The Scale for Estimating Prognosis of Epilepsy to predict in patients with epilepsy: A 506-Patient Cohort Study

The Scale for Estimating Prognosis of Epilepsy to predict in patients with epilepsy: A 506-Patient Cohort Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Scale for Estimating Prognosis of Epilepsy to predict in patients with epilepsy: A 506-Patient Cohort Study Xu Chen, Jian-qing Ge, Xiao-Bo Ma, Qiang Zhang, Xiao-hong LI, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8321804/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 16 Feb, 2026 Read the published version in BMC Neurology → Version 1 posted 10 You are reading this latest preprint version Abstract Objective This study aimed to evaluate the predictive performance of the Scale for Estimating Prognosis of Epilepsy (SEPE) in identifying drug-resistant epilepsy (DRE), using the 2010 International League Against Epilepsy (ILAE) definition as the reference standard. Methods A total of 506 hospitalized patients with epilepsy, including 57 who underwent epilepsy surgery, were enrolled. DRE was defined according to 2010 ILAE criteria, and the reproducibility of SEPE’s predictive risk factors was examined. SEPE scores were then assigned to all patients, and the concordance between SEPE-based predictions and ILAE-defined DRE diagnoses was assessed after one to two years of follow-up in the full cohort (n = 506) and in the subset excluding surgical cases (n = 449). Finally, distinct clinical patterns of DRE, including persistence and fluctuating forms, were identified, and the associations between SEPE scores and these subtypes were analyzed. Results Multivariate logistic regression identified seizures occurring across the sleep–wake cycle, multiple seizure types, and at least one seizure within two months as independent risk factors for DRE. The area under the ROC curve (AUC) for SEPE in identifying ILAE-defined DRE was 0.6827 (95% CI: 0.6322–0.7245) in the full cohort and 0.6812 (95% CI: 0.6302–0.7382) after excluding surgical cases. Among patients with SEPE scores ≥ 6, 91.2% met the ILAE criteria for DRE, with sensitivity of 63.9% and specificity of 96.2%, whereas 89.4% of those with scores ≤ 4 were drug-responsive, with sensitivity of 87.2% and specificity of 87.1%. For scores with 4 < SEPE < 6, 34% had DRE, 53% were drug-responsive, and 24.9% of patients with scores ≤ 3 achieved seizure freedom without antiseizure medications (ASMs). In patients with DRE defined by the ILAE criteria, SEPE scores ≥ 6 were associated with intractable DRE without remission, while scores ≤ 4 were frequently linked to seizure control following appropriate ASM adjustments. Conclusion The SEPE may serve as a useful tool for estimating the risk of DRE and for stratifying patients with epilepsy based on its constituent predictive factors. It may be particularly helpful for physicians—especially general neurologists who are not epilepsy specialists. DRE ILAE definition SEPE predicting factors Figures Figure 1 Figure 2 Figure 3 Introduction Epilepsy research is a multidisciplinary and interdisciplinary endeavor, encompassing a broad range of study areas. Over the past few decades, scientists in the basic sciences and epileptologists have been devoted to exploring epilepsy-associated genes through approaches such as single-cell genomics 1 and selective activation or inactivation of genes in vivo in rodent models 2 . By investigating changes in biomolecules, biochemistry, and electrophysiology of cortical neurons, researchers aim to deepen the understanding of the mechanisms underlying epileptogenesis and its related disorders. The ultimate goal is to improve current diagnostic and therapeutic approaches. However, in current clinical practice and research, patient history remains the predominant factor in the diagnosis of epilepsy, seizure types, treatment efficacy evaluation, and the determination of drug-resistant epilepsy. Clinicians have long hoped for the application of reliable biological markers that could reflect the processes of epileptogenesis and progression, but their implementation remains out of reach in the short term 3 . Globally, more than 50 million people are affected by epilepsy. From the perspective of disease-related economic burden, epilepsy accounts for approximately 13.5 million disability-adjusted life years (DALYs). Among these, patients with drug-resistant epilepsy are the major contributors to this burden 4 . The challenges of drug-resistant epilepsy extend well beyond mere seizure control, encompassing secondary structural and neurobiochemical changes that contribute to comorbidities such as cognitive impairment, psychiatric disorders, and adverse psychosocial outcomes. These complications not only reduce patients’ overall quality of life but also increase the risk of sudden unexpected death in epilepsy (SUDEP). Therefore, it is crucial to promptly diagnose DRE or predict its likelihood through specific risk factors. In recent years, published reviews on drug-resistant epilepsy emphasize that assessing an individual's likelihood of having DRE necessitates considering multiple factors. These reviews also highlight and recommend the SEPE 5 , 6 , 7 , 8 , which we had previously developed as a tool to aid in prognosis estimation. However, its single-center design and relatively small sample size may limit the reliability of the findings, underscoring the need for further validation. This study enrolled a cohort of 506 patients with epilepsy to evaluate the external validity of the SEPE and to assess its predictive performance using more comprehensive metrics.The study was structured in three stages: (i) reassessing risk factors associated with DRE, (ii) validating the external applicability of the SEPE, and (iii) examining the relationship between SEPE scores and DRE subtypes. Methods 1.Patients and c haracteristics of clinical data at enrolment The study recruited 543 hospitalized pediatric, adolescent, and adult patients with epilepsy, diagnosed at the Epilepsy Center of Nanjing Brain Hospital between January 1 and December 31, 2021. This center specializes in managing complex cases and evaluating newly diagnosed epilepsy. All participants met the diagnostic criteria for epilepsy established by the International League Against Epilepsy (ILAE) in 2014 9 . Exclusion criteria were: (i) acute symptomatic seizures related to recent central nervous system injury (e.g.,metabolic causes, poisoning, trauma, infection,); (ii) febrile seizures; and (iii) chronic epileptic seizures secondary to neoplasms, stroke, infection, encephalitis, trauma, etc. Data were collected from 543 patients, including 58 who underwent epilepsy surgery. Variables included age, sex, family history of epilepsy, history of febrile seizures, age at onset, epilepsy duration, seizure type, frequency, and relation to the sleep–wake cycle. Additional data covered antiseizure medications (ASMs) use and cranial MRI (3.0T) findings, including: hippocampal sclerosis; gray matter heterotopia; focal cortical dysplasia; ASL perfusion abnormalities; developmental anomalies (e.g., mega glomerular gyrus); and, in patients under 30, unexplained small foci with white matter changes such as punctate demyelination in the insula. The study also incorporated 24-hour video EEG, magnetoencephalography, PET-CT, ROSA-guided stereotactic EEG (in select patients), and second-generation sequencing(in a very small subset). 2.Drug-resistant epilepsy was distinguished and followed up The 543 patients enrolled in the study were defined into three groups based on ILAE definitions in 2010: drug-resistant epilepsy ( DRE), drug-responsive epilepsy, and an undefined category 10 . DRE was defined as failure of adequate trials of two tolerated and appropriately chosen and used ASM schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom. Drug-responsive epilepsy was defined as a seizure-free interval at least three times longer than before treatment or exceeding one year. Patients not clearly meeting either criterion were temporarily classified as "undefined" to indicate uncertain drug responsiveness. Telephone follow-ups began on March 18, 2023, with some patients follow-up conducted via an established WeChat group. The follow-ups covered various aspects, including seizure frequency, current ASMs regimen, recent changes in seizure type and manifestations, and the time of achieving ultimate seizure remission, concluding at the end of May 2023. Of the 543 patients in the initial cohort, follow-up data were unavailable for 35, and two experienced SUDEP, one of whom died several months after surgery during the postoperative follow-up period. Consequently, 506 patients, including 57 who underwent surgery, completed follow-up and were reclassified per ILAE definition. Patients lost to follow-up were excluded, and all analyses used a complete-case approach. The study did not involve any intervention or modification of patient care and posed no additional risk to participants. Therefore, it was granted an exemption from full IRB review by the Institutional Review Board of our hospital . 3.Stages definition and Data collection 3.1. Reassessing risk factors associated with DRE The data from 506 cases comprised three components: (i) Table 1 details associations between baseline characteristics—including preoperative data from 57 surgical cases, and their definition as DRE, drug-responsive epilepsy, or undefined epilepsy according to the 2010 ILAE criteria. The description also details 244 cases initially undefined, 214 with multiple seizure types, and seizure frequency defined using a two-month cutoff. (ii) Table 2 presents patients’ baseline characteristics and preoperative surgical data at enrollment, reassessed at 1–2 years of follow-up according to the 2010 ILAE definitions, when most initially undefined cases were redefined as either DRE or drug-responsive epilepsy. The description specifies the definition of seizure freedom. (iii) Table 3 illustrates the relationship between epilepsy classification, ASMs use, and the 2010 definition. The description presented other additional information. 3.2. External validation of the SEPE score In our 2021 study 5 , we followed 141 epilepsy patients for 4–9 years to identify DRE risk factors and developed the Scale for Estimating Prognosis of Epilepsy (SEPE), summarized in Table 5. A SEPE score ≥6 indicated high risk of drug resistance, while ≤4 predicted favorable ASM response. To validate SEPE in the current cohort of 506 patients, SEPE scores were assigned at baseline, and two specialists independently reviewed SEPE scores and ILAE definitions under blinded conditions. Discrepancies were resolved by consensus. Preoperative data for surgical patients were included. All participants were followed for 1–2 years and reclassified per ILAE criteria, with patients unable to be clearly defined designated as undefined. Discrepancies were resolved by consensus and the final findings were summarized in Table 6. Analyses were conducted as follows: (i) Correlation between SEPE scores and 2010 ILAE DRE definitions was assessed for all 506 patients, and consistency tested. (ii) After excluding 57 surgical cases, the remaining 449 patients were analyzed similarly. (iii) Among the 244 baseline undefined cases, SEPE scores were used to predict progression to DRE or drug-responsive epilepsy, and consistency with DRE definition assessed. The distribution of these data is summarized in Table 7. 3.2. To examine the relationship between SEPE scores and DRE subtypes (i) Epidemiological studies classify DRE into three subtypes 13,14 : (1) Initially drug-resistant, (2) Progressive drug-resistant, and (3) Fluctuating drug-resistant. The 2010 ILAE DRE definition includes a temporal component 15 : patients may develop DRE later or convert to drug-sensitive epilepsy after ASM adjustments or surgery. For clarity, persistently uncontrolled seizures despite pharmacological or surgical intervention are referred to as "intractable DRE." (ii) Among 506 patients, 142 had DRE at baseline. After 1–2 years, 141 additional patients met DRE criteria, including 43 transitioning from drug-responsive or undefined epilepsy, yielding 185 DRE cases. Of these, 129 received ASM alone, 56 underwent surgery . (iii) Of 185 DRE patients, 98 remained persistently drug-resistant ("intractable DRE"), with 70 on ASM therapy alone and 28 undergoing surgery. The remaining 87 exhibited fluctuating DRE; 59 were ASM-treated and alternated between drug-sensitive and resistant states, while 28 converted to drug-responsive epilepsy after surgery. (ⅳ) Among 506 patients, 214 exhibited two or more seizure types. Of these, 42.5% presented multiple seizure types early (within six months), 43% developed additional seizure types progressively over up to 10 years, and 14.5% presented new seizure types over 11–38 years. The distribution of these data is summarized in Table 12. Statistical analyses Most of the statistical analyses were performed using SPSS version 27.0. Age-related variables were summarized as means, standard deviations, and medians. Continuous variables were compared using one-way analysis of variance (ANOVA), and categorical variables across multiple groups were examined using the chi-square test with adjusted residual analysis (significance set at <0.05). A multiple stepwise logistic regression model was used to identify independent risk factors for drug-resistant epilepsy, with p <0.05 considered statistically significant. Additional analyses were conducted using R version 4.2.1.Receiver operating characteristic (ROC) curves were generated to evaluate the concordance between SEPE scores and the ILAE definition of DRE, with the area under the curve (AUC) and 95% confidence intervals estimated via bootstrapping. Two thresholds were examined: SEPE ≥6 (indicative of DRE) and SEPE ≤4 (indicative of drug responsiveness, including seizure freedom). Results 1.General characteristics Age of seizure onset ranged from 0.1 to 81 years, with cumulative distributions of 25.3% (≤10 years), 40.3% (≤14 years), 58.9% (≤20 years), and 95.7% (≤60 years). The 75th percentile age was ~31 years. Approximately 28% of patients had drug-resistant epilepsy (DRE), of these, ~10% received ASM monotherapy, while ~90% received combination therapy, commonly three ASMs. Epilepsy classification was not analyzed as a risk factor due to its dependence on seizure type and other biological markers. After over one year of follow-up, 50% of DRE patients undergoing surgery achieved drug-responsive status. 2.Risk factors for DRE Analysis of Tables 1 and 2 indicated that gender, childhood febrile seizures, and family history were not significant predictors. Multifocal EEG abnormalities were strongly associated with DRE (p < 0.001), as were earlier age of onset and longer epilepsy duration ( p < 0.001). Additional significant risk factors before and after 1–2 years of follow-up included seizures during both sleep and wake cycles(p < 0.001), multiple seizure types(p < 0.001), recurrence of one or more seizures within two months (p < 0.001), and cranial MRI abnormalities(p < 0.001), including hippocampal sclerosis, cortical dysplasia, and nonspecific changes (e.g., punctate ischemic foci) in patients <30 years without other intracranial diseases, ASL-MRI abnormalities were also used as reference criteria. Intellectual disability was significant at baseline (p = 0.008) but became borderline after follow-up (p = 0.058). Logistic regression identified three independent predictors of DRE: seizures during both sleep and wake, multiple seizure types, and one or more seizures within two months (Table 4). 3.External validation of the SEPE score: 3.1.Entire cohort (n = 506) (i) At baseline : Of the 136 patients with SEPE ≥6, 110 (80.9%) were categorized as DRE, 5 (3.7%) were drug-responsive, and 21 (15.4%) remained undefined. Among the 274 patients with SEPE ≤4, 99 (36.1%) were responsive, 4 (1.5%) had DRE, and 171 (62.4%) remained undefined. In the intermediate group (4 < SEPE < 6; n=96), 28 (29.2%) had DRE, 16 (16.7%) were responsive, and 52 (54.2%) remained undefined. Among surgically treated patients, only one responsive case had SEPE ≤4; of the remaining 56 DRE cases, 51 (91%) had SEPE ≥6, and 5 (9%) had SEPE scores between 4 and 6. (ii) After follow-up: Out of 136 patients with SEPE ≥6, 91 (66.9%) had DRE, 40 (29.4%) were drug-responsive (including 25 who transitioned from DRE after surgery), and 5 (3.7%) were undefined. Among 274 patients with SEPE ≤4, 234 (85.4%) were responsive, 17 (6.2%) had DRE, and 23 (8.4%) were undefined. Of the 96 patients with SEPE scores between 4 and 6, 33 (34.4%) had DRE, 51 (53.1%) were responsive to ASMs, and 12 (12.5%) had an undefined outcome. Among the 57 surgically treated patients at the end of follow-up, only one was drug-responsive with a SEPE ≤4. Of the remaining 56 with DRE, 28 transitioned to drug responsiveness (25 with SEPE ≥6 and 3 with scores of 4 < SEPE < 6), while the other 28 remained drug-resistant (26 with SEPE ≥6 and 2 with scores of 4 < SEPE < 6). (iii) ROC analysis showed AUC = 0.6827 (95% CI 0.6322–0.7245), accuracy 69.7%, sensitivity 64.5%, and specificity 72.0% (Table 8, Fig. 1). 3.2. Non-surgical subgroup (n = 449) (i) At baseline : Among 449 patients, 85 had SEPE ≥6, 59 (69.4%) were DRE, 5 (5.9%) responsive, and 21 (24.7%) undefined. Of 273 patients with SEPE ≤4, 98 (35.9%) were responsive, 4 (1.5%) DRE, and 171 (62.6%) undefined. In the intermediate group (n = 91, 4 < SEPE < 6), 23 (25.3%) were DRE, 16 (17.6%) responsive, and 52 (57.1%) undefined.. (ii) After follow-up: For the 85 patients with SEPE ≥6, 65 (76.5%) were confirmed as DRE, 15 (17.6%) responsive, and 5 (5.9%) undefined. Among those with SEPE ≤4 (n = 273), 233 (85.3%) were responsive, 17 (6.2%) DRE, and 23 (8.4%) undefined. In the intermediate group (n = 91), 31 (34.0%) developed DRE, 48 (52.8%) were responsive, and 12 (13.2%) undefined. (iii) ROC analysis yielded AUC = 0.6812 (95% CI 0.6302–0.7382), accuracy 72.9%, sensitivity 57.5%, and specificity 78.7% (Table 9, Fig. 2). 3.3.Patients with undefined epilepsy (n = 244) (i) At baseline: Among 244 patients with undefined epilepsy prior to follow-up, 21 had SEPE ≥6, 52 had 4 < SEPE < 6, and 171 had SEPE ≤4. (ii) After 1–2 years : Among 21 patients with SEPE ≥6, 11 (52%) developed DRE, 4 (19%) remained undefined, and 6 (29%) became drug-responsive; among 52 patients with 4 < SEPE < 6, 11 (21.2%) developed DRE, 10 (19.2%) remained undefined, and 31 (59.6%) became drug-responsive; among 171 patients with SEPE ≤4, 10 (5.9%) developed DRE, 17 (10%) remained undefined, and 144 (84.2%) became drug-responsive (including seizure-free). (iii) ROC analysis confirmed the predictive value of SEPE in this subgroup,AUC=0.5697(95%CI:0.4869–0.6666),Accuracy:72.77%,Sensitivity:34.38%,Specificity: 79.56%(Table 10, Fig. 3). 3.4. Diagnostic performance Among the 506 epilepsy patients, 136 had SEPE scores ≥6. At enrollment, 110 were defined as drug-resistant epilepsy (DRE). By the end of follow-up, an additional 14 cases (3 previously responsive and 11 undefined) transitioned to DRE, yielding a total of 124 out of 136 patients (91.2%) with DRE. In contrast, 274 patients had SEPE scores ≤4 at enrollment, including 99 defined as drug-responsive. During follow-up, 146 additional cases transitioned to drug-responsive epilepsy (4 from DRE and 142 from undefined). Altogether, 245 out of 274 patients (89.4%) with SEPE ≤4 were ultimately responsive. Overall, SEPE ≥6 predicted DRE with sensitivity 63.9%, specificity 96.2%, PPV 91.2%, and NPV 81.1%, while SEPE ≤4 predicted responsiveness with sensitivity 87.2%, specificity 87.1%, PPV 89.4%, and NPV 84.5% (see Table 11). In patients with SEPE ≤3, only 24.9% achieved seizure freedom, whereas in the intermediate group (4 < SEPE < 6), about one-third developed DRE and more than half became responsive. 4.Examining the relationship between SEPE scores and DRE subtypes 4.1.As shown in Table 13, among 129 non-surgically treated DRE patients, SEPE scores ≥6 predicted intractable DRE, scores ≤4 predicted fluctuating DRE (p<0.001). For 56 surgical patients, SEPE scores did not predict outcomes (p=0.72). 4.2.Later emergence of new seizure types was significantly associated with intractable postoperative DRE ( P = 0.027) see Table 14. Summary i. Among 506 patients (75th percentile age ~31 years), ~28% had DRE. Three independent risk factors for developing DRE were identified: seizures occurring during both sleep and wake cycles; at least one seizure within a two-month period; and multiple seizure types. ⅱ. Among 214 patients with multiple seizure types, 42.5% presented with multiple types simultaneously or within six months of onset, 43% developed new types over 0.6–10 years, and 14.5% developed new types after 11–38 years. ⅲ.Using the 2010 ILAE definition of DRE as the reference, we assessed the predictive validity of the SEPE scale. SEPE showed moderate concordance with the ILAE definition, supporting its utility as a practical tool for long-term prognosis. ⅳ.Among 506 epilepsy patients, 136 had SEPE ≥6, of whom 91.2% were drug-resistant epilepsy (sensitivity was 63.9%, specificity was 96.2%); 274 had SEPE ≤4, with 89.4% drug-responsive(sensitivity was 87.2% , specificity was 87.1%). The 96 patients with intermediate scores ( 4 < SEPE < 6 ) showed mixed outcomes, with 34.4% developing DRE and 53.1% responding to ASMs. ⅴ . Fluctuating DRE is characterized by alternating periods of drug responsiveness and resistance, whereas intractable DRE is defined by persistent lack of seizure control. ⅵ. In non-surgically treated DRE patients, SEPE ≥6 predicted intractable DRE, whereas in patients with SEPE ≤4, DRE tended to follow a fluctuating course Ⅶ. Later emergence of new seizure types (in years) was associated with a higher likelihood of postoperative intractable DRE. Discussion Our study belongs to an interconnected series of investigations centered on validating the practical utility of the SEPE scale in clinical settings. We verified the reliability of SEPE using the 2010 ILAE definition of DRE as the benchmark and further evaluated its ability to differentiate DRE subtypes. Extensive literature has identified independent risk factors for DRE, including multiple seizure types, status epilepticus, high seizure frequency, intellectual disability, early onset, and cranial MRI abnormalities 16 , 17 . Systematic reviews also highlight abnormal EEG, febrile seizures, and poor initial ASM response 18 , while the TASK1 study has provided a comprehensive list of over 40 risk factors linked to DRE 19 ; however, reproducibility remains a challenge. In our reassessment, we confirmed three independent risk factors: (1) seizures during both sleep and wake cycles, (2) ≥ 1 seizure in two months, and (3) multiple seizure types, consistent with earlier findings 5 . Multifocal EEG abnormalities showed diagnostic value but require further validation. Although the statistical significance of intellectual disability varied between baseline and follow-up, previous studies have consistently reported its association with DRE 20 , 21 . MRI abnormalities: hippocampal sclerosis, cortical dysplasia, or ASL changes remained significant risk factors. Family history, however, was not confirmed. Although it did not emerge as a risk factor for DRE in this study, family history remains a component of the SEPE scale based on evidence from previous research 5 , 22 , 23 . Due to current limitations in scientific and medical knowledge, substantial challenges remain in elucidating the underlying mechanisms of epilepsy and its clinical manifestations, which complicates accurate diagnosis 24 , 25 . Likewise, predicting DRE based on these markers is complex and variable. Many predictive studies lack reproducibility and offer recommendations without sufficient supporting evidence, raising concerns about the credibility of research in this field 26 . Predictive scales should ideally meet five essential criteria 27 . First, they should integrate both clinically relevant features and biologically meaningful indicators, analyzed statistically to yield a simplified tool suitable for clinical application. Second, the required parameters should be readily obtainable in large general hospitals. Third, scale cut-off points must demonstrate strong predictive validity. Fourth, calculated scores should enable an initial stratified assessment of prognosis. Finally, the scale should exhibit reasonably accurate predictive performance. The SEPE scale essentially fulfills all of these criteria. During the entire observation period, 91.2% of patients with SEPE ≥ 6 were DRE, while 89.4% with SEPE ≤ 4 were drug-responsive. In intermediate group (4–6 points), 34% developed DRE and 53% were responsive. Among SEPE ≤ 3, about 25% achieved seizure freedom. In 506 patients, SEPE showed predictive accuracy with AUC 0.6827 (95% CI: 0.6322–0.7245); excluding surgery cases yielded similar results. Among 244 undefined patients, SEPE maintained predictive value (AUC 0.5697): 52% with SEPE ≥ 6 became DRE, while 84.2% with SEPE ≤ 4 were responsive. Overall, SEPE provides clear, quantitative, and clinically relevant predictors compared to prior models 28 , 29 , which may be particularly helpful for physicians—especially general neurologists who are not epilepsy specialists. Observational studies indicate that DRE is a dynamic condition: 20%–38% of patients may enter remission, yet 16%–58% of these may subsequently revert to DRE 30 , 31 , 32 , 33 . In our cohort of 185 patients diagnosed with DRE per ILAE definition at baseline and follow-up, 98 were persistently intractable, while the remainder exhibited a fluctuating course, accounting for 47% of all DRE cases. Among 129 non-surgically treated patients with DRE, 70 were persistently intractable, while 59 (45.7%) exhibited a fluctuating course. Patients with DRE and a SEPE score ≤ 4 had a higher likelihood of achieving seizure remission through ASM dose adjustments or switching to alternative ASMs. Previous studies have reported that even among patients who have failed 2–5 ASMs, switching to another ASM can induce remission in approximately 17% of cases 34 . Among 56 surgical patients, outcomes divided evenly between postoperative remission and persistent intractability. SEPE was not predictive, but later emergence of new seizure types correlated with poorer surgical results (P = 0.027). Existing surgical prediction tools (ESN, m-SFS) 35 , 36 remain limited, highlighting the need for additional markers. Over time, some patients with epilepsy may experience progressive structural damage to the nervous system 37 . In general, the presence of different seizure types is considered to reflect distinct epileptogenic foci, particularly in cases of focal seizures 38 . It is possible that newly emerging seizure types during the course of epilepsy represent the development of new epileptogenic zones or an expansion of existing foci, which may indicate a progressive worsening of the condition. Given the diverse clinical manifestations of drug-resistant epilepsy (DRE), some researchers have proposed the term ‘spectrum of drug-resistant epilepsy’ to more comprehensively capture its subtypes 39 . That is, DRE should be regarded as a spectrum of disorders with varying clinical presentations and neurobiological features, rather than a homogeneous disease entity 40 . Recently, scholars have suggested 19 that to better integrate clinical and preclinical research and ensure the definition of DRE reflects the interplay of pathophysiology, diagnosis, and treatment, the 2010 ILAE definition should be revised Conclusion In this study, we confirmed the reproducibility of the risk factors underlying the SEPE scale, and, using the 2010 ILAE definition as a reference, consistency testing demonstrated that SEPE is a practical tool for estimating DRE risk and stratifying patients. Patients with SEPE ≥ 6 had a 91.2% probability of DRE, whereas those with SEPE ≤ 4 were 89.4% likely to remain drug-sensitive. Among 185 ILAE-defined DRE cases, SEPE ≥ 6 was associated with a low likelihood of remission under antiseizure medications alone, while SEPE ≤ 4 predicted responsiveness to dose adjustment or drug substitution. In surgical patients, later emergence of new seizure types was an adverse prognostic marker. Declarations Ethics approval and consent to participate This study was reviewed and determined to be exempt from full ethical review by the Ethics Committee of Jen Ching Memorial Hospital (23001-IRB-Exempt-2023-02-20). Potential Conflicts of Interest Nothing to report. Author Contribution X Chen. contributed to the conception and design of the study; X Chen., JQ Ge., XB Ma., Q Zhang.and Q YANG.contributed to the acquisition and analysis of data; X Chen., XB Ma., Q Zhang., and Q YANG contributed to validation; X Chen.,Xh LI.contributed to supervision.; X Chen.contributed to writing - original draft. Acknowledgments The authors thank the physicians of the Department of Neurology and the Epilepsy Center at Nanjing Brain Hospital for their support and assistance in collecting patient data. We also thank the patients with epilepsy and their families for their cooperation and support during the telephone follow-ups. 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Gabriel Servilha-Menezes,Norberto Garcia-Cairasco.A complex systems view on the current hypotheses of epilepsy pharmacoresistance. Epilepsia Open. 2022;7(Suppl. 1):S8–22. Wirrell EC, Nabbout R, Scheffer IE, et al. Methodology for classification and definition of epilepsy syndromes with list of syndromes: report of the ILAE Task Force on Nosology and Definitions. Epilepsia. 2022;63:1333–48. Löscher et al. Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options. Pharmacol Rev 72:606–38, July 2020. Rajiv Jalan F, Saliba MP. Alex Amoros. Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure. J Hepatol · June 2014. Geng H, Chen X. Development and validation of a nomogram for the early prediction of drug resistance in children with epilepsy. Front Pediatr. 2022;10:905177. Boonluksiri P, Visuthibhan A, Katanyuwong K. Clinical prediction rule of drug resistant epilepsy in children. J Epilepsy Res. 2015;5:84–8. Berg AT, Vickrey BG, Testa FM, Levy SR, Shinnar S, DiMario F, et al. How long does it take for epilepsy to become intractable? A prospective investigation. Ann Neurol. 2006;60:73–9. Choi H, Heiman G, Pandis D, Cantero J, Resor SR, Gilliam FG, et al. Seizure remission and relapse in adults with intractable epilepsy: a cohort study. Epilepsia. 2008;49:1440–5. Callaghan B, Schlesinger M, Rodemer W, Pollard J, Hesdorffer D, Allen Hauser W, et al. Remission and relapse in a drugresistant epilepsy population followed prospectively. Epilepsia. 2011;52:619–26. Brodie MJ, Barry SJ, Bamagous GA, Norrie JD, Kwan P. Patterns of treatment response in newly diagnosed epilepsy. Neurology. 2012;78:1548–54. Janmohamed M, Hakeem H, Ooi S, Hakami S, Vu L, Perucca P, et al. Treatment outcomes of newly diagnosed epilepsy: a systematic review and meta-analysis. CNS Drugs. 2023;37:13–30. Lara, Jehi. Development and validation of nomograms to provide individualised predictions of seizure outcomes after epilepsy surgery: a retrospective analysis. thelancet com/neurology Published online January. 2015;29. http://dx.doi.org/10.1016/S1474-4422(14)70325-4 . Garcia C, Gracia, et al. Seizure freedom score: A new simple method to predict success of epilepsy surgery. Epilepsia. 2015;56(3):359–65. Laxer KD, et al. The consequences of refractory epilepsy and its treatment. J Epilepsy Behav. 2014;37:59–70. Adams, Victor’s. PRINCIPLES OF NEUROLOGY ELEVENTH EDITION.M.CARDINAL MANIFESTATIONS OF NEUROLOGIC DISEASE. P338. Löscher et al. Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options. J Pharmacol Rev 72:606–38, July 2020. Fattorusso et al. The Pharmacoresistant Epilepsy: An Overview on Existant and New Emerging Therapies.J.Frontiers in Neurology.June 2021 | Volume 12 | Article 674483. Tables Table 1 to 14 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table114.docx Cite Share Download PDF Status: Published Journal Publication published 16 Feb, 2026 Read the published version in BMC Neurology → Version 1 posted Editorial decision: Revision requested 05 Jan, 2026 Reviews received at journal 04 Jan, 2026 Reviewers agreed at journal 04 Jan, 2026 Reviews received at journal 28 Dec, 2025 Reviewers agreed at journal 28 Dec, 2025 Reviewers invited by journal 17 Dec, 2025 Editor invited by journal 16 Dec, 2025 Editor assigned by journal 15 Dec, 2025 Submission checks completed at journal 15 Dec, 2025 First submitted to journal 09 Dec, 2025 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-8321804","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":562058761,"identity":"5cc678ab-da5f-4f1f-88fe-42d717665999","order_by":0,"name":"Xu 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18:07:06","extension":"html","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":188303,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8321804/v1/3e22f1a825aab221facb6f37.html"},{"id":98775574,"identity":"083c8658-c100-4a15-a739-97a4f1be5bd0","added_by":"auto","created_at":"2025-12-22 12:20:21","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":47264,"visible":true,"origin":"","legend":"\u003cp\u003eThe ROC curves of SEPE scores versus the diagnostic definition of ILAE in 506 patients after follow-up are presented\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8321804/v1/3e941ab95923a14447faea80.png"},{"id":98639570,"identity":"eac71ce1-b573-44e4-88fc-e15abbf461af","added_by":"auto","created_at":"2025-12-19 18:07:06","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":50312,"visible":true,"origin":"","legend":"\u003cp\u003eROC curves comparing SEPE scores with the diagnostic definition of ILAE in a cohort of 449 patients during follow-up\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8321804/v1/27cb3c03835a0187294a92c7.png"},{"id":98775689,"identity":"f5ff72d1-3eb1-42eb-8d0a-586038392986","added_by":"auto","created_at":"2025-12-22 12:20:50","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":23039,"visible":true,"origin":"","legend":"\u003cp\u003eROC curves of SEPE scores against the ILAE definition in 244 patients with undefined epilepsy post-follow-up\u003c/p\u003e","description":"","filename":"floatimage5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8321804/v1/330758d579c4225737f4c10f.jpeg"},{"id":103251393,"identity":"d838409e-444b-4e79-95b6-af897ded00ee","added_by":"auto","created_at":"2026-02-23 16:08:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":907855,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8321804/v1/4e107bc4-f410-440a-a8c9-a967a0882e9b.pdf"},{"id":98639571,"identity":"3f1d335f-e87e-46a0-a933-7adc88d2c326","added_by":"auto","created_at":"2025-12-19 18:07:06","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":51886,"visible":true,"origin":"","legend":"","description":"","filename":"Table114.docx","url":"https://assets-eu.researchsquare.com/files/rs-8321804/v1/d27078cc798cf7712f492a04.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"The Scale for Estimating Prognosis of Epilepsy to predict in patients with epilepsy: A 506-Patient Cohort Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEpilepsy research is a multidisciplinary and interdisciplinary endeavor, encompassing a broad range of study areas. Over the past few decades, scientists in the basic sciences and epileptologists have been devoted to exploring epilepsy-associated genes through approaches such as single-cell genomics\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e and selective activation or inactivation of genes in vivo in rodent models\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. By investigating changes in biomolecules, biochemistry, and electrophysiology of cortical neurons, researchers aim to deepen the understanding of the mechanisms underlying epileptogenesis and its related disorders. The ultimate goal is to improve current diagnostic and therapeutic approaches. However, in current clinical practice and research, patient history remains the predominant factor in the diagnosis of epilepsy, seizure types, treatment efficacy evaluation, and the determination of drug-resistant epilepsy. Clinicians have long hoped for the application of reliable biological markers that could reflect the processes of epileptogenesis and progression, but their implementation remains out of reach in the short term \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eGlobally, more than 50\u0026nbsp;million people are affected by epilepsy. From the perspective of disease-related economic burden, epilepsy accounts for approximately 13.5\u0026nbsp;million disability-adjusted life years (DALYs). Among these, patients with drug-resistant epilepsy are the major contributors to this burden \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. The challenges of drug-resistant epilepsy extend well beyond mere seizure control, encompassing secondary structural and neurobiochemical changes that contribute to comorbidities such as cognitive impairment, psychiatric disorders, and adverse psychosocial outcomes. These complications not only reduce patients’ overall quality of life but also increase the risk of sudden unexpected death in epilepsy (SUDEP).\u003c/p\u003e \u003cp\u003eTherefore, it is crucial to promptly diagnose DRE or predict its likelihood through specific risk factors. In recent years, published reviews on drug-resistant epilepsy emphasize that assessing an individual's likelihood of having DRE necessitates considering multiple factors. These reviews also highlight and recommend the SEPE\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e, which we had previously developed as a tool to aid in prognosis estimation. However, its single-center design and relatively small sample size may limit the reliability of the findings, underscoring the need for further validation.\u003c/p\u003e \u003cp\u003eThis study enrolled a cohort of 506 patients with epilepsy to evaluate the external validity of the SEPE and to assess its predictive performance using more comprehensive metrics.The study was structured in three stages: (i) reassessing risk factors associated with DRE, (ii) validating the external applicability of the SEPE, and (iii) examining the relationship between SEPE scores and DRE subtypes.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003e1.Patients and c\u003c/strong\u003e\u003cstrong\u003eharacteristics of clinical data at enrolment\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study recruited 543 hospitalized pediatric, adolescent, and adult patients with epilepsy, diagnosed at the Epilepsy Center of Nanjing Brain Hospital between January 1 and December 31, 2021. This center specializes in managing complex cases and evaluating newly diagnosed epilepsy. All participants met the diagnostic criteria for epilepsy established by the International League Against Epilepsy (ILAE) in 2014 \u003csup\u003e9\u003c/sup\u003e. Exclusion criteria were: (i) acute symptomatic seizures related to recent central nervous system injury (e.g.,metabolic causes, poisoning, trauma, infection,); (ii) febrile seizures; and (iii) chronic epileptic seizures secondary to neoplasms, stroke, infection, encephalitis, trauma, etc.\u003c/p\u003e\n\u003cp\u003eData were collected from 543 patients, including 58 who underwent epilepsy surgery. Variables included age, sex, family history of epilepsy, history of febrile seizures, age at onset, epilepsy duration, seizure type, frequency, and relation to the sleep\u0026ndash;wake cycle. Additional data covered antiseizure medications (ASMs) use and cranial MRI (3.0T) findings, including: hippocampal sclerosis; gray matter heterotopia; focal cortical dysplasia; ASL perfusion abnormalities; developmental anomalies (e.g., mega glomerular gyrus); and, in patients under 30, unexplained small foci with white matter changes such as punctate demyelination in the insula. The study also incorporated 24-hour video EEG, magnetoencephalography, PET-CT, ROSA-guided stereotactic EEG (in select patients), and second-generation sequencing(in a very small subset).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.Drug-resistant epilepsy was distinguished and followed up\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe 543 patients enrolled in the study were defined into three groups based on ILAE definitions in 2010: \u003cstrong\u003edrug-resistant epilepsy (\u003c/strong\u003eDRE), drug-responsive epilepsy, and an undefined category\u003csup\u003e10\u003c/sup\u003e. DRE was defined as failure of adequate trials of two tolerated and appropriately chosen and used ASM schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom. Drug-responsive epilepsy was defined as a seizure-free interval at least three times longer than before treatment or exceeding one year. Patients not clearly meeting either criterion were temporarily classified as \u0026quot;undefined\u0026quot; to indicate uncertain drug responsiveness.\u003c/p\u003e\n\u003cp\u003eTelephone follow-ups began on March 18, 2023, with some patients follow-up conducted via an established WeChat group. The follow-ups covered various aspects, including seizure frequency, current ASMs regimen, recent changes in seizure type and manifestations, and the time of achieving ultimate seizure remission, concluding at the end of May 2023.\u003c/p\u003e\n\u003cp\u003eOf the 543 patients in the initial cohort, follow-up data were unavailable for 35, and two experienced SUDEP, one of whom died several months after surgery during the postoperative follow-up period. Consequently, 506 patients, including 57 who underwent surgery, completed follow-up and were reclassified per ILAE definition. Patients lost to follow-up were excluded, and all analyses used a complete-case approach.\u003c/p\u003e\n\u003cp\u003eThe study did not involve any intervention or modification of patient care and posed no additional risk to participants. Therefore, it was granted an exemption from full IRB review by the Institutional Review Board of our hospital .\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.Stages definition and Data collection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.1.\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Reassessing risk factors associated with DRE\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data from 506 cases comprised three components:\u003cbr\u003e\u0026nbsp;(i) Table 1 details associations between baseline characteristics\u0026mdash;including preoperative data from 57 surgical cases, and their definition as DRE, drug-responsive epilepsy, or undefined epilepsy according to the 2010 ILAE criteria. The description also details 244 cases initially undefined, 214 with multiple seizure types, and seizure frequency defined using a two-month cutoff.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(ii) Table 2 presents patients\u0026rsquo; baseline characteristics and preoperative surgical data at enrollment, reassessed at 1\u0026ndash;2 years of follow-up according to the 2010 ILAE definitions, when most initially undefined cases were redefined as either DRE or drug-responsive epilepsy. The description specifies the definition of seizure freedom.\u003c/p\u003e\n\u003cp\u003e(iii) Table 3 illustrates the relationship between epilepsy classification, ASMs use, and the 2010 definition. The description presented other additional information.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2. External validation of the SEPE score\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn our 2021 study \u003csup\u003e5\u003c/sup\u003e, we followed 141 epilepsy patients for 4\u0026ndash;9 years to identify DRE risk factors and developed the Scale for Estimating Prognosis of Epilepsy (SEPE), summarized in Table 5. A SEPE score \u0026ge;6 indicated high risk of drug resistance, while \u0026le;4 predicted favorable ASM response.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo validate SEPE in the current cohort of 506 patients, SEPE scores were assigned at baseline, and two specialists independently reviewed SEPE scores and ILAE definitions under blinded conditions. Discrepancies were resolved by consensus. Preoperative data for surgical patients were included. All participants were followed for 1\u0026ndash;2 years and reclassified per ILAE criteria, with patients unable to be clearly defined designated as undefined. Discrepancies were resolved by consensus and the final findings were summarized in\u0026nbsp;Table 6.\u003c/p\u003e\n\u003cp\u003eAnalyses were conducted as follows:\u003cbr\u003e\u0026nbsp; \u0026nbsp;(i) Correlation between SEPE scores and 2010 ILAE DRE definitions was assessed for all 506 patients, and consistency tested.\u003cbr\u003e\u0026nbsp; \u0026nbsp;(ii)\u0026nbsp;After excluding 57 surgical cases, the remaining 449 patients were analyzed similarly.\u003cbr\u003e\u0026nbsp; \u0026nbsp;(iii)\u0026nbsp;Among the 244 baseline undefined cases, SEPE scores were used to predict progression to DRE or drug-responsive epilepsy, and consistency with DRE definition assessed. The distribution of these data is summarized in Table 7.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2.\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;To examine the relationship between SEPE scores and DRE subtypes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(i) Epidemiological studies classify DRE into three subtypes\u003csup\u003e13,14\u003c/sup\u003e: (1) Initially drug-resistant, (2) Progressive drug-resistant, and (3) Fluctuating drug-resistant. The 2010 ILAE DRE definition includes a temporal component\u003csup\u003e15\u003c/sup\u003e: patients may develop DRE later or convert to drug-sensitive epilepsy after ASM adjustments or surgery. For clarity, persistently uncontrolled seizures despite pharmacological or surgical intervention are referred to as \u0026quot;intractable DRE.\u0026quot;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;(ii) Among 506 patients, 142 had DRE at baseline. After 1\u0026ndash;2 years, 141 additional patients met DRE criteria, including 43 transitioning from drug-responsive or undefined epilepsy, yielding 185 DRE cases. Of these, 129 received ASM alone, 56 underwent surgery .\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;(iii) Of 185 DRE patients, 98 remained persistently drug-resistant (\u0026quot;intractable DRE\u0026quot;), with 70 on ASM therapy alone and 28 undergoing surgery. The remaining 87 exhibited fluctuating DRE; 59 were ASM-treated and alternated between drug-sensitive and resistant states, while 28 converted to drug-responsive epilepsy after surgery.\u003c/p\u003e\n\u003cp\u003e(ⅳ) Among 506 patients, 214 exhibited two or more seizure types. Of these, 42.5% presented multiple seizure types early (within six months), 43% developed additional seizure types progressively over up to 10 years, and 14.5% presented new seizure types over 11\u0026ndash;38 years.\u003c/p\u003e\n\u003cp\u003eThe distribution of these data is summarized in Table 12.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analyses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMost of the statistical analyses were performed using SPSS version 27.0. Age-related variables were summarized as means, standard deviations, and medians. Continuous variables were compared using one-way analysis of variance (ANOVA), and categorical variables across multiple groups were examined using the chi-square test with adjusted residual analysis (significance set at \u0026lt;0.05). A multiple stepwise logistic regression model was used to identify independent risk factors for drug-resistant epilepsy, with p \u0026lt;0.05 considered statistically significant.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAdditional analyses were conducted using R version 4.2.1.Receiver operating characteristic (ROC) curves were generated to evaluate the concordance between SEPE scores and the ILAE definition of DRE, with the area under the curve (AUC) and 95% confidence intervals estimated via bootstrapping. Two thresholds were examined: SEPE \u0026ge;6 (indicative of DRE) and SEPE \u0026le;4 (indicative of drug responsiveness, including seizure freedom).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e1.General characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAge of seizure onset ranged from 0.1 to 81 years, with cumulative distributions of 25.3% (\u0026le;10 years), 40.3% (\u0026le;14 years), 58.9% (\u0026le;20 years), and 95.7% (\u0026le;60 years). The 75th percentile age was ~31 years. Approximately 28% of patients had drug-resistant epilepsy (DRE), of these, ~10% received ASM monotherapy, while ~90% received combination therapy, commonly three ASMs. Epilepsy classification was not analyzed as a risk factor due to its dependence on seizure type and other biological markers. After over one year of follow-up, 50% of DRE patients undergoing surgery achieved drug-responsive status.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.Risk factors for DRE\u003c/strong\u003e\u003cbr\u003e\u0026nbsp; \u0026nbsp; Analysis of Tables 1 and 2 indicated that gender, childhood febrile seizures, and family history were not significant predictors. Multifocal EEG abnormalities were strongly associated with DRE (p \u0026lt; 0.001), as were earlier age of onset and longer epilepsy duration ( p \u0026lt; 0.001). Additional significant risk factors before and after 1\u0026ndash;2 years of follow-up included seizures during both sleep and wake cycles(p \u0026lt; 0.001), multiple seizure types(p \u0026lt; 0.001), recurrence of one or more seizures within two months (p \u0026lt; 0.001), and cranial MRI abnormalities(p \u0026lt; 0.001), including hippocampal sclerosis, cortical dysplasia, and nonspecific changes (e.g., punctate ischemic foci) in patients \u0026lt;30 years without other intracranial diseases, ASL-MRI abnormalities were also used as reference criteria.\u003c/p\u003e\n\u003cp\u003eIntellectual disability was significant at baseline (p = 0.008) but became borderline after follow-up (p = 0.058).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLogistic regression identified three independent predictors of DRE: seizures during both sleep and wake, multiple seizure types, and one or more seizures within two months (Table 4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.External validation of the SEPE score:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.1.Entire cohort (n = 506)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;(i) \u003cstrong\u003eAt baseline\u003c/strong\u003e: Of the 136 patients with SEPE \u0026ge;6, 110 (80.9%) were categorized as DRE, 5 (3.7%) were drug-responsive, and 21 (15.4%) remained undefined. Among the 274 patients with SEPE \u0026le;4, 99 (36.1%) were responsive, 4 (1.5%) had DRE, and 171 (62.4%) remained undefined. In the intermediate group (4 \u0026lt; SEPE \u0026lt; 6; n=96), 28 (29.2%) had DRE, 16 (16.7%) were responsive, and 52 (54.2%) remained undefined. Among surgically treated patients, only one responsive case had SEPE \u0026le;4; of the remaining 56 DRE cases, 51 (91%) had SEPE \u0026ge;6, and 5 (9%) had SEPE scores between 4 and 6.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;(ii) \u003cstrong\u003eAfter follow-up:\u0026nbsp;\u003c/strong\u003eOut of 136 patients with SEPE \u0026ge;6, 91 (66.9%) had DRE, 40 (29.4%) were drug-responsive (including 25 who transitioned from DRE after surgery), and 5 (3.7%) were undefined. Among 274 patients with SEPE \u0026le;4, 234 (85.4%) were responsive, 17 (6.2%) had DRE, and 23 (8.4%) were undefined. Of the 96 patients with SEPE scores between 4 and 6, 33 (34.4%) had DRE, 51 (53.1%) were responsive to ASMs, and 12 (12.5%) had an undefined outcome. Among the 57 surgically treated patients at the end of follow-up, only one was drug-responsive with a SEPE \u0026le;4. Of the remaining 56 with DRE, 28 transitioned to drug responsiveness (25 with SEPE \u0026ge;6 and 3 with scores of 4 \u0026lt; SEPE \u0026lt; 6), while the other 28 remained drug-resistant (26 with SEPE \u0026ge;6 and 2 with scores of 4 \u0026lt; SEPE \u0026lt; 6).\u003c/p\u003e\n\u003cp\u003e(iii) ROC analysis showed AUC = \u003cstrong\u003e0.6827\u003c/strong\u003e (95% CI 0.6322\u0026ndash;0.7245), accuracy 69.7%, sensitivity 64.5%, and specificity 72.0% (Table 8, Fig. 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2. Non-surgical subgroup (n = 449)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;(i) \u003cstrong\u003eAt baseline\u003c/strong\u003e: Among 449 patients, 85 had SEPE \u0026ge;6, 59 (69.4%) were DRE, 5 (5.9%) responsive, and 21 (24.7%) undefined. Of 273 patients with SEPE \u0026le;4, 98 (35.9%) were responsive, 4 (1.5%) DRE, and 171 (62.6%) undefined. In the intermediate group (n = 91, 4 \u0026lt; SEPE \u0026lt; 6), 23 (25.3%) were DRE, 16 (17.6%) responsive, and 52 (57.1%) undefined..\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;(ii) \u003cstrong\u003eAfter follow-up:\u003c/strong\u003e For the 85 patients with SEPE \u0026ge;6, 65 (76.5%) were confirmed as DRE, 15 (17.6%) responsive, and 5 (5.9%) undefined. Among those with SEPE \u0026le;4 (n = 273), 233 (85.3%) were responsive, 17 (6.2%) DRE, and 23 (8.4%) undefined. In the intermediate group (n = 91), 31 (34.0%) developed DRE, 48 (52.8%) were responsive, and 12 (13.2%) undefined.\u003c/p\u003e\n\u003cp\u003e(iii) ROC analysis yielded AUC = \u003cstrong\u003e0.6812\u003c/strong\u003e (95% CI 0.6302\u0026ndash;0.7382), accuracy 72.9%, sensitivity 57.5%, and specificity 78.7% (Table 9, Fig. 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.3.Patients with undefined epilepsy (n = 244)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;(i) \u003cstrong\u003eAt baseline:\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eAmong 244 patients with undefined epilepsy prior to follow-up, 21 had SEPE \u0026ge;6, 52 had 4 \u0026lt; SEPE \u0026lt; 6, and 171 had SEPE \u0026le;4.\u003c/p\u003e\n\u003cp\u003e(ii) \u003cstrong\u003eAfter 1\u0026ndash;2 years\u003c/strong\u003e: Among 21 patients with SEPE \u0026ge;6, 11 (52%) developed DRE, 4 (19%) remained undefined, and 6 (29%) became drug-responsive; among 52 patients with 4 \u0026lt; SEPE \u0026lt; 6, 11 (21.2%) developed DRE, 10 (19.2%) remained undefined, and 31 (59.6%) became drug-responsive; among 171 patients with SEPE \u0026le;4, 10 (5.9%) developed DRE, 17 (10%) remained undefined, and 144 (84.2%) became drug-responsive (including seizure-free).\u003c/p\u003e\n\u003cp\u003e(iii) ROC analysis confirmed the predictive value of SEPE in this subgroup,AUC=0.5697(95%CI:0.4869\u0026ndash;0.6666),Accuracy:72.77%,Sensitivity:34.38%,Specificity: 79.56%(Table 10, Fig. 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.4. Diagnostic performance\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong the 506 epilepsy patients, 136 had SEPE scores \u0026ge;6. At enrollment, 110 were defined as drug-resistant epilepsy (DRE). By the end of follow-up, an additional 14 cases (3 previously responsive and 11 undefined) transitioned to DRE, yielding a total of 124 out of 136 patients (91.2%) with DRE.\u003c/p\u003e\n\u003cp\u003eIn contrast, 274 patients had SEPE scores \u0026le;4 at enrollment, including 99 defined as drug-responsive. During follow-up, 146 additional cases transitioned to drug-responsive epilepsy (4 from DRE and 142 from\u0026nbsp;undefined). Altogether, 245 out of 274 patients (89.4%) with SEPE \u0026le;4 were ultimately responsive.\u003c/p\u003e\n\u003cp\u003eOverall, SEPE \u0026ge;6 predicted DRE with sensitivity 63.9%, specificity 96.2%, PPV 91.2%, and NPV 81.1%, while SEPE \u0026le;4 predicted responsiveness with sensitivity 87.2%, specificity 87.1%, PPV 89.4%, and NPV 84.5% (see Table 11).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn patients with SEPE \u0026le;3, only 24.9% achieved seizure freedom, whereas in the intermediate group (4 \u0026lt; SEPE \u0026lt; 6), about one-third developed DRE and more than half became responsive.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4.Examining the relationship between SEPE scores and DRE subtypes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e4.1.As shown in Table 13, among 129 non-surgically treated DRE patients, SEPE scores \u0026ge;6 predicted intractable DRE, scores \u0026le;4 predicted fluctuating DRE (p\u0026lt;0.001). For 56 surgical patients, SEPE scores did not predict outcomes (p=0.72).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e4.2.Later emergence of new seizure types was significantly associated with intractable postoperative DRE (\u003cem\u003eP\u003c/em\u003e = 0.027) see Table 14.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSummary\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ei. Among 506 patients (75th percentile age ~31 years), ~28% had DRE. Three independent risk factors for developing DRE were identified: seizures occurring during both sleep and wake cycles; at least one seizure within a two-month period; and multiple seizure types.\u003c/p\u003e\n\u003cp\u003eⅱ. Among 214 patients with multiple seizure types, 42.5% presented with multiple types simultaneously or within six months of onset, 43% developed new types over 0.6\u0026ndash;10 years, and 14.5% developed new types after 11\u0026ndash;38 years.\u003c/p\u003e\n\u003cp\u003eⅲ.Using the 2010 ILAE definition of DRE as the reference, we assessed the predictive validity of the SEPE scale. SEPE showed moderate concordance with the ILAE definition, supporting its utility as a practical tool for long-term prognosis.\u003c/p\u003e\n\u003cp\u003eⅳ.Among 506 epilepsy patients, 136 had SEPE \u0026ge;6, of whom 91.2% were drug-resistant epilepsy (sensitivity was 63.9%, specificity was 96.2%); 274 had SEPE \u0026le;4, with 89.4% drug-responsive(sensitivity was 87.2% , specificity was 87.1%). The 96 patients with intermediate scores (\u003cstrong\u003e4 \u0026lt; SEPE \u0026lt; 6\u003c/strong\u003e) showed mixed outcomes, with 34.4% developing DRE and 53.1% responding to ASMs.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eⅴ\u003c/strong\u003e\u003cstrong\u003e.\u0026nbsp;\u003c/strong\u003eFluctuating DRE is characterized by alternating periods of drug responsiveness and resistance, whereas intractable DRE is defined by persistent lack of seizure control.\u003c/p\u003e\n\u003cp\u003eⅵ. In non-surgically treated DRE patients, SEPE \u0026ge;6 predicted intractable DRE, whereas in patients with SEPE \u0026le;4, DRE tended to follow a fluctuating course\u003c/p\u003e\n\u003cp\u003eⅦ. Later emergence of new seizure types (in years) was associated with a higher likelihood of postoperative \u003cstrong\u003eintractable\u0026nbsp;\u003c/strong\u003eDRE.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur study belongs to an interconnected series of investigations centered on validating the practical utility of the SEPE scale in clinical settings. We verified the reliability of SEPE using the 2010 ILAE definition of DRE as the benchmark and further evaluated its ability to differentiate DRE subtypes.\u003c/p\u003e \u003cp\u003eExtensive literature has identified independent risk factors for DRE, including multiple seizure types, status epilepticus, high seizure frequency, intellectual disability, early onset, and cranial MRI abnormalities \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Systematic reviews also highlight abnormal EEG, febrile seizures, and poor initial ASM response \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e, while the TASK1 study has provided a comprehensive list of over 40 risk factors linked to DRE\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e; however, reproducibility remains a challenge. In our reassessment, we confirmed three independent risk factors: (1) seizures during both sleep and wake cycles, (2)\u0026thinsp;\u0026ge;\u0026thinsp;1 seizure in two months, and (3) multiple seizure types, consistent with earlier findings \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Multifocal EEG abnormalities showed diagnostic value but require further validation. Although the statistical significance of intellectual disability varied between baseline and follow-up, previous studies have consistently reported its association with DRE \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. MRI abnormalities: hippocampal sclerosis, cortical dysplasia, or ASL changes remained significant risk factors. Family history, however, was not confirmed. Although it did not emerge as a risk factor for DRE in this study, family history remains a component of the SEPE scale based on evidence from previous research\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e,\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eDue to current limitations in scientific and medical knowledge, substantial challenges remain in elucidating the underlying mechanisms of epilepsy and its clinical manifestations, which complicates accurate diagnosis\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. Likewise, predicting DRE based on these markers is complex and variable. Many predictive studies lack reproducibility and offer recommendations without sufficient supporting evidence, raising concerns about the credibility of research in this field\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003ePredictive scales should ideally meet five essential criteria \u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. First, they should integrate both clinically relevant features and biologically meaningful indicators, analyzed statistically to yield a simplified tool suitable for clinical application. Second, the required parameters should be readily obtainable in large general hospitals. Third, scale cut-off points must demonstrate strong predictive validity. Fourth, calculated scores should enable an initial stratified assessment of prognosis. Finally, the scale should exhibit reasonably accurate predictive performance. The SEPE scale essentially fulfills all of these criteria.\u003c/p\u003e \u003cp\u003eDuring the entire observation period, 91.2% of patients with SEPE\u0026thinsp;\u0026ge;\u0026thinsp;6 were DRE, while 89.4% with SEPE\u0026thinsp;\u0026le;\u0026thinsp;4 were drug-responsive. In intermediate group (4\u0026ndash;6 points), 34% developed DRE and 53% were responsive. Among SEPE\u0026thinsp;\u0026le;\u0026thinsp;3, about 25% achieved seizure freedom. In 506 patients, SEPE showed predictive accuracy with AUC 0.6827 (95% CI: 0.6322\u0026ndash;0.7245); excluding surgery cases yielded similar results. Among 244 undefined patients, SEPE maintained predictive value (AUC 0.5697): 52% with SEPE\u0026thinsp;\u0026ge;\u0026thinsp;6 became DRE, while 84.2% with SEPE\u0026thinsp;\u0026le;\u0026thinsp;4 were responsive. Overall, SEPE provides clear, quantitative, and clinically relevant predictors compared to prior models \u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e,\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e, which may be particularly helpful for physicians\u0026mdash;especially general neurologists who are not epilepsy specialists.\u003c/p\u003e \u003cp\u003eObservational studies indicate that DRE is a dynamic condition: 20%\u0026ndash;38% of patients may enter remission, yet 16%\u0026ndash;58% of these may subsequently revert to DRE \u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e,\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. In our cohort of 185 patients diagnosed with DRE per ILAE definition at baseline and follow-up, 98 were persistently intractable, while the remainder exhibited a fluctuating course, accounting for 47% of all DRE cases. Among 129 non-surgically treated patients with DRE, 70 were persistently intractable, while 59 (45.7%) exhibited a fluctuating course. Patients with DRE and a SEPE score\u0026thinsp;\u0026le;\u0026thinsp;4 had a higher likelihood of achieving seizure remission through ASM dose adjustments or switching to alternative ASMs. Previous studies have reported that even among patients who have failed 2\u0026ndash;5 ASMs, switching to another ASM can induce remission in approximately 17% of cases \u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAmong 56 surgical patients, outcomes divided evenly between postoperative remission and persistent intractability. SEPE was not predictive, but later emergence of new seizure types correlated with poorer surgical results (P\u0026thinsp;=\u0026thinsp;0.027). Existing surgical prediction tools (ESN, m-SFS)\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e,\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e remain limited, highlighting the need for additional markers.\u003c/p\u003e \u003cp\u003eOver time, some patients with epilepsy may experience progressive structural damage to the nervous system \u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e. In general, the presence of different seizure types is considered to reflect distinct epileptogenic foci, particularly in cases of focal seizures \u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. It is possible that newly emerging seizure types during the course of epilepsy represent the development of new epileptogenic zones or an expansion of existing foci, which may indicate a progressive worsening of the condition.\u003c/p\u003e \u003cp\u003eGiven the diverse clinical manifestations of drug-resistant epilepsy (DRE), some researchers have proposed the term \u0026lsquo;spectrum of drug-resistant epilepsy\u0026rsquo; to more comprehensively capture its subtypes \u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e. That is, DRE should be regarded as a spectrum of disorders with varying clinical presentations and neurobiological features, rather than a homogeneous disease entity \u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e. Recently, scholars have suggested \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e that to better integrate clinical and preclinical research and ensure the definition of DRE reflects the interplay of pathophysiology, diagnosis, and treatment, the 2010 ILAE definition should be revised\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn this study, we confirmed the reproducibility of the risk factors underlying the SEPE scale, and, using the 2010 ILAE definition as a reference, consistency testing demonstrated that SEPE is a practical tool for estimating DRE risk and stratifying patients. Patients with SEPE ≥ 6 had a 91.2% probability of DRE, whereas those with SEPE ≤ 4 were 89.4% likely to remain drug-sensitive. Among 185 ILAE-defined DRE cases, SEPE ≥ 6 was associated with a low likelihood of remission under antiseizure medications alone, while SEPE ≤ 4 predicted responsiveness to dose adjustment or drug substitution. In surgical patients, later emergence of new seizure types was an adverse prognostic marker.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eEthics approval and consent to participate\u003c/h2\u003e \u003cp\u003e This study was reviewed and determined to be exempt from full ethical review by the Ethics Committee of Jen Ching Memorial Hospital (23001-IRB-Exempt-2023-02-20).\u003c/p\u003e \u003ch2\u003ePotential Conflicts of Interest\u003c/h2\u003e \u003cp\u003eNothing to report.\u003c/p\u003e \u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eX Chen. contributed to the conception and design of the study; X Chen., JQ Ge., XB Ma., Q Zhang.and Q YANG.contributed to the acquisition and analysis of data; X Chen., XB Ma., Q Zhang., and Q YANG contributed to validation; X Chen.,Xh LI.contributed to supervision.; X Chen.contributed to writing - original draft.\u003c/p\u003e\u003ch2\u003eAcknowledgments\u003c/h2\u003e \u003cp\u003eThe authors thank the physicians of the Department of Neurology and the Epilepsy Center at Nanjing Brain Hospital for their support and assistance in collecting patient data. We also thank the patients with epilepsy and their families for their cooperation and support during the telephone follow-ups.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe data supporting this study were obtained from the hospital\u0026rsquo;s medical record system and are not publicly available due to patient privacy and ethical restrictions. De-identified data may be available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBlumcke I, Budday S, et al. Neocortical development and epilepsy: insights from focal cortical dysplasia and brain tumours. Lancet Neurol. 2021;20:943\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eColasante G, Qiu Y, Massimino L et al. 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Likelihood of seizure remission in an adult population with refractory epilepsy. Ann Neurol. 2007;62:382\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrorson LO, Wranne L. Long-term prognosis in childhood epilepsy: survival and seizure prognosis. Epilepsia. 1987;28:324\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen Z, Brodie MJ, Liew D, Kwan P. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a 30-year longitudinal cohort study. JAMA Neurol. 2018;75:279\u0026ndash;86. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/jamaneurol.2017.3949\u003c/span\u003e\u003cspan address=\"10.1001/jamaneurol.2017.3949\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHitiris N, Mohanraj R, Norrie J, Sills GJ, Brodie MJ. Predictors of pharmacoresistant epilepsy. Epilepsy Res. 2007;75:192\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGabriel Servilha-Menezes,Norberto Garcia-Cairasco.A complex systems view on the current hypotheses of epilepsy pharmacoresistance. Epilepsia Open. 2022;7(Suppl. 1):S8\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWirrell EC, Nabbout R, Scheffer IE, et al. Methodology for classification and definition of epilepsy syndromes with list of syndromes: report of the ILAE Task Force on Nosology and Definitions. Epilepsia. 2022;63:1333\u0026ndash;48.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eL\u0026ouml;scher et al. Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options. Pharmacol Rev 72:606\u0026ndash;38, July 2020.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRajiv Jalan F, Saliba MP. Alex Amoros. Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure. J Hepatol \u0026middot; June 2014.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGeng H, Chen X. Development and validation of a nomogram for the early prediction of drug resistance in children with epilepsy. Front Pediatr. 2022;10:905177.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBoonluksiri P, Visuthibhan A, Katanyuwong K. Clinical prediction rule of drug resistant epilepsy in children. J Epilepsy Res. 2015;5:84\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBerg AT, Vickrey BG, Testa FM, Levy SR, Shinnar S, DiMario F, et al. How long does it take for epilepsy to become intractable? A prospective investigation. Ann Neurol. 2006;60:73\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChoi H, Heiman G, Pandis D, Cantero J, Resor SR, Gilliam FG, et al. 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Development and validation of nomograms to provide individualised predictions of seizure outcomes after epilepsy surgery: a retrospective analysis. thelancet com/neurology Published online January. 2015;29. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1016/S1474-4422(14)70325-4\u003c/span\u003e\u003cspan address=\"10.1016/S1474-4422(14)70325-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGarcia C, Gracia, et al. Seizure freedom score: A new simple method to predict success of epilepsy surgery. Epilepsia. 2015;56(3):359\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLaxer KD, et al. The consequences of refractory epilepsy and its treatment. J Epilepsy Behav. 2014;37:59\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAdams, Victor\u0026rsquo;s. PRINCIPLES OF NEUROLOGY ELEVENTH EDITION.M.CARDINAL MANIFESTATIONS OF NEUROLOGIC DISEASE. P338.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eL\u0026ouml;scher et al. Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options. J Pharmacol Rev 72:606\u0026ndash;38, July 2020.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFattorusso et al. The Pharmacoresistant Epilepsy: An Overview on Existant and New Emerging Therapies.J.Frontiers in Neurology.June 2021 | Volume 12 | Article 674483.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 to 14 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":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"DRE, ILAE definition, SEPE, predicting factors","lastPublishedDoi":"10.21203/rs.3.rs-8321804/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8321804/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eThis study aimed to evaluate the predictive performance of the Scale for Estimating Prognosis of Epilepsy (SEPE) in identifying drug-resistant epilepsy (DRE), using the 2010 International League Against Epilepsy (ILAE) definition as the reference standard.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA total of 506 hospitalized patients with epilepsy, including 57 who underwent epilepsy surgery, were enrolled. DRE was defined according to 2010 ILAE criteria, and the reproducibility of SEPE\u0026rsquo;s predictive risk factors was examined. SEPE scores were then assigned to all patients, and the concordance between SEPE-based predictions and ILAE-defined DRE diagnoses was assessed after one to two years of follow-up in the full cohort (n\u0026thinsp;=\u0026thinsp;506) and in the subset excluding surgical cases (n\u0026thinsp;=\u0026thinsp;449). Finally, distinct clinical patterns of DRE, including persistence and fluctuating forms, were identified, and the associations between SEPE scores and these subtypes were analyzed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eMultivariate logistic regression identified seizures occurring across the sleep\u0026ndash;wake cycle, multiple seizure types, and at least one seizure within two months as independent risk factors for DRE. The area under the ROC curve (AUC) for SEPE in identifying ILAE-defined DRE was 0.6827 (95% CI: 0.6322\u0026ndash;0.7245) in the full cohort and 0.6812 (95% CI: 0.6302\u0026ndash;0.7382) after excluding surgical cases. Among patients with SEPE scores\u0026thinsp;\u0026ge;\u0026thinsp;6, 91.2% met the ILAE criteria for DRE, with sensitivity of 63.9% and specificity of 96.2%, whereas 89.4% of those with scores\u0026thinsp;\u0026le;\u0026thinsp;4 were drug-responsive, with sensitivity of 87.2% and specificity of 87.1%. For scores with 4\u0026thinsp;\u0026lt;\u0026thinsp;SEPE\u0026thinsp;\u0026lt;\u0026thinsp;6, 34% had DRE, 53% were drug-responsive, and 24.9% of patients with scores\u0026thinsp;\u0026le;\u0026thinsp;3 achieved seizure freedom without antiseizure medications (ASMs). In patients with DRE defined by the ILAE criteria, SEPE scores\u0026thinsp;\u0026ge;\u0026thinsp;6 were associated with intractable DRE without remission, while scores\u0026thinsp;\u0026le;\u0026thinsp;4 were frequently linked to seizure control following appropriate ASM adjustments.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe SEPE may serve as a useful tool for estimating the risk of DRE and for stratifying patients with epilepsy based on its constituent predictive factors. It may be particularly helpful for physicians\u0026mdash;especially general neurologists who are not epilepsy specialists.\u003c/p\u003e","manuscriptTitle":"The Scale for Estimating Prognosis of Epilepsy to predict in patients with epilepsy: A 506-Patient Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-19 18:06:56","doi":"10.21203/rs.3.rs-8321804/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-01-05T06:44:42+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-04T14:04:05+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"129942207416486370543696144634394047181","date":"2026-01-04T13:17:24+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-28T19:09:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"208655125145805020143427508737182990740","date":"2025-12-28T17:55:27+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-17T06:15:27+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-12-16T14:06:32+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-15T07:24:29+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-15T07:21:07+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Neurology","date":"2025-12-10T00:54:23+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"57287298-ad68-4dec-99b6-2873dd1dbacb","owner":[],"postedDate":"December 19th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-02-23T16:06:19+00:00","versionOfRecord":{"articleIdentity":"rs-8321804","link":"https://doi.org/10.1186/s12883-026-04666-2","journal":{"identity":"bmc-neurology","isVorOnly":false,"title":"BMC Neurology"},"publishedOn":"2026-02-16 15:58:19","publishedOnDateReadable":"February 16th, 2026"},"versionCreatedAt":"2025-12-19 18:06:56","video":"","vorDoi":"10.1186/s12883-026-04666-2","vorDoiUrl":"https://doi.org/10.1186/s12883-026-04666-2","workflowStages":[]},"version":"v1","identity":"rs-8321804","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8321804","identity":"rs-8321804","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}