysis exclusively included anatomical location as TIF, which demonstrated effects comparable to those in the univariable model. Multifocal intraparenchymal tumors and location in the frontal, parietal, temporal, and central lobes, had significantly higher ORs than the reference category “other”. Extraparenchymal tumors in the osseous/meningeal convexity also showed a significant OR of 3.69 (CI 1.25–11.64, p = 0.0204). These findings are visualized in a topographic heatmap ( Fig. 2 ). For TEFs, multivariable analysis revealed differences from the univariable results, notably the decrease in effect size and significance in the normal weight group compared to the obese reference (OR 3.34, p = 0.0058 vs. OR 2.34, p = 0.0851). The same effect was observed for pathological Na + /K + (OR 1.73, p = 0.0424 vs. OR 1.04, p = 0.9098). In contrast, male sex (OR 1.77, CI 1.03–3.08, p = 0.0411) and smoking per pack-year (OR 1.013, CI 1.0–1.026, p = 0.0435) preserved their effect size and significance. A heatmap risk assessment tool combining relevant TEF ORs was generated (Fig. 3 ). Discussion Our study underlines the previously reported strong association of specific TIFs with TRE, while additionally demonstrating the hitherto underexplored relevance of certain TEFs. Regarding histopathology, our data confirm that WHO grade 1/2 neuroepithelial tumors show higher, while pituitary adenomas/craniopharyngiomas and schwannomas exhibiting low seizure incidences, although smaller incidence differences and thus lesser significance among histopathological subgroups were noted compared to current literature [ 8 , 11 , 12 , 17 ]. Anatomical location, especially the central lobe with its near-unconditional seizure association, plays a critical role in TRE risk, with the frontal, parietal, and temporal lobes also notably being rated as related lobar regions [ 1 , 7 – 10 ]. Male sex, low BMI, and high smoking pack-years were identified as relevant independent TEFs associated with TRE. Thus, our data support previous reports that seizure incidence vary widely across different tumor types [ 1 , 8 , 14 , 17 , 18 , 24 – 27 ]. The overall seizure incidence in our cohort was 29.5%, aligning with the range of 30–50% [ 1 ]. WHO grade 3/4 gliomas showed incidences of 32.7%, consistent with the 20–40% reported in literature [ 17 , 24 , 25 ]. WHO grade 1/2 gliomas, typically associated with a 60–80% seizure risk [ 1 , 8 , 17 , 18 ], exhibited a lower incidence (43.6%) in our study, with a non-significant OR of 1.61 compared to the reference group. This discrepancy may be attributed to the inclusion of low-risk (20%) ependymomas [ 17 ] in the group of WHO grade 1/2 neuroepithelial tumors. Primary CNS lymphomas, comprising 2–4% of CNS tumors, present seizures in about one-third of cases [ 26 ]. Our results showed a comparable subgroup occurrence (3.5%) and seizure incidence (38.5%). As with other tumors, cortical involvement significantly increases seizure risk [ 14 , 26 , 27 ]. Meningioma’s seizure incidence of 23.5 % align with current data [ 17 ]. Their extraparenchymal location triggers seizres probably mainly via pressure effects and edema [ 27 , 28 ], making them more epileptogenic at the convexity, where they interact with the cortex, than near the skull base. Metastases showed a seizure incidence of 40%, exceeding the reports of 10% or even lifetime risk of 35% [ 17 , 29 ], potentially due to wide range of possible differences in histopathological origin, location or growth progression. Schwannoma and pituitary adenomas/craniopharyngiomas demonstrated low seizure incidences. Their peripheral locations limit cortical impact, aligning with available, but limited data [ 30 ], which again supports the hypothesis that anatomical location is more decisive than histopathological entity. Admittedly, since certain tumors occur preferentially in specific regions, it is almost impossible whether pathology or location drive differential risk. We found no evidence for a correlation between tumor diameter and TRE. Instead, we confirmed that specific anatomical features, particularly a location in the central lobe, cortical involvement or intraparenchymal multifocality, exhibit a strong association with TRE. While some studies suggested an inverse association of tumor size and TRE [ 19 , 20 ], others emphasized the importance of progression and growth over an isolated snapshot of tumor size [ 18 ]. Our data exceeds the previously reported strong association between anatomical tumor location and TRE incidence [ 2 , 8 – 10 , 12 , 31 ]. Frontal, parietal, and temporal lobes — excluding the occipital lobe — showed similar seizure incidences (35–38%) with significantly higher ORs (3.4–3.8) in multivariable analysis compared to deeper subcortical structures. Lobar cortices, with their dense, highly interconnected neuronal networks, are prone to hyperexcitability and facilitated propagation, leading to unregulated discharges and thus TRE [ 32 , 33 ]. Additionally, seizures in cortical regions, which are involved in conscious perception, may be more noticeable than those in subcortical areas that regulate automated processes. Subcortical regions also help suppress the spread of seizures in the cortex due to their unique connectivity patterns and lower synchronization, providing a natural inhibitory effect [ 34 ]. The central lobe warrants special attention: it exhibits an exceptionally high seizure incidence (91.3%) and OR (58.15) in multivariable analysis, surpassing all other factor in their association with TRE. This supports prior studies identifying the central lobe as a distinct seizure-related entity [ 11 , 12 , 15 ]. It remains unclear, however, whether the central lobe's parenchyma is inherently more epileptogenic or whether seizures originating here may be recognized earlier due to more pronounced motor manifestations [ 15 , 16 , 35 , 36 ]. Intraparenchymal multifocality also emerged as a pro-epileptogenic feature, showing a seizure incidence of 41.5% and an OR of 3.45 in multivariable analysis, supporting a correlation between tumor burden and TRE [ 7 ]. Upper extraparenchymal tumors, such as meningiomas, presented seizure incidence around 30% with an OR about 3.7, likely due to their interaction with the cerebral cortex, particularly when arising from dural folds or located in the convexity regions. In contrast, cranial base meningiomas exhibited lower seizure incidences and ORs, likely due to less direct cortical impact and their positioning over less epileptogenic brain areas. In addition to TIFs, TEFs, particularly male sex, low BMI, and smoking were associated with TRE. Based on the effect size of the ORs for alcohol abuse and the additional evidence level for pathological Na + /K + levels in the univariable analysis, our study suggests a possibly interrelated association of these variables with TRE. Aside from basic characteristics like age and sex, patient-specific factors related to TRE have been underexplored. Some studies suggested associations of male sex and younger age with seizure risk [ 18 – 21 , 26 , 29 ]. Our results confirm male sex as an independent risk factor, though no significant differences were observed among ages. For BMI, our results indicate a protective effect for overweight and obese individuals compared to lower BMI. Underweight patients, with a seizure incidence of 42.9%, appear at significantly higher risk. This aligns with studies linking extreme BMI, including underweight, to increased seizure risk in TRE [ 37 ]. Conversely, while obesity has been associated with drug-resistant epilepsy and cognitive decline in idiopathic epilepsy, its role in TRE remains less clear [ 38 – 40 ]. Smoking was associated with increased seizure incidence, with a notable OR rise per pack-year (OR 1.013) in multivariable analysis. Alcohol abuse also showed an elevated seizure incidence, but lacked statistical significance in our study, as in a similar Italian study [ 41 ]. Nevertheless, further investigation remains reasonable, given that irregular and heavy alcohol consumption, especially withdrawal, generally lower seizure thresholds [ 42 , 43 ]. Existing data mostly link smoking and thus elevated CO-Hb levels [ 44 – 46 ], as well as excessive alcohol consumption, to increased seizure risk in primary epilepsy [ 46 ]. Finally, we suspected an association between Na + /K + alterations and TRE, since this may disrupt neuronal action potentials and affect excitability, and play a role in inhibitory GABA homeostasis via K + Cl − (KCC2) and Na + K + 2Cl − (NKCC) co-transporters [ 7 ]. While pathological Na + /K + levels were linked to increased seizure incidences in univariable analysis (OR 1.73), this was not confirmed in multivariable analysis. This study has its limitations, notably the small sample size for subgroups. Yet, the clinical data were systematically collected in a standardized, prospective workflow, ensuring high completeness and minimal missing information. Observer-dependency in image analysis was addressed by having two blinded raters and a strictly defined binary topographic-anatomical classification. Given the exploratory nature of the study and scarce literature on TEFs, the proposed association remains preliminary, requiring further validation and refinement. Conclusion This study aimed to explore the interplay of specific TIFs and TEFs with TRE. Among the TIFs, a cortical location, especially in the central lobe, emerged as the most significant and independent association with TRE. Among the TEFs, male sex, low BMI and smoking with increasing pack-years revealed also strong associations with TRE. Our findings underline the importance of developing a holistic risk assessment including TIFs and TEFs to guide clinical decision and patient lifestyle modification. Declarations Author Contribution O.R. did the main part of the data collection, carried out the statistics on his own, created all figures and wrote the whole manuscript up to the final version. C.S. and K.A. supervised and initiated the study.L.R., as the head of the department, facilitated the study, provided the necessary infrastructure, and contributed to the revision and finalization of the manuscript.A.C. and C.S. conducted the collection and analysis of imaging data and anatomical localization, with N.K. serving as a senior advisor on this topic.M.W. provided critical input on histopathological classification and contributed to the revision and finalization of the manuscript.V.S. offered strategic and advisory support for statistical analysis.L.Z., F.V., and S.V. contributed to the discussion and conducted the literature review.All authors reviewed the final manuscript. Funding: There was no funding or financing for this project. Conflicts of interest/Competing interests: None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Ethical approval: Ethics board approval was obtained prior to data collection from the Cantonal Ethics Committee of Zurich (KEK-ZH-Nr. 01120). All methods were carried out in accordance with relevant guidelines and regulations. Consent to participate/Consent for publication: Informedgeneral consent for scientific use of all medical data was obtained from all patients upon admission to the hospital. Availability of code, data and material: All data and code generated or analyzed during this study are included in this published article and its supplementary information files. References van Breemen MS, Wilms EB, Vecht CJ (2007) Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management. 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Neuro Oncol 23:1231-1251. https://doi.org/10.1093/neuonc/noab106 Salmaggi A, Riva M, Silvani A, Merli R, Tomei G, Lorusso L, Russo A, Marchioni E, Imbesi F; Lombardia Neuro-oncology Group (2005) A multicentre prospective collection of newly diagnosed glioblastoma patients in Lombardia, Italy. Neurol Sci 26(4):227–234. https://doi.org/10.1007/s10072-005-0465-y Weller M, Stupp R, Wick W (2012) Epilepsy meets cancer: when, why, and what to do about it? Lancet Oncol 13(9):e375–e382. https://doi.org/10.1016/S1470-2045(12)70266-8 Fox J, Ajinkya S, Houston P, Lindhorst S, Cachia D, Olar A, Kutluay E (2019) Seizures in patients with primary central nervous system lymphoma: Prevalence and associated features. J Neurol Sci 400:34–38. https://doi.org/10.1016/j.jns.2019.03.011 Akeret K, Vasella F, Staartjes VE, Velz J, Müller T, Neidert MC, Weller M, Regli L, Serra C, Krayenbühl N (2022) Anatomical phenotyping and staging of brain tumours. Brain 145(3):1162–1176. https://doi.org/10.1093/brain/awab352 Kawaguchi T, Kameyama S, Tanaka R (1996) Peritumoral edema and seizure in patients with cerebral convexity and parasagittal meningiomas. Neurol Med Chir (Tokyo) 36(8):568–573; discussion 573–574. https://doi.org/10.2176/nmc.36.568 Lamba N, Catalano PJ, Cagney DN, Haas-Kogan DA, Bubrick EJ, Wen PY, Aizer AA (2021) Seizures among patients with brain metastases: A population- and institutional-level analysis. Neurology 96(8):e1237–e1250. https://doi.org/10.1212/WNL.0000000000011459 Lo AC, Howard AF, Nichol A, Sidhu K, Abdulsatar F, Hasan H, Goddard K (2014) Long-term outcomes and complications in patients with craniopharyngioma: the British Columbia Cancer Agency experience. Int J Radiat Oncol Biol Phys 88(5):1011–1018. https://doi.org/10.1016/j.ijrobp.2014.01.019 Zhang J, Yao L, Peng S, Fang Y, Tang R, Liu J (2019) Correlation between glioma location and preoperative seizures: a systematic review and meta-analysis. Neurosurg Rev 42(3):603–618. https://doi.org/10.1007/s10143-018-1014-5 Spencer SS (2002) Neural networks in human epilepsy: evidence of and implications for treatment. Epilepsia 43(3):219–227. https://doi.org/10.1046/j.1528-1157.2002.26901.x Novak L, Emri M, Molnar P, Balkay L, Lengyel Z, Tron L (2004) Subcortical [18F]fluorodeoxyglucose uptake in lesional epilepsy in patients with intracranial tumour. Nucl Med Commun 25(2):123–128. https://doi.org/10.1097/00006231-200402000-00005 Norden AD, Blumenfeld H (2002) The role of subcortical structures in human epilepsy. Epilepsy Behav 3(3):219–231. https://doi.org/10.1016/s1525-5050(02)00029-x Chouinard PA, Paus T (2006) The primary motor and premotor areas of the human cerebral cortex. Neuroscientist 12(2):143–152. https://doi.org/10.1177/1073858405284255 Telfeian AE, Connors BW (1998) Layer-specific pathways for the horizontal propagation of epileptiform discharges in neocortex. Epilepsia 39(7):700–708. https://doi.org/10.1111/j.1528-1157.1998.tb01154.x Gao S, Juhaeri J, Dai WS (2008) The incidence rate of seizures in relation to BMI in UK adults. Obesity (Silver Spring) 16(9):2126–2132. https://doi.org/10.1038/oby.2008.310 Chen M, Wu X, Zhang B, Shen S, He L, Zhou D (2021) Associations of overweight and obesity with drug-resistant epilepsy. Seizure 92:94–99. https://doi.org/10.1016/j.seizure.2021.07.019 Janousek J, Barber A, Goldman L, Klein P (2013) Obesity in adults with epilepsy. Epilepsy Behav 28(3):391–394. https://doi.org/10.1016/j.yebeh.2013.05.012 Baxendale S, McGrath K, Donnachie E, Wintle S, Thompson P, Heaney D (2015) The role of obesity in cognitive dysfunction in people with epilepsy. Epilepsy Behav 45:187–190. https://doi.org/10.1016/j.yebeh.2015.01.032 Leone MA, Ivashynka AV, Tonini MC, Bogliun G, Montano V, Ravetti C, Gambaro P, Paladin F, Beghi E; ARES (Alcohol Related Seizures) study group (2011) Risk factors for a first epileptic seizure symptomatic of brain tumour or brain vascular malformation. A case control study. Swiss Med Wkly 141:w13155. https://doi.org/10.4414/smw.2011.13155 Woo KN, Kim K, Ko DS, Kim HW, Kim YH (2022) Alcohol consumption on unprovoked seizure and epilepsy: An updated meta-analysis. Drug Alcohol Depend 232:109305. https://doi.org/10.1016/j.drugalcdep.2022.109305 Hillbom M, Pieninkeroinen I, Leone M (2003) Seizures in alcohol-dependent patients: epidemiology, pathophysiology and management. CNS Drugs 17:1013–1030. https://doi.org/10.2165/00023210-200317140-00002 Rong L, Frontera AT Jr, Benbadis SR (2014) Tobacco smoking, epilepsy, and seizures. Epilepsy Behav 31:210–218. https://doi.org/10.1016/j.yebeh.2013.11.022 Johnson AL, McLeish AC, Shear PK, Sheth A, Privitera M (2019) The role of cigarette smoking in epilepsy severity and epilepsy-related quality of life. Epilepsy Behav 93:38–42. https://doi.org/10.1016/j.yebeh.2019.01.041 Dworetzky BA, Bromfield EB, Townsend MK, Kang JH (2010) A prospective study of smoking, caffeine, and alcohol as risk factors for seizures or epilepsy in young adult women: data from the Nurses' Health Study II. Epilepsia 51(2):198–205. https://doi.org/10.1111/j.1528-1167.2009.02268.x Additional Declarations No competing interests reported. Supplementary Files 10.Supplements.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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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-6403995","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":459352086,"identity":"d35c3d10-bbb1-4a57-9ad3-54616a4cc939","order_by":0,"name":"Omar Rafi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0klEQVRIiWNgGAWjYLCCCgMbOX4QI6GAWC1nDNKMJRtAWgyI1sJwONHgAIhFjBZ+Bt6HHw4UMCcYn1+d+OGBAYM8v9gB/FokG9iNJQ4YsOWZ3Xi7WQLoMMOZsxPwazE4wMYg/cGAp9jsxtkNIC0JBrcJa2H+ccBAInHzjLObfxCrhQ3oMIPEDfy924izRbKZjc3igEGCscQN3m0WCQYShP3Cz97GfOPAn/9y/P1nN9/8UWEjzy9NQAsDM4whAVYpQUA5qn0HSFE9CkbBKBgFIwkAAPDfQZU0vJQLAAAAAElFTkSuQmCC","orcid":"","institution":"Department of Neurosurgery, Clinical Neuroscience Center, University Hospital Zurich, University of Zurich, Zurich","correspondingAuthor":true,"prefix":"","firstName":"Omar","middleName":"","lastName":"Rafi","suffix":""},{"id":459352093,"identity":"ea89d263-58e6-48e6-9bfe-8f125bdb7c5c","order_by":1,"name":"Alessandro Carretta","email":"","orcid":"","institution":"Department of Neurosurgery, Clinical Neuroscience Center, University Hospital Zurich, University of Zurich, Zurich","correspondingAuthor":false,"prefix":"","firstName":"Alessandro","middleName":"","lastName":"Carretta","suffix":""},{"id":459352095,"identity":"3fcbe232-b182-4665-90db-0ea865f076e5","order_by":2,"name":"Luca Zanuttini","email":"","orcid":"","institution":"Department of Neurosurgery, Clinical Neuroscience Center, University Hospital Zurich, University of Zurich, Zurich","correspondingAuthor":false,"prefix":"","firstName":"Luca","middleName":"","lastName":"Zanuttini","suffix":""},{"id":459352096,"identity":"94a700f9-de2b-48e5-8e6f-e91fa631bb8a","order_by":3,"name":"Victor Staartjes","email":"","orcid":"","institution":"Department of Neurosurgery, Clinical Neuroscience Center, University Hospital Zurich, University of Zurich, Zurich","correspondingAuthor":false,"prefix":"","firstName":"Victor","middleName":"","lastName":"Staartjes","suffix":""},{"id":459352097,"identity":"c4538a2e-74ee-4dc9-af83-2bb015fd4d12","order_by":4,"name":"Flavio Vasella","email":"","orcid":"","institution":"Department of Neurosurgery, Clinical Neuroscience Center, University Hospital Zurich, University of Zurich, Zurich","correspondingAuthor":false,"prefix":"","firstName":"Flavio","middleName":"","lastName":"Vasella","suffix":""},{"id":459352098,"identity":"29bbdb3f-d573-4a9c-9865-682bed537858","order_by":5,"name":"Stefanos Voglis","email":"","orcid":"","institution":"Department of Neurosurgery, Clinical Neuroscience Center, University Hospital Zurich, University of Zurich, Zurich","correspondingAuthor":false,"prefix":"","firstName":"Stefanos","middleName":"","lastName":"Voglis","suffix":""},{"id":459352099,"identity":"08f904b7-eab6-4315-90d8-681325017c33","order_by":6,"name":"Michael Weller","email":"","orcid":"","institution":"Department of Neurology, Clinical Neuroscience Center, University Hospital Zurich, University of Zurich, Zurich","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Weller","suffix":""},{"id":459352100,"identity":"287fbd72-f802-4217-a20c-70b9b9bc470f","order_by":7,"name":"Niklaus Krayenbühl","email":"","orcid":"","institution":"Division of Pediatric Neurosurgery, University Children's Hospital, Zurich","correspondingAuthor":false,"prefix":"","firstName":"Niklaus","middleName":"","lastName":"Krayenbühl","suffix":""},{"id":459352102,"identity":"162a69ca-4e77-48da-983a-9ebf14c58bed","order_by":8,"name":"Luca Regli","email":"","orcid":"","institution":"Department of Neurosurgery, Clinical Neuroscience Center, University Hospital Zurich, University of Zurich, Zurich","correspondingAuthor":false,"prefix":"","firstName":"Luca","middleName":"","lastName":"Regli","suffix":""},{"id":459352103,"identity":"8a5db95d-eb54-4eda-a9d9-2c2d6ec6199d","order_by":9,"name":"Carlo Serra","email":"","orcid":"","institution":"Department of Neurosurgery, Clinical Neuroscience Center, University Hospital Zurich, University of Zurich, Zurich","correspondingAuthor":false,"prefix":"","firstName":"Carlo","middleName":"","lastName":"Serra","suffix":""},{"id":459352104,"identity":"f165cb5d-bc30-497e-b9e3-6155ed629bb6","order_by":10,"name":"Kevin Akeret","email":"","orcid":"","institution":"Department of Neurosurgery, Clinical Neuroscience Center, University Hospital Zurich, University of Zurich, Zurich","correspondingAuthor":false,"prefix":"","firstName":"Kevin","middleName":"","lastName":"Akeret","suffix":""}],"badges":[],"createdAt":"2025-04-08 13:53:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6403995/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6403995/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83435612,"identity":"eba472ad-3200-45fd-b793-88066bfbd190","added_by":"auto","created_at":"2025-05-26 08:26:08","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":386763,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot displaying multivariable analysis (OR, 95% CI) of TIFs and TEFs, which included significant subcategories in univariable binary logistic regression. Reference subcategories (OR = 1) were: female (sex), BMI ≥ 30, normal Na\u003csup\u003e+\u003c/sup\u003e/K\u003csup\u003e+\u003c/sup\u003e blood levels (= 135–145 mmol/L and 3.5–5.0 mmol/L), and “other” (anatomical location).\u003c/p\u003e","description":"","filename":"Fig1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6403995/v1/9868de970715aeb27a8213ec.jpeg"},{"id":83435615,"identity":"c8f2926f-49d6-468c-bb83-d3ab93aaa38c","added_by":"auto","created_at":"2025-05-26 08:26:08","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":653781,"visible":true,"origin":"","legend":"\u003cp\u003eHeatmap visualizing the topography-specific ORs for TRE based on a multivariable regression model. Intraparenchymal and extraparenchymal brain tumor locations are compared to the reference “other” (shown as grey intraparenchymal regions in \u003cstrong\u003eA, B \u003c/strong\u003eand\u003cstrong\u003e C\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA/B\u003c/strong\u003e lateral and medial views of brain hemisphere showing the frontal, parietal, temporal, occipital, central lobes and cerebellum. \u003cstrong\u003eC\u003c/strong\u003e coronal cut at parietal lobe level (front-back axis) illustrating parietal, temporal lobes and falx cerebri (intracranial dural folds).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eD/E\u003c/strong\u003e sagittal and axial view of the skull and base presenting the osseus/meningeal convexity and different fossa allocations.\u003c/p\u003e","description":"","filename":"Fig2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6403995/v1/8491ecdc5d6d8ff8b34499dc.jpeg"},{"id":83435620,"identity":"1377ebde-bbec-47ed-8779-2067b1c0bb9c","added_by":"auto","created_at":"2025-05-26 08:26:08","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":414177,"visible":true,"origin":"","legend":"\u003cp\u003eA TEF risk assessment heatmap calculates combined ORs of relevant TEFs from the multivariable analysis. A female, obese, non-smoking patient (OR 1) serves as the reference. In comparison, a male, underweight, heavily smoking patient (100 PY) has a calculated OR of 26.73. Depending on TEFs present in a patient, a combined OR can be described for the association with TRE.\u003c/p\u003e","description":"","filename":"Fig3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6403995/v1/6ec7bd833257428a0c50bb2d.jpeg"},{"id":87938119,"identity":"db07f25c-1165-4466-86b9-7c72c14d8349","added_by":"auto","created_at":"2025-07-30 14:47:14","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1969913,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6403995/v1/10f4335a-dd34-43a5-85cc-b541c3c035f3.pdf"},{"id":83435609,"identity":"1398b70e-be30-4059-b0ac-13c9d98945e4","added_by":"auto","created_at":"2025-05-26 08:26:08","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":29115,"visible":true,"origin":"","legend":"","description":"","filename":"10.Supplements.docx","url":"https://assets-eu.researchsquare.com/files/rs-6403995/v1/c904d09b7843628a3f74ab2c.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Intrinsic and extrinsic risk factors in tumor-related epilepsy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eTumor-related epilepsy (TRE) represents a frequent and debilitating neurological complication, further exacerbating the clinical burden and quality-of-life impairment in patients with brain tumors [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Nevertheless, due to well-known side effects of antiseizure medication and an incomplete understanding of TRE\u0026rsquo;s pathophysiology and seizure risk stratification, the prophylactic use of antiseizure medication is generally not recommended [\u003cspan additionalcitationids=\"CR3 CR4\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Further insights into all seizure risk factors, including less-studied tumor-extrinsic factors (TEFs), are needed. These insights could enhance clinical management and reveal potential benefits through lifestyle changes [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe most prominent known tumor-intrinsic factor (TIF) is anatomical location, with particularly the temporal and frontal lobes associated with higher risks [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan additionalcitationids=\"CR8 CR9 CR10 CR11 CR12 CR13\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. However, the anatomical distinction of a central lobe [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], as opposed to the traditional frontal-parietal lobe concept, appears especially relevant in the context of TRE, given its strong observed association with seizure incidence [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Other TIFs such as histopathology have also exhibit associations with higher incidences of 60\u0026ndash;100% in patients with WHO grade 1/2 neuroepithelial tumors and rather low incidences in patients with WHO grade 3/4 gliomas between 30\u0026ndash;50 % [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In contrast, associaions of seizure risk with tumor size remain controversial [\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCertain TEFs like sex, age, lifestyle, and pathological laboratory levels may also be related to TRE. However, current data on this is limited, with only some indications that younger age and male sex might be associated with higher seizure risks [\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Further investigation into these factors is particularly important, as they could serve for initial risk stratification in clinical practice and are potentially modifiable.\u003c/p\u003e \u003cp\u003eThe objective of this study was to deepen our insights into the relevance of competitive or synergistic TIFs and TEFs. Therefore, we aimed to screen for factors with the strongest associations, emphasize anatomical predispositions linked to TRE, identify clinically relevant and early detectable TEFs, and thus contribute to a more comprehensive framework for risk stratification.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e5.1 Study population\u003c/h2\u003e \u003cp\u003eDuring 2020, we conducted a weekly standardized approach to collect epidemiologic, clinical, imaging, and histopathological data for all patients undergoing brain tumor surgery. The final inclusion criteria were: (I) histopathological diagnosis of a primary or secondary brain tumor after resection or biopsy; (II) no use of prophylactic antiseizure medication; (III) availability of a standardized preoperative MRI (for technical details, see \u003cem\u003eSupplementary Methods\u003c/em\u003e). Patients with inconclusive histopathological results, secondary intracranial pathology such as vascular or infectious diseases, or a history of previous structural lesions or cranial surgery were excluded.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e5.2 Data collection\u003c/h2\u003e \u003cp\u003eEthics board approval was obtained prior to data gathering from the Cantonal Ethics Committee of Zurich (KEK-ZH-Nr. 01120). Informed general consent for scientific use of all medical data was obtained from all patients upon admission to the hospital.\u003c/p\u003e \u003cp\u003eThe definitive histopathological diagnosis was made after biopsy or surgery by independent analysis from our Neuropathology department and categorized according to the \u003cem\u003e2021 WHO Classification of Tumors of the Central Nervous System\u003c/em\u003e [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Two neurosurgeons (CS, AC) independently collected and analyzed topographical data using standard morphological MR sequences (T1, T1 with contrast, T2, FLAIR), being blinded to the histopathological and tumor-extrinsic data. The standard approach was to describe infiltrated, but not displaced or edematous structures. Imaging data were analyzed for following tumor features: (I) diameter; (II) intraparenchymal uni- vs. multifocality (included larger tumors encompassing multiple regions), and if unifocal; (III) exact lobar location; or (IV) extraparenchymal location. We applied the concept of a central lobe on a lobar level, composed of the precentral, postcentral and subcentral gyrus and paracentral lobule [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], excluding these areas in the frontal and parietal lobes.\u003c/p\u003e \u003cp\u003eTRE was defined as seizures occurring preoperatively without prior antiseizure medication. The presence or absence of TRE was collected as a binary categorical variable (yes vs. no). The collected TEFs included demographic characteristics (sex and age), lifestyle factors (BMI, smoking behavior [in pack-years] and alcohol abuse) and electrolyte disturbances, particularly pathological Na\u003csup\u003e+\u003c/sup\u003e/K\u003csup\u003e+\u003c/sup\u003e levels. While age and pack-years were recorded as continuous data, sex (male vs. female), BMI categories (underweight [BMI\u0026thinsp;\u0026lt;\u0026thinsp;18.5], normal weight [BMI 18.5\u0026ndash;24.9], overweight [BMI 25\u0026ndash;29.9], obese [BMI\u0026thinsp;\u0026ge;\u0026thinsp;30]), alcohol abuse (yes vs. no) or pathological Na\u003csup\u003e+\u003c/sup\u003e/K\u003csup\u003e+\u003c/sup\u003e levels (yes vs. no) were collected as categorical variables. Normal Na\u003csup\u003e+\u003c/sup\u003e/K\u003csup\u003e+\u003c/sup\u003e levels were defined as 135\u0026ndash;145 mmol/L and 3.5\u0026ndash;5.0 mmol/L. The most recent result before a seizure was used; if unavailable, the pre-surgery blood result was selected.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e5.3 Statistical Analysis\u003c/h2\u003e \u003cp\u003eThe primary objective of our study was to describe the association of the incidence of preoperative TRE (dependent variable) with independent variables including TIFs (histopathology, tumor diameter, anatomical location) and TEFs (sex, age, BMI, smoking, alcohol abuse, pathological Na\u003csup\u003e+\u003c/sup\u003e/K\u003csup\u003e+\u003c/sup\u003e levels). The following statistical approach was applied to assess the association of TIFs and TEFs with TRE: (I) crosstabs provided a descriptive overview of the quantitative distribution of subgroups within each variable. If counts were \u0026lt;\u0026thinsp;10, expressions were combined or merged with an existing group; (II) seizure risk was calculated, and univariable binary logistic regression assessed the isolated effect size (odds ratio [OR], 95% confidence intervals [CI], p value); (III) for variables with multiple expressions, the most frequent was generally chosen as the reference level, unless subgroup sizes were similar, in which case a content-related reference was selected; (IV) only statistically significant TIFs and TEFs (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) were included in the multivariable binary logistic regression model to assess the real effect size and interactions, but also to prevent overfitting and to improve model stability by reducing noise and unnecessary predictors. Significant factors in this analysis were interpreted having independent associations with TRE; (V) to prepare for combining relevant TEFs in a heatmap, interaction effects were tested using hierarchical logistic regression. A model with main effects was compared to one including all two- and three-way interactions via chi-square deviance tests. This methodological prerequisite showed no significant improvement (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05), indicating no significant interactions. Continuous variables were displayed as means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviations and categorical data as absolute numbers and percentages with CIs. Analyses were conducted using R 4.4.1 and RStudio 2024.04.2\u0026thinsp;+\u0026thinsp;764.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eAll descriptive data and the results from univariable analysis are displayed in \u003cem\u003eSupplementary Table\u0026nbsp;1.\u003c/em\u003e Of 373 patients, most patients suffered from WHO grade 3/4 gliomas (n\u0026thinsp;=\u0026thinsp;98, 26.3%), meningioma (n\u0026thinsp;=\u0026thinsp;81, 21.7%), or metastasis (n\u0026thinsp;=\u0026thinsp;80, 21.5%), while fewer patients had WHO grade 1/2 neuroepithelial tumors (n\u0026thinsp;=\u0026thinsp;16, 4.3%), schwannoma (n\u0026thinsp;=\u0026thinsp;14, 3.6%), or primary CNS lymphoma (n\u0026thinsp;=\u0026thinsp;13, 3.5%). The average tumor diameter was 36 mm, with most tumors located intraparenchymally, particularly in the temporal lobe (n\u0026thinsp;=\u0026thinsp;48, 12.9%), frontal lobe (n\u0026thinsp;=\u0026thinsp;36, 9.7%), or were multifocal (n\u0026thinsp;=\u0026thinsp;41, 11%). The cerebellum (n\u0026thinsp;=\u0026thinsp;18, 4.8%) and occipital lobe (n\u0026thinsp;=\u0026thinsp;14, 3.8%) were least affected. Among extraparenchymal tumors, a location over the convexity was most common (n\u0026thinsp;=\u0026thinsp;39, 10.5%), while the anterior cranial fossa was the least common location (n\u0026thinsp;=\u0026thinsp;15, 4%). 194 patients (52%) were female, mean age was 55 years, 176 patients were of normal weight (47.2%) and 126 patients (33.8%) were overweight. Patients had an average of 11.5 smoking pack-years (SD 20.9), while 5.7% had a history of alcohol abuse, and 19.9% presented with pathological Na\u003csup\u003e+\u003c/sup\u003e/K\u003csup\u003e+\u003c/sup\u003e levels either during hospitalization or near a seizure event.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e6.1 Univariable analysis\u003c/h2\u003e \u003cp\u003eWhile differences in seizure incidence were minor across histopathological subgroups, anatomical location revealed pronounced associations with TRE in the univariable analysis of TIFs. WHO grade 3/4 gliomas served as the reference histopathological category with a seizure incidence of 32.7% (CI 31.7\u0026ndash;33.6). WHO grade 1/2 neuroepithelial tumors counted the highest incidence at 43.6% (CI 41.3\u0026ndash;46.2), while only pituitary adenomas/craniopharyngiomas showed a significantly lower incidence of 6.3% (CI 5.4\u0026ndash;7.1) with an OR of 0.14 (CI 0.02\u0026ndash;0.5, p\u0026thinsp;=\u0026thinsp;0.0092) compared to WHO grade 3/4 gliomas. Tumor diameter showed no association with TRE (OR 1.00, CI 0.987\u0026ndash;1.014, p\u0026thinsp;=\u0026thinsp;0.9425). For location, compared to the \u0026ldquo;other\u0026rdquo; reference group (14% incidence, CI 4.4\u0026ndash;23.6), multifocal intraparenchymal tumors and those in the frontal, parietal, and temporal lobes had increased seizure incidences of 35\u0026ndash;42% with ORs of 3.47\u0026ndash;4.35. The central lobe had the highest incidence at 91.3% (CI 79.8\u0026ndash;100) and an OR of 64.5 (CI 14.88\u0026ndash;466.3, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). The low incidence (3.6%\u0026ndash;9,5%) of extraparenchymal tumors in the cranial base were similar to the low seizure incidence (14%) of the reference group.\u003c/p\u003e \u003cp\u003eAmong TEFs, male sex, underweight or normal BMI, increasing pack-years, and abnormal Na\u003csup\u003e+\u003c/sup\u003e/K\u003csup\u003e+\u003c/sup\u003e levels were associated with an increased seizure incidence, whereas different ages and alcohol abuse demonstrated little to no isolated effects. Males had a higher seizure incidence with 35.8% (CI 35.1\u0026ndash;36.5) than females (23.7%, CI 23.1\u0026ndash;24.3), resulting in a OR of 1.79 (CI 1.14\u0026ndash;2.82, p\u0026thinsp;=\u0026thinsp;0.0113) for males. Among weight categories, obese patients showed the lowest seizure incidence (14%, CI 13\u0026ndash;15) compared to overweight (25.4%, CI 24.6\u0026ndash;26.2), normal weight (35.2%, CI 34.5\u0026ndash;35.9), and underweight (42.9%, CI 40.7\u0026ndash;45). Using obesity as the reference, normal weight and underweight patients had ORs of 3.34 (CI 1.5\u0026ndash;8.52, p\u0026thinsp;=\u0026thinsp;0.0058) and 4.61 (CI 1.44\u0026ndash;15.54, p\u0026thinsp;=\u0026thinsp;0.011). Smoking was linked to an increased risk (OR 1.015 per pack-year, CI 1.005\u0026ndash;1.026, p\u0026thinsp;=\u0026thinsp;0.003). Patients with pathological Na\u003csup\u003e+\u003c/sup\u003e/K\u003csup\u003e+\u003c/sup\u003e levels had a seizure incidence of 39.2% (CI 38.1\u0026ndash;40.3) versus 27.1% (CI 26.6\u0026ndash;27.6) in patients with normal Na\u003csup\u003e+\u003c/sup\u003e/K\u003csup\u003e+\u003c/sup\u003e levels (OR 1.73, CI 1.01\u0026ndash;2.94, p\u0026thinsp;=\u0026thinsp;0.0424).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e6.2 Multivariable analysis\u003c/h2\u003e \u003cp\u003eIn contrast to the univariable model, the combined testing in the multivariable analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) revealed strong associations with TRE for the subgroups male sex (ref. female), underweight (ref. obese), increasing pack-years, most cortical regions, especially the central lobe, and multifocality (ref. \"other\") compared to their reference categories. Notably, normal BMI and abnormal Na\u003csup\u003e+\u003c/sup\u003e/K\u003csup\u003e+\u003c/sup\u003e levels showed no, while extraparenchymal location in the osseous/meningeal convexity demonstrated secondarily significant associations, which could indicate existing multicollinearity or confounding among the tested independent variables.\u003c/p\u003e \u003cp\u003eGiven the absence of relevant differences in seizure incidence and nonsignificant ORs within the subcategories of histopathology and tumor diameter in the univariable analysis, the multivariable analysis exclusively included anatomical location as TIF, which demonstrated effects comparable to those in the univariable model. Multifocal intraparenchymal tumors and location in the frontal, parietal, temporal, and central lobes, had significantly higher ORs than the reference category \u0026ldquo;other\u0026rdquo;. Extraparenchymal tumors in the osseous/meningeal convexity also showed a significant OR of 3.69 (CI 1.25\u0026ndash;11.64, p\u0026thinsp;=\u0026thinsp;0.0204). These findings are visualized in a topographic heatmap \u003cem\u003e(\u003c/em\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cem\u003e).\u003c/em\u003e\u003c/p\u003e\u003cp\u003eFor TEFs, multivariable analysis revealed differences from the univariable results, notably the decrease in effect size and significance in the normal weight group compared to the obese reference (OR 3.34, p\u0026thinsp;=\u0026thinsp;0.0058 vs. OR 2.34, p\u0026thinsp;=\u0026thinsp;0.0851). The same effect was observed for pathological Na\u003csup\u003e+\u003c/sup\u003e/K\u003csup\u003e+\u003c/sup\u003e (OR 1.73, p\u0026thinsp;=\u0026thinsp;0.0424 vs. OR 1.04, p\u0026thinsp;=\u0026thinsp;0.9098). In contrast, male sex (OR 1.77, CI 1.03\u0026ndash;3.08, p\u0026thinsp;=\u0026thinsp;0.0411) and smoking per pack-year (OR 1.013, CI 1.0\u0026ndash;1.026, p\u0026thinsp;=\u0026thinsp;0.0435) preserved their effect size and significance. A heatmap risk assessment tool combining relevant TEF ORs was generated (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur study underlines the previously reported strong association of specific TIFs with TRE, while additionally demonstrating the hitherto underexplored relevance of certain TEFs. Regarding histopathology, our data confirm that WHO grade 1/2 neuroepithelial tumors show higher, while pituitary adenomas/craniopharyngiomas and schwannomas exhibiting low seizure incidences, although smaller incidence differences and thus lesser significance among histopathological subgroups were noted compared to current literature [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Anatomical location, especially the central lobe with its near-unconditional seizure association, plays a critical role in TRE risk, with the frontal, parietal, and temporal lobes also notably being rated as related lobar regions [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Male sex, low BMI, and high smoking pack-years were identified as relevant independent TEFs associated with TRE.\u003c/p\u003e \u003cp\u003eThus, our data support previous reports that seizure incidence vary widely across different tumor types [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan additionalcitationids=\"CR25 CR26\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. The overall seizure incidence in our cohort was 29.5%, aligning with the range of 30\u0026ndash;50% [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. WHO grade 3/4 gliomas showed incidences of 32.7%, consistent with the 20\u0026ndash;40% reported in literature [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. WHO grade 1/2 gliomas, typically associated with a 60\u0026ndash;80% seizure risk [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], exhibited a lower incidence (43.6%) in our study, with a non-significant OR of 1.61 compared to the reference group. This discrepancy may be attributed to the inclusion of low-risk (20%) ependymomas [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] in the group of WHO grade 1/2 neuroepithelial tumors. Primary CNS lymphomas, comprising 2\u0026ndash;4% of CNS tumors, present seizures in about one-third of cases [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Our results showed a comparable subgroup occurrence (3.5%) and seizure incidence (38.5%). As with other tumors, cortical involvement significantly increases seizure risk [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Meningioma\u0026rsquo;s seizure incidence of 23.5 % align with current data [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Their extraparenchymal location triggers seizres probably mainly via pressure effects and edema [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], making them more epileptogenic at the convexity, where they interact with the cortex, than near the skull base. Metastases showed a seizure incidence of 40%, exceeding the reports of 10% or even lifetime risk of 35% [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], potentially due to wide range of possible differences in histopathological origin, location or growth progression. Schwannoma and pituitary adenomas/craniopharyngiomas demonstrated low seizure incidences. Their peripheral locations limit cortical impact, aligning with available, but limited data [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e], which again supports the hypothesis that anatomical location is more decisive than histopathological entity. Admittedly, since certain tumors occur preferentially in specific regions, it is almost impossible whether pathology or location drive differential risk.\u003c/p\u003e \u003cp\u003eWe found no evidence for a correlation between tumor diameter and TRE. Instead, we confirmed that specific anatomical features, particularly a location in the central lobe, cortical involvement or intraparenchymal multifocality, exhibit a strong association with TRE. While some studies suggested an inverse association of tumor size and TRE [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], others emphasized the importance of progression and growth over an isolated snapshot of tumor size [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Our data exceeds the previously reported strong association between anatomical tumor location and TRE incidence [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Frontal, parietal, and temporal lobes \u0026mdash; excluding the occipital lobe \u0026mdash; showed similar seizure incidences (35\u0026ndash;38%) with significantly higher ORs (3.4\u0026ndash;3.8) in multivariable analysis compared to deeper subcortical structures. Lobar cortices, with their dense, highly interconnected neuronal networks, are prone to hyperexcitability and facilitated propagation, leading to unregulated discharges and thus TRE [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Additionally, seizures in cortical regions, which are involved in conscious perception, may be more noticeable than those in subcortical areas that regulate automated processes. Subcortical regions also help suppress the spread of seizures in the cortex due to their unique connectivity patterns and lower synchronization, providing a natural inhibitory effect [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. The central lobe warrants special attention: it exhibits an exceptionally high seizure incidence (91.3%) and OR (58.15) in multivariable analysis, surpassing all other factor in their association with TRE. This supports prior studies identifying the central lobe as a distinct seizure-related entity [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. It remains unclear, however, whether the central lobe's parenchyma is inherently more epileptogenic or whether seizures originating here may be recognized earlier due to more pronounced motor manifestations [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Intraparenchymal multifocality also emerged as a pro-epileptogenic feature, showing a seizure incidence of 41.5% and an OR of 3.45 in multivariable analysis, supporting a correlation between tumor burden and TRE [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Upper extraparenchymal tumors, such as meningiomas, presented seizure incidence around 30% with an OR about 3.7, likely due to their interaction with the cerebral cortex, particularly when arising from dural folds or located in the convexity regions. In contrast, cranial base meningiomas exhibited lower seizure incidences and ORs, likely due to less direct cortical impact and their positioning over less epileptogenic brain areas.\u003c/p\u003e \u003cp\u003eIn addition to TIFs, TEFs, particularly male sex, low BMI, and smoking were associated with TRE. Based on the effect size of the ORs for alcohol abuse and the additional evidence level for pathological Na\u003csup\u003e+\u003c/sup\u003e/K\u003csup\u003e+\u003c/sup\u003e levels in the univariable analysis, our study suggests a possibly interrelated association of these variables with TRE. Aside from basic characteristics like age and sex, patient-specific factors related to TRE have been underexplored. Some studies suggested associations of male sex and younger age with seizure risk [\u003cspan additionalcitationids=\"CR19 CR20\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Our results confirm male sex as an independent risk factor, though no significant differences were observed among ages. For BMI, our results indicate a protective effect for overweight and obese individuals compared to lower BMI. Underweight patients, with a seizure incidence of 42.9%, appear at significantly higher risk. This aligns with studies linking extreme BMI, including underweight, to increased seizure risk in TRE [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Conversely, while obesity has been associated with drug-resistant epilepsy and cognitive decline in idiopathic epilepsy, its role in TRE remains less clear [\u003cspan additionalcitationids=\"CR39\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Smoking was associated with increased seizure incidence, with a notable OR rise per pack-year (OR 1.013) in multivariable analysis. Alcohol abuse also showed an elevated seizure incidence, but lacked statistical significance in our study, as in a similar Italian study [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Nevertheless, further investigation remains reasonable, given that irregular and heavy alcohol consumption, especially withdrawal, generally lower seizure thresholds [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. Existing data mostly link smoking and thus elevated CO-Hb levels [\u003cspan additionalcitationids=\"CR45\" citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e], as well as excessive alcohol consumption, to increased seizure risk in primary epilepsy [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. Finally, we suspected an association between Na\u003csup\u003e+\u003c/sup\u003e/K\u003csup\u003e+\u003c/sup\u003e alterations and TRE, since this may disrupt neuronal action potentials and affect excitability, and play a role in inhibitory GABA homeostasis via K\u003csup\u003e+\u003c/sup\u003eCl\u003csup\u003e\u0026minus;\u003c/sup\u003e (KCC2) and Na\u003csup\u003e+\u003c/sup\u003eK\u003csup\u003e+\u003c/sup\u003e2Cl\u003csup\u003e\u0026minus;\u003c/sup\u003e (NKCC) co-transporters [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. While pathological Na\u003csup\u003e+\u003c/sup\u003e/K\u003csup\u003e+\u003c/sup\u003e levels were linked to increased seizure incidences in univariable analysis (OR 1.73), this was not confirmed in multivariable analysis.\u003c/p\u003e \u003cp\u003eThis study has its limitations, notably the small sample size for subgroups. Yet, the clinical data were systematically collected in a standardized, prospective workflow, ensuring high completeness and minimal missing information. Observer-dependency in image analysis was addressed by having two blinded raters and a strictly defined binary topographic-anatomical classification. Given the exploratory nature of the study and scarce literature on TEFs, the proposed association remains preliminary, requiring further validation and refinement.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study aimed to explore the interplay of specific TIFs and TEFs with TRE. Among the TIFs, a cortical location, especially in the central lobe, emerged as the most significant and independent association with TRE. Among the TEFs, male sex, low BMI and smoking with increasing pack-years revealed also strong associations with TRE. Our findings underline the importance of developing a holistic risk assessment including TIFs and TEFs to guide clinical decision and patient lifestyle modification.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eO.R. did the main part of the data collection, carried out the statistics on his own, created all figures and wrote the whole manuscript up to the final version. C.S. and K.A. supervised and initiated the study.L.R., as the head of the department, facilitated the study, provided the necessary infrastructure, and contributed to the revision and finalization of the manuscript.A.C. and C.S. conducted the collection and analysis of imaging data and anatomical localization, with N.K. serving as a senior advisor on this topic.M.W. provided critical input on histopathological classification and contributed to the revision and finalization of the manuscript.V.S. offered strategic and advisory support for statistical analysis.L.Z., F.V., and S.V. contributed to the discussion and conducted the literature review.All authors reviewed the final manuscript.\u003c/p\u003e\u003cp\u003e\u003cem\u003eFunding:\u003c/em\u003e There was no funding or financing for this project.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConflicts of interest/Competing interests:\u0026nbsp;\u003c/em\u003eNone of the authors has any conflict of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEthical approval:\u0026nbsp;\u003c/em\u003eEthics board approval was obtained prior to data collection from the Cantonal Ethics Committee of Zurich (KEK-ZH-Nr. 01120). All methods were carried out in accordance with relevant guidelines and regulations.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConsent to participate/Consent for publication:\u0026nbsp;\u003c/em\u003eInformedgeneral consent for scientific use of all medical data was obtained from all patients upon admission to the hospital.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAvailability of code, data and material:\u0026nbsp;\u003c/em\u003eAll data and code generated or analyzed during this study are included in this published article and its supplementary information files.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003evan Breemen MS, Wilms EB, Vecht CJ (2007) Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management. Lancet Neurol 6:421\u0026ndash;430. https://doi.org/10.1016/S1474-4422(07)70103-5\u003c/li\u003e\n\u003cli\u003eWychowski T, Wang H, Buniak L, Henry JC, Mohile N (2013) Considerations in prophylaxis for tumor-associated epilepsy: prevention of status epilepticus and tolerability of newer generation AEDs. Clin Neurol Neurosurg 115:2365\u0026ndash;2369. https://doi.org/10.1016/j.clineuro.2013.08.023\u003c/li\u003e\n\u003cli\u003eGlantz MJ, Cole BF, Forsyth PA, Recht LD, Wen PY, Chamberlain MC et al (2000) Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 54:1886\u0026ndash;1893. https://doi.org/10.1212/wnl.54.10.1886\u003c/li\u003e\n\u003cli\u003eSirven JI, Wingerchuk DM, Drazkowski JF, Lyons MK, Zimmerman RS (2004) Seizure prophylaxis in patients with brain tumors: a meta-analysis. 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Epilepsia 39(7):700\u0026ndash;708. https://doi.org/10.1111/j.1528-1157.1998.tb01154.x\u003c/li\u003e\n\u003cli\u003eGao S, Juhaeri J, Dai WS (2008) The incidence rate of seizures in relation to BMI in UK adults. Obesity (Silver Spring) 16(9):2126\u0026ndash;2132. https://doi.org/10.1038/oby.2008.310\u003c/li\u003e\n\u003cli\u003eChen M, Wu X, Zhang B, Shen S, He L, Zhou D (2021) Associations of overweight and obesity with drug-resistant epilepsy. Seizure 92:94\u0026ndash;99. https://doi.org/10.1016/j.seizure.2021.07.019\u003c/li\u003e\n\u003cli\u003eJanousek J, Barber A, Goldman L, Klein P (2013) Obesity in adults with epilepsy. Epilepsy Behav 28(3):391\u0026ndash;394. https://doi.org/10.1016/j.yebeh.2013.05.012\u003c/li\u003e\n\u003cli\u003eBaxendale S, McGrath K, Donnachie E, Wintle S, Thompson P, Heaney D (2015) The role of obesity in cognitive dysfunction in people with epilepsy. 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CNS Drugs 17:1013\u0026ndash;1030. https://doi.org/10.2165/00023210-200317140-00002\u003c/li\u003e\n\u003cli\u003eRong L, Frontera AT Jr, Benbadis SR (2014) Tobacco smoking, epilepsy, and seizures. Epilepsy Behav 31:210\u0026ndash;218. https://doi.org/10.1016/j.yebeh.2013.11.022\u003c/li\u003e\n\u003cli\u003eJohnson AL, McLeish AC, Shear PK, Sheth A, Privitera M (2019) The role of cigarette smoking in epilepsy severity and epilepsy-related quality of life. Epilepsy Behav 93:38\u0026ndash;42. https://doi.org/10.1016/j.yebeh.2019.01.041\u003c/li\u003e\n\u003cli\u003eDworetzky BA, Bromfield EB, Townsend MK, Kang JH (2010) A prospective study of smoking, caffeine, and alcohol as risk factors for seizures or epilepsy in young adult women: data from the Nurses\u0026apos; Health Study II. Epilepsia 51(2):198\u0026ndash;205. https://doi.org/10.1111/j.1528-1167.2009.02268.x\u003c/li\u003e\n\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":"Anatomy, Glioma, Metastases, Seizure, Topography","lastPublishedDoi":"10.21203/rs.3.rs-6403995/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6403995/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003ePurpose:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThis study consolidated evidence on the association of tumor-intrinsic and investigated the underexplored association of tumor-extrinsic factors with tumor-related epilepsy, aiming to contribute to the overall risk assessment for clinical management in tumor-related epilepsy.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eOver a period of one year (2020), we prospectively collected imaging and clinical data of 373 patients with histopathologically confirmed brain tumors. Assessed tumor-intrinsic factors included histopathology, diameter and anatomical location, with the central lobe comprising the precentral, postcentral and subcentral gyrus and paracentral lobule. Tumor-extrinsic factors comprised sex, age, BMI, smoking, alcohol abuse, and Na\u003csup\u003e+\u003c/sup\u003e/K\u003csup\u003e+\u003c/sup\u003e imbalances. We applied univariable and multivariable binary logistic regression to characterize the associations between tumor-intrinsic and tumor-extrinsic factors with tumor-related epilepsy.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults:\u003c/b\u003e\u003c/p\u003e \u003cp\u003ePreoperative seizures occurred in 29.5% (n\u0026thinsp;=\u0026thinsp;110) of patients, with cortical locations \u0026mdash; particularly the central lobe (91.3%, n\u0026thinsp;=\u0026thinsp;21) \u0026mdash; posing the highest seizure incidence among all factors. In univariable analysis, compared to WHO grade 3/4 gliomas, WHO grade 1/2 neuroepithelial tumors exhibited moderately higher, whereas pituitary adenomas/ craniopharyngiomas and schwannomas showed lower incidences of preoperative seizures. In multivariable analysis, the central lobe (OR 58.15), other cortical locations (OR 3.47\u0026ndash;3.76), male sex (OR 1.77), low BMI (OR 4.61) and smoking (OR 1.013 per pack-year), revealed significant associations (p\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eCortical location, especially in the central lobe, male sex, low BMI and smoking, are independently associated with tumor-related epilepsy. Our findings support the importance of considering both tumor-intrinsic and tumor-extrinsic factors to develop a holistic seizure-risk assessment and highlight the need for larger, prospective studies to refine clinical management and potentially pharmacological seizure prophylaxis.\u003c/p\u003e","manuscriptTitle":"Intrinsic and extrinsic risk factors in tumor-related epilepsy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-26 08:26:03","doi":"10.21203/rs.3.rs-6403995/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":"18c04cd4-3ff5-4b19-ae13-c4b061526a25","owner":[],"postedDate":"May 26th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-09T00:43:15+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-26 08:26:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6403995","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6403995","identity":"rs-6403995","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}