Haihui Jiang, Linxi Cao, Xiaodong Chen, Siqi Tong, Qinghui Zhu, Jun Yang, Song Lin, Yong Cui
{"title":"Clinical Impact of MGMT Promoter Methylation in IDH-Mutant Gliomas: Influence of Threshold Selection and Clinical Confounding.","authors":"Haihui Jiang, Linxi Cao, Xiaodong Chen, Siqi Tong, Qinghui Zhu, Jun Yang, Song Lin, Yong Cui","doi":"10.1002/acn3.70528","DOIUrl":"10.1002/acn3.70528","url":null,"abstract":"<p><strong>Background: </strong>The clinical relevance of MGMT promoter methylation in IDH-mutant gliomas remains controversial in the era of molecular classification. We aimed to systematically evaluate its clinical relevance by integrating quantitative assessment, cutoff exploration, and adjustment for clinical confounding.</p><p><strong>Methods: </strong>A total of 558 patients with WHO grade 2-3 IDH-mutant gliomas were retrospectively analyzed. MGMT promoter methylation was quantified by pyrosequencing. Survival outcomes were assessed using Kaplan-Meier analysis and multivariable Cox regression. Multiple cutoff thresholds were examined, and PSM was applied to balance baseline characteristics.</p><p><strong>Results: </strong>Quantitative methylation stratification demonstrated significantly shorter PFS and OS in unmethylated tumors compared with methylated tumors. However, no clear stepwise association between increasing methylation levels and survival was observed. Across cutoff thresholds (9%-25%), MGMT promoter methylation was consistently associated with improved PFS, whereas its association with OS varied and diminished at higher cutoffs. In the unmatched cohort, MGMT promoter methylation was significantly associated with prolonged PFS (HR = 0.53, 95% CI: 0.33-0.85, p = 0.009) and OS (HR = 0.39, 95% CI: 0.21-0.75, p = 0.005). Following PSM, the direction and magnitude of these associations remained comparable (PFS: HR = 0.47, 95% CI: 0.23-0.98, p = 0.044; OS: HR = 0.35, 95% CI: 0.12-1.05, p = 0.06), although statistical significance was less consistent.</p><p><strong>Conclusion: </strong>MGMT promoter methylation is associated with favorable clinical outcomes in IDH-mutant gliomas. Its prognostic significance appears to be influenced by treatment context, methodological factors, and cohort characteristics. These findings support a context-dependent interpretation of MGMT methylation and highlight the need for standardized analytical approaches in future studies.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13554488/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148910255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Samantha Mombelli, Karine Lacourse, Hélène Blais, Anne-Sophie Deshaies-Rugama, Cynthia Thompson, Alex Desautels, Jacques Montplaisir, Milan Nigam, Christophe Moderie, Boshra Khajehpiri, Catherine Duclos, Jean Marc Lina, Julie Carrier, Nadia Gosselin
{"title":"Boundary-Dependent Sleep-Wake Dysregulation in Idiopathic Hypersomnia.","authors":"Samantha Mombelli, Karine Lacourse, Hélène Blais, Anne-Sophie Deshaies-Rugama, Cynthia Thompson, Alex Desautels, Jacques Montplaisir, Milan Nigam, Christophe Moderie, Boshra Khajehpiri, Catherine Duclos, Jean Marc Lina, Julie Carrier, Nadia Gosselin","doi":"10.1002/acn3.70522","DOIUrl":"10.1002/acn3.70522","url":null,"abstract":"<p><strong>Objective: </strong>Idiopathic hypersomnia (IH) presents with excessive daytime sleepiness (EDS) despite apparently preserved nocturnal sleep, challenging traditional models of hypersomnolence based on sleep loss or fragmentation. We aimed to test the hypothesis that EDS in IH reflects excessive stabilization of the sleep state, consistent with dysfunctional thalamocortical control rather than impaired sleep quantity or continuity.</p><p><strong>Methods: </strong>We analyzed overnight polysomnography from 62 IH and 81 age- and sex-matched healthy controls using sleep bout duration, sleep stage transition dynamics, and automated spindle detection. Principal component analyses derived composite indices of NREM and REM sleep stability. Group differences were assessed using ANCOVAs controlling for age and sex, and associations with EDS severity were examined.</p><p><strong>Results: </strong>Compared with controls, IH patients showed reduced transitions from N3 sleep toward lighter stages and wakefulness. Moreover, REM sleep was characterized by longer durations, fewer transitions to wakefulness, and more frequent transitions to lighter stages. In parallel, spindle amplitude was reduced in IH while spindle density was preserved, and smaller spindle amplitudes were associated with shorter latencies on the Multiple Sleep Latency Test.</p><p><strong>Interpretation: </strong>IH is characterized by excessive N3 stabilization and reduction in transitions toward wakefulness in both NREM and REM sleep. These findings suggest that altered sleep-wake dynamics, rather than impaired sleep continuity, may contribute to persistent daytime sleepiness in IH and support sleep stability as a potential target for future research and therapeutic strategies.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13538280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148878575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gaia Fattorini, Valerio Licursi, Gianmarco Dalla Zanna, Flavio Dal Canto, Melissa Barghigiani, Nunzio Setola, Salvatore Rossi, Antonio Funcis, Filippo M Santorelli, Gabriella Silvestri, Carlo Casali, Francesca Sardina, Cinzia Rinaldo
{"title":"Validation of a Cellular Imaging-Based Method as a Potential Biomarker for SPG4 Hereditary Spastic Paraplegia.","authors":"Gaia Fattorini, Valerio Licursi, Gianmarco Dalla Zanna, Flavio Dal Canto, Melissa Barghigiani, Nunzio Setola, Salvatore Rossi, Antonio Funcis, Filippo M Santorelli, Gabriella Silvestri, Carlo Casali, Francesca Sardina, Cinzia Rinaldo","doi":"10.1002/acn3.70482","DOIUrl":"10.1002/acn3.70482","url":null,"abstract":"<p><strong>Background: </strong>Hereditary Spastic Paraplegia (HSP) comprises a group of rare genetic diseases characterized by length-dependent axonal degeneration of the corticospinal tracts and dorsal columns, whose main clinical feature is spastic gait. Pathogenic variants in the SPG4 gene cause Spastic Paraplegia Type 4 (SPG4-HSP), the most common form of HSP. SPG4/SPAST encodes spastin, a protein involved in microtubule regulation and lipid droplet behavior. SPG4-HSP shows extreme heterogeneity in both clinical manifestations and genetics. Although no cure is currently available, several strategies aimed at restoring spastin levels are emerging; however, SPG4-HSP still lacks accessible cellular readouts for clinical studies. This study evaluates a cell-imaging approach that quantifies the distance between nucleus and cell centroid (dcnc) in peripheral blood mononuclear cells (PBMCs) in a genetically and clinically heterogeneous SPG4-HSP cohort.</p><p><strong>Methods: </strong>PBMCs from 48 molecularly confirmed SPG4-HSP patients and 21 healthy controls (HC) were analyzed by automated cell imaging. Dcnc and additional cytoskeletal and lipid droplet-related parameters were measured. Patient-level discrimination was assessed via cross-validated classification; correlations with molecular and clinical features were explored.</p><p><strong>Results: </strong>At the patient level, dcnc distinguishes SPG4-HSP from HC, independently of mutation type and disease severity, supporting robust cross-validated classification and inverse correlation with spastin protein levels.</p><p><strong>Conclusion: </strong>Dcnc is a robust, non-invasive, and mutation-independent cellular candidate biomarker for SPG4-HSP. It also offers preliminary evidence consistent with spastin target engagement supporting evaluation in future clinical trials.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13538279/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148878584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"RETRACTION: Differential Involvement of Ras-GRF1 and Ras-GRF2 in L-DOPA-Induced Dyskinesia.","authors":"","doi":"10.1002/acn3.70515","DOIUrl":"10.1002/acn3.70515","url":null,"abstract":"<p><strong>Retraction: </strong>S. Bido, N. Solari, M. Indrigo, A. D'Antoni, R. Brambilla, M. Morari, and S. Fasano, \"Differential Involvement of Ras-GRF1 and Ras-GRF2 in L-DOPA-Induced Dyskinesia,\" Annals of Clinical and Translational Neurology 2, no. 6 (2015): 662-678, https://doi.org/10.1002/acn3.202. The above article, published online on 24 April 2015 in Wiley Online Library (wileyonlinelibrary.com) has been retracted by agreement between the journal Editor-in-Chief, Ahmet Hoke; American Neurological Association; and John Wiley & Sons, Inc. US. The retraction has been agreed upon following an investigation into concerns raised by a third party. Several image overlaps and duplicated elements in Figures 1, 3, 6, and 7 were identified across different panels even though the corresponding images represent different samples. Accordingly, the editors have lost confidence in the data presented and consider the conclusions of this manuscript insufficiently supported. The authors have been informed of the decision to retract but remained unresponsive.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":"1963"},"PeriodicalIF":3.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13494127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The Case of an 18-Year-Old Female With Persistent Vague Pain in the Top of the Occiput.","authors":"Jianping Zhong, Binglin Lai","doi":"10.1002/acn3.70511","DOIUrl":"10.1002/acn3.70511","url":null,"abstract":"","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":"1961-1962"},"PeriodicalIF":3.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13451946/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148688354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
R W van Steenhoven, N Satyadev, A E M Bastiaansen, Y D Piura, J Kerstens, Y S Crijnen, J Brenner, T Brand, T M Bienfait, S Veenbergen, J M de Vries, F J de Jong, E G P Dopper, P A E Sillevis Smitt, H Seelaar, G S Day, M J Titulaer
{"title":"Early Recognition of Treatment-Responsive Rapidly Progressive Dementia: The Modified STAM3<sup>m</sup>P Score.","authors":"R W van Steenhoven, N Satyadev, A E M Bastiaansen, Y D Piura, J Kerstens, Y S Crijnen, J Brenner, T Brand, T M Bienfait, S Veenbergen, J M de Vries, F J de Jong, E G P Dopper, P A E Sillevis Smitt, H Seelaar, G S Day, M J Titulaer","doi":"10.1002/acn3.70434","DOIUrl":"10.1002/acn3.70434","url":null,"abstract":"<p><p>Early identification of patients with treatment-responsive rapidly progressive dementia (RPD) is important as early treatment improves outcomes. The STAM<sub>3</sub>P score identifies treatment-responsive RPD using \"high risk\" presenting features. We optimized performance by adding a time component (i.e., dementia within 3 months) and validated the modified \"STAM3<sup>m</sup>P score\" in two independent cohorts (n = 302). A STAM3<sup>m</sup>P score ≥ 1 identified 96% of patients with treatment-responsive RPD; ≥ 3 features were highly specific (98%). These data suggest that ≥ 1 STAM3<sup>m</sup>P features effectively identifies treatment-responsive RPD and may be used to prioritize investigations, whereas ≥ 3 STAM3<sup>m</sup>P features are highly specific and may inform early treatment decisions.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":"1956-1960"},"PeriodicalIF":3.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394507/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148040336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Adya Sapra, Nagendra K Rai, Timothy D Niepokny, Haley Courtney, Ajai Tripathi, Ranjan Dutta
{"title":"Region Specific miRNA-mRNA Networks in Gray and White Matter Lesions of Progressive Multiple Sclerosis.","authors":"Adya Sapra, Nagendra K Rai, Timothy D Niepokny, Haley Courtney, Ajai Tripathi, Ranjan Dutta","doi":"10.1002/acn3.70488","DOIUrl":"10.1002/acn3.70488","url":null,"abstract":"<p><strong>Objective: </strong>Multiple sclerosis (MS) is a neurodegenerative demyelinating disease of the central nervous system. This study aimed to identify micro-RNA (miRNA)-mRNA regulatory networks underlying region-specific molecular mechanisms in white matter and gray matter lesions in progressive MS.</p><p><strong>Methods: </strong>Global miRNA and mRNA expression profiling were previously performed on white matter and gray matter lesion tissues from postmortem progressive MS brains. These datasets were integrated using Ingenuity Pathway Analysis (IPA) to identify enriched canonical pathways based on experimentally validated miRNA target genes. Functional effects of selected miRNAs were evaluated in primary oligodendrocyte progenitor cells (OPCs) following miRNA mimic transfection using immunocytochemistry and qPCR.</p><p><strong>Results: </strong>Nine miRNAs were commonly dysregulated in both White Matter lesions (WMLs) and Gray Matter lesions (GMLs). Pathway analysis identified two major downstream pathways-cellular senescence and EIF2 signaling-with opposing predicted activation states (activated in White Matter lesions and inhibited in Gray Matter lesions). Among the shared miRNAs, miR-30a and miR-100 exhibited opposing expression patterns, with downregulation in GMLs and upregulation in WMLs, and both were predicted to regulate each pathway. Corresponding target genes of these miRNAs were significantly dysregulated in MS lesions. In primary Oligodendrocyte Progenitor Cells, overexpression of miR-30a or miR-100 significantly reduced proliferation and impaired differentiation, accompanied by decreased expression of their respective target genes.</p><p><strong>Interpretation: </strong>These findings identify miRNAs commonly dysregulated across white matter and gray matter lesions in progressive multiple sclerosis. Furthermore, this study also identifies distinct miRNA-mRNA networks and miRNA-driven regulatory mechanisms that contribute to region-specific impairment of oligodendrocyte maturation and remyelination.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13530336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148862741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Data-Driven SuStaIn Model of Disability Progression in Amyotrophic Lateral Sclerosis.","authors":"Giammarco Milella, Veria Vacchiano, Vittorio Velucci, Stefano Zoccolella, Rocco Liguori, Giovanni Defazio","doi":"10.1002/acn3.70519","DOIUrl":"10.1002/acn3.70519","url":null,"abstract":"<p><strong>Objective: </strong>To determine whether ordinal Subtype and Stage Inference (SuStaIn) applied to routine ALSFRS-R item scores can identify reproducible disability progression patterns in amyotrophic lateral sclerosis (ALS) and provide clinically meaningful staging.</p><p><strong>Methods: </strong>We analysed baseline ALSFRS-R item responses from 866 PRO-ACT participants. Ordinal SuStaIn inferred subtype-specific sequences of functional deterioration and assigned each participant to a subtype and a SuStaIn-derived functional stage. Longitudinal stability was assessed across 3625 consecutive follow-up visit pairs from 697 participants. Structural reproducibility was evaluated in an independent cohort of 301 consecutive ALS patients. Associations of baseline subtype and stage with survival and subsequent ALSFRS-R decline were examined using Cox and piecewise-linear models.</p><p><strong>Results: </strong>A three-subtype solution identified fine motor-, gross motor- and bulbar-predominant patterns of early disability. Within each subtype, SuStaIn reconstructed ordered multidomain sequences of functional deterioration and assigned each participant a SuStaIn-derived stage. Subtype assignment was stable across 90.4% of consecutive visit pairs, and stage was non-decreasing in 98.8%. Subtype-specific event ordering was reproduced in the validation cohort. Higher baseline stage was associated with increased mortality risk in the fine motor- and gross motor-predominant subtypes, but not clearly in the bulbar-predominant subtype. Baseline stage showed subtype-dependent, non-linear associations with subsequent functional decline, with acceleration up to mid-stage breakpoints in the fine motor- and gross motor-predominant subtypes and less evident stage-dependent acceleration in the bulbar-predominant subtype.</p><p><strong>Interpretation: </strong>Routine ALSFRS-R item-level data can define clinically interpretable ALS progression subtypes and latent SuStaIn-derived functional stages. Joint subtype-stage modelling may refine prognostic stratification and support prognosis-informed trial enrichment.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13527182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148862729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Matteo Zanovello, Francesca Serani, Alen Bebeti, Federica Paredi, Giulia Quadrio, Andrea Fortuna, Giacomo Maria Minicuci, Elena Pegoraro, Annachiara Cagnin, Diego Cecchin, Gianni Sorarù
{"title":"Metabolic and Fluid Biomarkers Support Microglia Activation in Amyotrophic Lateral Sclerosis.","authors":"Matteo Zanovello, Francesca Serani, Alen Bebeti, Federica Paredi, Giulia Quadrio, Andrea Fortuna, Giacomo Maria Minicuci, Elena Pegoraro, Annachiara Cagnin, Diego Cecchin, Gianni Sorarù","doi":"10.1002/acn3.70521","DOIUrl":"10.1002/acn3.70521","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis is an incurable neurodegenerative disease involving motor neuron degeneration and metabolic and immune dysfunction. We combined clinical data, cerebrospinal fluid biomarkers and fluorodeoxyglucose positron emission tomography with magnetic resonance imaging to investigate the role of reactive microglia in disease pathogenesis. Patients showed increased cerebrospinal fluid levels of neurofilament light chain and chitinases, along with hypermetabolism in the medulla oblongata. Chitinase levels correlated with brainstem metabolism and clinical severity. These findings suggest a link between microglial activation, brainstem hypermetabolism and disease progression in amyotrophic lateral sclerosis, supporting a central role for neuroinflammation in disease pathogenesis.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13527181/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148862723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Nationwide Survey of Association Between Fever and Epileptic Seizure in CDKL5 Deficiency Disorder Revealed Therapeutic Implications.","authors":"Siyi Wang, Jialin Du, Jinghui Liu, Dongmei Hu, Hongxin Wang, Xiaoxiao Man, Lehong Gao, Shimin Hu, Xianghong Meng, Hongyang Zhao, Minjing Hu, Yingxue Yang, Zhiqi Xiong, Liankun Ren","doi":"10.1002/acn3.70517","DOIUrl":"10.1002/acn3.70517","url":null,"abstract":"<p><strong>Objective: </strong>CDKL5 deficiency disorder (CDD) is a rare, severe developmental and epileptic encephalopathy. There is a pressing need to develop effective and sustainable therapeutic strategies. We aimed to investigate the causal association between febrile episodes and epileptic seizures for therapeutic implications in CDD patients.</p><p><strong>Methods: </strong>The study was a nationwide, cross-sectional survey on CDD patients in China (ClinicalTrials.gov, NCT06663163). Detailed phenotypic and genotypic data were collected through an online questionnaire with uploaded original medical records, genetic testing results, and peri-fever seizure diaries. The primary outcome was changes in epileptic seizure frequency during and post-fever phases compared to a 1-month pre-fever phase based on seizure diaries.</p><p><strong>Results: </strong>Between October 2024 and December 2024, we received 131 questionnaires. Forty-seven questionnaires were removed after excluding duplicates and missing data. Ultimately, 84 eligible participants with complete uploads were included, from 26 of 34 (76.5%) province-level regions in China. Among these, 47 (56.0%) patients had significant decreased seizure frequency only during febrile episodes, and 27 (32.1%) patients with daily seizures achieved at least a seizure-free day. Notably, 20 patients (23.8%) exhibited post-fever seizure reduction: 12 (25.5%) for 3 days to 1 week, and 6 (12.8%) for more than 2 weeks (maximum > 40 days). The effect was independent of patients' clinical and genetic characteristics.</p><p><strong>Interpretation: </strong>Our findings, for the first time, revealed that fever-related seizure reduction is a distinctive and prevalent genotype-phenotype for CDD, thereby providing evidence for further fundamental research into the underlying mechanisms and offering potential clinical implications for seizure control in CDD.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13507912/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148816829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}