Immunotherapy-related factors associated with early and sustained remission in anti-LGI1 encephalitis

Immunotherapy-related factors associated with early and sustained remission in anti-LGI1 encephalitis | 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 Article Immunotherapy-related factors associated with early and sustained remission in anti-LGI1 encephalitis Louis Cousyn, Déborah Guéry, Marion Houot, Natalia Shor, Jérôme Honnorat, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9245619/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract While delayed or suboptimal immunotherapy may lead to neurological sequelae, there is still no consensus on the early management of anti-LGI1 encephalitis. We aimed to identify immunotherapy-related factors associated with early and sustained remission in patients with anti-LGI1 encephalitis. We retrospectively included 42 patients with anti-LGI1 encephalitis who received at least one line of immunotherapy. Early remission was assessed 6 months after immunotherapy initiation and sustained remission 6 months after discontinuation of all immunotherapy drugs, using predefined composite criteria. Univariable Firth’s penalised logistic regression estimated odds ratios (ORs) with 95% confidence intervals (CIs). Overall, 31/42 patients (73.8%) achieved early remission and 35/39 (89.7%) sustained remission. A “full corticosteroid protocol”, defined as high-dose intravenous methylprednisolone followed by oral prednisone at 1 mg/kg/day with subsequent monthly tapering, was strongly associated with early remission (OR 7.45, 95% CI 1.47–74.96, p = 0.01). In contrast, cyclophosphamide exposure was associated with lower odds of early remission (OR 0.15, 95% CI 0.03–0.61, p = 0.007), probably reflecting confounding by indication. No variable showed a clear association with sustained remission, with only 4/39 patients failing to remit. Early remission was more frequent in patients who received an intensive corticosteroid regimen. These findings support the importance of first-line corticosteroids and should be confirmed in larger, prospective studies. Biological sciences/Immunology Health sciences/Neurology Biological sciences/Neuroscience LGI1 antibodies First-line immunotherapy Early management Corticosteroid protocol Figures Figure 1 Figure 2 1. Introduction Leucine-rich, glioma-inactivated 1 (LGI1) is a glycoprotein involved in a trans-synaptic multiprotein complex including ADAM22 (A Disintegrin And Metalloproteinase 22) and ADAM23, which regulates Kv1.1 channels and the synaptic expression of AMPA receptors. 1 , 2 IgG autoantibodies directed against LGI1 are responsible for autoimmune encephalitis targeting both frontal and mesial temporal lobes, respectively causing faciobrachial tonic-dystonic seizures, and mesial temporal lobe seizures and/or limbic cognitive impairment. 3 – 5 Early administration of immunotherapy is now recommended to manage these clinical manifestations, including seizures that are usually refractory to antiseizure medications. 6 – 9 However, while delayed or suboptimal immunotherapy may lead to neurological sequelae – mainly hippocampal sclerosis with cognitive disorders and/or drug-resistant epilepsy – there is still no consensus on the early management of anti-LGI1 encephalitis. A small clinical trial highlighted the superiority of intravenous immunoglobulin (IVIg) over placebo in controlling all types of seizures and improving cognitive impairment. 10 A retrospective study compared the efficacy of corticosteroids (intravenous, oral, or both) and IVIg as single acute immunotherapies. 11 Corticosteroids were associated with a better chance of seizure freedom and functional and cognitive improvement. Favourable outcomes were reported after prolonged corticosteroids without steroid-sparing maintenance immunotherapy in an uncontrolled, retrospective study. 12 Consistent with these observations, a recent multicentre cohort study found that intravenous pulsed methylprednisolone was associated with favourable functional outcomes at 12 months. 13 No prospective studies have investigated the benefits of additional second-line immunotherapies that might be considered for anti-LGI1 encephalitis, such as rituximab or cyclophosphamide. A German registry has suggested that rituximab may lower relapse rates. 14 In line with this, an Australian cohort reported that rituximab, after adjustment for concomitant immunotherapies, was associated with a markedly prolonged time to first clinical relapse in anti-LGI1 encephalitis. 13 Furthermore, a recent prospective cohort study has identified an association between persistent cognitive disorders and the lack of early rituximab use. 15 In these studies, no detailed first-line immunotherapy protocol was reported prior to the introduction of rituximab. It would be valuable to determine the need for a second-line treatment following a standardized first-line strategy. In this study, we aimed to evaluate immunotherapy-related factors associated with early and sustained remission. 2. Methods Patient selection and data collection We retrospectively screened all patients with encephalitis and anti-LGI1 antibodies treated at the Pitié-Salpêtrière Hospital (Paris, France) and the Hospices Civils de Lyon (French Reference Centre for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Lyon, France), between August 15th, 2005, and February 19th, 2022. Detection of anti-LGI1 antibodies was performed in serum and/or cerebrospinal fluid (CSF) samples using indirect immunofluorescence, ELISA (Euroimmun®, Germany), and cell-based assays as previously described 16 . We selected patients who received at least one line of immunotherapy (see flow chart in Supplementary Fig. 1). Patients with intercurrent disorders causing seizures or rapidly progressive cognitive disorders were excluded to strictly analyse the effects of immunotherapy on the course of encephalitis. We only included patients for whom the entire medical chart was available in order to accurately define the timing of the different outcomes. Clinical and neurological data were retrospectively collected. Functional consequences were graded using the modified Rankin Scale (mRS) at the onset and last follow-up. Brain MRIs were reviewed by a neuroradiologist (NS). Under the applicable French regulatory framework for retrospective observational studies, written informed consent was not required, and patients were informed about the use of their anonymised data. For patients treated at Pitié-Salpêtrière Hospital, the study complied with the CNIL framework (French data protection authority; No. 2211991). For patients treated at the Hospices Civils de Lyon, the study was also approved by the Institutional Review Board of the Hospices Civils de Lyon (IRB 00013204). All procedures were conducted in accordance with relevant guidelines and regulations and with the Declaration of Helsinki. Remission criteria and time points We established a composite set of remission criteria (Table 1 ). Remission was evaluated at two time points: six months after the initiation of immunotherapy for ‘early’ remission (t R1 ) and six months after the discontinuation of all immunotherapy drugs for ‘sustained’ remission (t R2 ). Table 1 legend: Remission was certain if all five criteria were met. If biological and radiological controls were not available, clinical remission was defined as follows: criteria 1–3 were met and clinical stability or improvement was noticed six months later (while immunotherapy had been discontinued). 1 Resolution or absence of tonic-dystonic seizures 2 Significant reduction of mesial temporal lobe seizure frequency (“very much improved” according to the Clinical Global Impression – Improvement [CGI-I] scale) and no focal to bilateral tonic-clonic seizures nor status epilepticus (in patients with appropriate and well-conducted antiseizure medications) 3 Resolution of confusion and spatiotemporal disorientation, and significant improvement of cognitive disorders (if available, improvement of ≥ 5 points in the MMSE score). Persistent visuospatial dysfunction, verbal memory impairment or dysexecutive syndrome are potential sequelae, which do not necessarily reflect an active encephalitis. 4 Disappearance of anti-LGI1 antibodies in blood and CSF 5 Disappearance of hippocampal swelling on brain MRI and/or hypermetabolism(s) on brain FDG-PET Relapse criteria We established relapse criteria in Table 2 . Short-term relapse was defined as occurring during immunotherapy drug tapering (e.g., corticosteroids) or within six months after complete discontinuation, and long-term relapse as occurring more than six months after discontinuation. Table 2 legend: Relapse was defined as follows: 1 major criterion or 2 minor criteria Major criterion 1 Recurrence or appearance of tonic-dystonic seizures Minor criteria 1 Recurrence of symptoms suggesting involvement of the limbic system not explained by another affection: rapidly progressive and significant cognitive disorders (loss of ≥ 5 points in the MMSE score) and/or significant increase in the mesial temporal lobe seizure frequency (“very much worse” according to the Clinical Global Impression – Improvement [CGI-I] scale) 2 Reappearance of anti-LGI1 antibodies in blood or CSF and/or unexplained hyponatremia 3 Reappearance of hippocampal swelling on brain MRI and/or hypermetabolism on brain FDG-PET Statistical Analyses We analysed early (tR1) and sustained (tR2) remission as two distinct binary outcomes. For each outcome, associations with candidate therapeutic and clinical variables were assessed using univariable Firth’s penalised logistic regression (one model per predictor) to obtain bias-reduced estimates in the context of small samples and potential separation. No correction for multiple testing was applied, as this was an exploratory analysis aimed at identifying candidate predictors for subsequent investigation. Continuous predictors (age and time to immunotherapy) were z-standardised (mean-centred and scaled by the sample standard deviation), so odds ratios (ORs) reflect the change in odds of remission per 1-standard-deviation (SD) increase. Baseline disability was summarised by the modified Rankin Scale (mRS; 0–6) entered per 1-point increase; all other predictors were analysed as binary variables. Models were fitted on complete cases for the outcome–predictor pair, so the number of observations could vary across analyses. We prespecified that models would not be fitted when fewer than 10 complete observations were available, or when either the outcome or the predictor showed no variability; such associations were reported as not estimable. Effect sizes are reported as ORs, computed as OR = exp(β), where β is the Firth’s penalised regression coefficient. 95% confidence intervals (CIs) for ORs were derived from the profile penalised likelihood rather than Wald intervals. Because ORs are not directly comparable across predictors of different measurement scales (e.g. per 1-SD for continuous variables vs binary contrasts), we additionally computed the area under the receiver operating characteristic curve (AUC) for each univariable model to provide a standardised measure of association. When feasible, 95% CIs for AUC were obtained by nonparametric class-stratified bootstrap (1,000 resamples) using pROC; if ROC estimation failed, AUC was computed using the rank-based formulation equivalent to the Mann–Whitney U (Wilcoxon rank-sum) statistic, and CIs were derived using the same class-stratified bootstrap scheme. A fixed random seed was used to ensure reproducibility. The delay between disease onset and initiation of immunotherapy was compared between patients with and without neurological sequelae (epilepsy and/or cognitive impairment) at last follow-up using the Wilcoxon-Mann-Whitney test. All analyses were performed in R (version 4.5.1; R Foundation for Statistical Computing, Vienna, Austria). 3. Results Study patients We included 42 patients with anti-LGI1 encephalitis. Median age at onset was 64.5 years [56.3–73.0], and 27/42 (64.3%) were male (Table 3). At presentation, most patients had cognitive impairment (37/42, 88.1%) and mesial temporal lobe seizures (34/42, 81.0%); faciobrachial dystonic seizures were observed in 28/42 (66.7%), and psychiatric symptoms in 21/42 (50.0%). Median [Q1-Q3] baseline mRS was 3 [2.3–3.0]. Immunotherapy was initiated after a median delay of 4 months [1.0–6.8] from first symptoms. Most patients received corticosteroids (35/42, 83.3%), often as high-dose intravenous methylprednisolone followed by oral prednisone, and a large majority received IVIg (34/42, 81.0%). A ‘full corticosteroid protocol’, defined as high-dose intravenous methylprednisolone (typically 1,000 mg/day) followed by oral prednisone at 1 mg/kg/day with subsequent monthly tapering, was administered in 17/42 patients (40.5%). Table 3. Clinical features, therapeutics and outcome of patients Table 3 legend: mRS: modified Rankin Scale; IV: intravenous; NA: not applicable; NS: non-significant; Q1: first quartile; Q3: third quartile *Second-line therapies refer here to rituximab and/or cyclophosphamide. Total n=42 Demographic characteristics Age at onset, median [Q1;Q3], years 64.5 [56.3;73.0] Female, n (%) 15 (35.7) Clinical symptoms at onset Cognitive impairment, n (%) 37 (88.1) Psychiatric symptoms, n (%) 21 (50.0) Faciobrachial dystonic seizures, n (%) 28 (66.7) Mesial temporal lobe seizures, n (%) 34 (81.0) mRS, median [Q1;Q3] 3 [2.3;3] Immunotherapy Time to initiation, median [Q1;Q3], months 4 [1;6.8] Corticosteroids (CS), n (%) 35 (83.3) IV methylprednisolone (MP), n (%) 28 (66.7) 1000mg/day 21 (50.0) Oral CS, n (%) 30 (71.4) 1mg/kg/day, n (%) 27 (64.3) IV MP and oral CS, n (%) 23 (54.8) 1000mg/day and 1mg/kg/day, respectively, n (%) 17 (40.5) IV immunoglobulin, n (%) 34 (81.0) Rituximab, n (%) 18 (42.9) Cyclophosphamide, n (%) 17 (40.5) Plasma exchange, n (%) 2 (4.8) Mycophenolate mofetil, n (%) 6 (14.3) Azathioprine, n (%) 1 (2.4) Clinical remission Early remission, n (%) 31 (73.8) Sustained remission, n (%) 35/39 (89.7) Relapse Short-term relapse, n (%) 3 (7.1) Long-term relapse, n (%) 5/39 (12.8) Evolution Follow-up, median [Q1;Q3], years 3.4 [2.2;5.5] mRS at last follow-up, median [Q1;Q3] 1.0 [1.0;2.0] Neurological sequelae at last follow-up Cognitive impairment, n (%) 21 (50.0) Drug-resistant epilepsy, n (%) 6/41 (14.6) Hippocampal atrophy, n (%) 30/38 (78.9) Adverse events Serious adverse events, n (%) 11 (26.2) Second-line therapies included rituximab (18/42, 42.9%) and cyclophosphamide (17/42, 40.5%). Therapeutic factors associated with remission Early remission (t R1 ) Six months after initiation of immunotherapy, 31/42 patients (73.8%) fulfilled the predefined criteria for early remission. In univariable Firth’s penalised logistic regression models, only two treatment-related variables showed clear associations with early remission (Fig. 1 A and Supplementary Table 1). First, the full corticosteroid protocol was strongly associated with early remission (odds ratio [OR] 7.45, 95% confidence interval [CI] 1.47–74.96, p = 0.01; AUC 0.71, 95% CI 0.59–0.82). Second, exposure to cyclophosphamide was associated with lower odds of early remission (OR 0.15, 95% CI 0.03–0.61, p = 0.007; AUC 0.73, 95% CI 0.58–0.87), indicating a statistically significant negative association. For all other immunotherapy-related variables (intravenous methylprednisolone alone, oral prednisone alone, any corticosteroids, IVIg, rituximab, plasma exchanges, long-term oral immunosuppression, and delay to immunotherapy) and patient-related factors (age, sex, baseline mRS), the 95% CIs for the ORs all crossed 1.0, and AUCs remained modest (typically 0.49–0.64) with 95% CIs crossing 0.5, indicating no robust association with early remission. Sustained remission (t R2 ) Among the 39 patients with sufficient follow-up to evaluate t R2 , 35 (89.7%) achieved sustained remission six months after complete discontinuation of immunotherapy. In this context of a very high event rate and a small number of failures (4/39, 10.3%), none of the tested variables showed a statistically robust association with sustained remission in univariable Firth models (Fig. 1 B and Supplementary Table 2). Neurological sequelae at last follow-up At last follow-up (median 3.4 years [2.2–5.5]), overall disability was low, with a median mRS of 1.0 [1.0–2.0] (Table 3). Disability was primarily attributable to cognitive impairment, which persisted in 21/42 patients (50.0%). Drug-resistant epilepsy was present in 6/41 patients (14.6%), and hippocampal atrophy was identified in 30/38 (78.9%). A longer delay between disease onset and initiation of immunotherapy was associated with neurological sequelae (epilepsy and/or cognitive impairment): median 4.0 months [3.0–7.3] in patients with sequelae vs. 1.0 month [1.0–5.0] in those without sequelae (p = 0.04). Adverse events Serious adverse events were reported in 11 patients (26.2%) and included infectious complications (in 3 patients who received both rituximab and cyclophosphamide), steroid-induced diabetes (n = 2), osteoporosis (n = 2), severe cutaneous adverse drug reactions (n = 2), cardiovascular events (n = 2) and significant weight gain (n = 1). 4. Discussion In this study, we evaluated immunotherapy-related factors associated with early and sustained remission using Firth’s penalised logistic regression. Three main findings emerged. First, most patients achieved early (73.8%) and sustained (89.7%) remission under the immunotherapy strategies used in clinical practice. Second, a full corticosteroid protocol – high-dose intravenous methylprednisolone followed by oral prednisone at 1 mg/kg/day – was strongly associated with higher odds of early remission. Third, exposure to cyclophosphamide was associated with lower odds of early remission, but this association should be interpreted cautiously, as cyclophosphamide was preferentially used in more severe or refractory cases. No factor showed a statistically robust association with sustained remission, largely because only four patients failed to reach t R2 . Our results support a central role for sufficiently intensive corticosteroid therapy in achieving rapid disease control in anti-LGI1 encephalitis. Previous studies have shown that corticosteroids are more effective than IVIg alone in improving seizures and functional outcomes in the acute phase 11 , that they can reduce the risk of future relapses 17 , and that prolonged corticosteroid courses may lead to favourable long-term outcomes without maintenance immunotherapy. 12 Additional studies have also suggested that corticosteroids administered as intravenous pulses are associated with fewer long-term seizures and favourable functional outcomes. 13 , 18 We extend these findings and suggest that a “full” corticosteroid protocol, rather than corticosteroid exposure per se, is the treatment component most strongly associated with early remission. Clinically, this argues against prematurely tapering corticosteroids or using submaximal doses in this indication, although our observational design precludes firm causal conclusions. In contrast, we did not observe a clear association between the use of rituximab or cyclophosphamide and early or sustained remission. Registry data have suggested that rituximab may reduce the risk of relapse in autoimmune encephalitis 13 , 14 , and early rituximab use has been associated with better cognitive outcomes in anti-LGI1 encephalitis. 15 However, these studies did not detail the underlying first-line immunotherapy protocol. In our cohort, second-line agents were probably introduced in more severe or refractory cases, which introduces strong confounding by indication and limits the interpretability of their apparent effects. The absence of a detectable association with remission in our models should therefore not be interpreted as evidence of inefficacy, but rather as reflecting limited power and clinical heterogeneity. We also confirmed that anti-LGI1 encephalitis is usually a monophasic autoimmune disorder with a relatively low relapse risk. Only 12.8% of patients experienced long-term relapse, and most patients achieved sustained remission after withdrawal of immunotherapy, in line with previous series reporting rare relapses but frequent hippocampal atrophy and persistent cognitive impairment. 7 , 19 , 20 In our study, longer delays to immunotherapy were associated with neurological sequelae, underscoring the need for early recognition and prompt treatment. Taken together, these data argue for an approach combining early diagnosis, intensive first-line corticosteroid therapy with a prolonged taper, and careful long-term follow-up. Based on our findings and on published evidence, we propose a pragmatic first-line immunotherapy strategy tailored to the pattern of neurological involvement (Fig. 2 ). High-dose intravenous methylprednisolone followed by oral prednisone at 1 mg/kg/day should be considered the backbone of treatment, maintained until clear clinical improvement, with a slow taper over several months. In cases with mesial temporal lobe involvement – such as mesial temporal lobe seizures, limbic cognitive impairment, or hippocampal MRI/PET lesions – adding IVIg may help to protect particularly vulnerable hippocampal structures. Second-line agents such as rituximab or cyclophosphamide should be reserved for severe, refractory, or relapsing cases after careful risk–benefit assessment, especially in older patients at increased risk of treatment-related complications. This study has several limitations. Its retrospective, non-randomized design and modest sample size inherently limit statistical power and increase the risk of residual confounding. We relied on univariable Firth models, prioritizing robust estimation over multivariable adjustment; as a result, we cannot fully disentangle the independent effects of correlated treatment decisions. Confounding by indication is a major concern, particularly for second-line therapies that were preferentially used in more severe cases. In addition, remission and relapse were defined using composite criteria that combined clinical, biological, and imaging data; although these definitions were prespecified and applied systematically, retrospective assessment of cognitive outcomes was limited by the absence of standardized neuropsychological testing in all patients. Despite these limitations, our work provides clinically relevant information for the management of anti-LGI1 encephalitis. It suggests that early remission may be more likely in patients who receive a full, high-dose corticosteroid protocol, and it reinforces the need to minimize delays to immunotherapy initiation. Prospective, multicentre studies with standardized treatment pathways and long-term cognitive follow-up will be needed to confirm these associations and to clarify the optimal timing and indications for second-line immunotherapies. Declarations Funding: this work was supported by a public grant overseen by the Agence Nationale de la Recherche (ANR) as part of the “Investissements d’Avenir” ANR-10-IAIHU-06 and ANR-18-RHUS-0012, and grants from the Fondation de l’Assistance Publique-Hôpitaux de Paris (EPIRES – Marie Laure PLV Merchandising). This study was also performed within the framework of the LABEX CORTEX of the Université Claude Bernard Lyon 1, within the program "Investissements d'Avenir" (ANR-11-LABX-0042) operated by the ANR. Disclosure of conflicts of interest: V. Navarro reports fees from Boards with UCB Pharma, Angelini Pharma, and Jazz Pharma. The remaining authors have no conflicts of interest. Ethical approval: We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Data availability: The datasets used and analysed during the current study are available from the corresponding author on reasonable request. Author Contribution L.C. and V.N. conceived the study. L.C. and D.G. collected the data. L.C. and M.H. performed the statistical analyses. N.S. reviewed brain MRIs. L.C. drafted the manuscript. J.H., S.R. and V.N. critically revised the manuscript. All authors reviewed the manuscript. References Baudin, P., Cousyn, L. & Navarro, V. The LGI1 protein: molecular structure, physiological functions and disruption-related seizures. Cell. Mol. Life Sci. 79 , 16 (2021). Fels, E. et al. Role of LGI1 protein in synaptic transmission: From physiology to pathology. Neurobiol. Dis. 160 , 105537 (2021). Irani, S. R. et al. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann. Neurol. 69 , 892–900 (2011). Navarro, V. et al. Motor cortex and hippocampus are the two main cortical targets in LGI1-antibody encephalitis. 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Clinical and Prognostic Value of Immunogenetic Characteristics in Anti-LGI1 Encephalitis. Neurol. Neuroimmunol. Neuroinflamm . 8 , e974 (2021). Campetella, L. et al. Predictors and Clinical Characteristics of Relapses in LGI1-Antibody Encephalitis. Neurol. Neuroimmunol. Neuroinflammation . 11 , e200228 (2024). Lin, N. et al. Long-term seizure outcomes in patients with anti-Leucine-rich glioma-inactivated 1 encephalitis. Epilepsy Behav. 122 , 108159 (2021). Guery, D. et al. Long-term evolution and prognostic factors of epilepsy in limbic encephalitis with LGI1 antibodies. J. Neurol. 269 , 5061–5069 (2022). Shen, C. H. et al. Seizures and risk of epilepsy in anti-NMDAR, anti-LGI1, and anti-GABABR encephalitis. Ann. Clin. Transl. Neurol. 7 , 1392–1399 (2020). Additional Declarations No competing interests reported. Supplementary Files SupplementaryFig1.pptx Supplementarytables.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 17 May, 2026 Reviewers invited by journal 06 May, 2026 Editor assigned by journal 20 Apr, 2026 Editor invited by journal 08 Apr, 2026 Submission checks completed at journal 06 Apr, 2026 First submitted to journal 06 Apr, 2026 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-9245619","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":635902957,"identity":"2848ac09-4e2b-4bae-9f6b-b0a78944f830","order_by":0,"name":"Louis Cousyn","email":"","orcid":"","institution":"AP-HP, Pitié-Salpêtrière University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Louis","middleName":"","lastName":"Cousyn","suffix":""},{"id":635902958,"identity":"5b1a0f22-46c3-4884-ae3b-d13b6519a40a","order_by":1,"name":"Déborah Guéry","email":"","orcid":"","institution":"Hospices Civils de Lyon and Lyon 1 University","correspondingAuthor":false,"prefix":"","firstName":"Déborah","middleName":"","lastName":"Guéry","suffix":""},{"id":635902959,"identity":"d7fd54d6-fdc4-4177-ac26-3fb7bc8965c9","order_by":2,"name":"Marion Houot","email":"","orcid":"","institution":"AP-HP, Pitié-Salpêtrière University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Marion","middleName":"","lastName":"Houot","suffix":""},{"id":635902961,"identity":"da0629cc-6903-493b-9c4c-43ae0317fb7b","order_by":3,"name":"Natalia Shor","email":"","orcid":"","institution":"AP-HP, Pitié-Salpêtrière University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Natalia","middleName":"","lastName":"Shor","suffix":""},{"id":635902963,"identity":"9ac41551-2590-4f6f-b0ec-17e1466e07c1","order_by":4,"name":"Jérôme Honnorat","email":"","orcid":"","institution":"Hospices Civils de Lyon","correspondingAuthor":false,"prefix":"","firstName":"Jérôme","middleName":"","lastName":"Honnorat","suffix":""},{"id":635902966,"identity":"95276e16-a3c7-4b40-98cb-d8a8a064f869","order_by":5,"name":"Sylvain Rheims","email":"","orcid":"","institution":"Hospices Civils de Lyon and Lyon 1 University","correspondingAuthor":false,"prefix":"","firstName":"Sylvain","middleName":"","lastName":"Rheims","suffix":""},{"id":635902967,"identity":"9b23f9aa-ad1b-4b00-9590-41e157a311cb","order_by":6,"name":"Vincent Navarro","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA70lEQVRIiWNgGAWjYDACZjS+HAMDD5CyIajFAM43hmhJI2gXQktiAyEtBsd5D374uOMPgzn7GcPPlXts0vtn9x57wJBwD7eWw3zJkjPPGDBY9uQYS555lpY74865dAOGhGKcWiSbecyYedsMGAwOpCVINhw4nNtwI8dMgvFHAn4tf0Fazj9L/gnUki4P0sKQgFsLPzNQCyNIy43kYyBbEgyI0GIs2dtmzGNw4/Exy4YDaYYb75wxN0jAo4WN/4zhh59tcnIG5xObbzYcsJGXu91j9uADHi0wwINgSjCwMRDWgAJAWkbBKBgFo2AUIAEAN79PH2QCufMAAAAASUVORK5CYII=","orcid":"","institution":"AP-HP, Pitié-Salpêtrière University Hospital","correspondingAuthor":true,"prefix":"","firstName":"Vincent","middleName":"","lastName":"Navarro","suffix":""}],"badges":[],"createdAt":"2026-03-27 14:08:50","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9245619/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9245619/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":109331952,"identity":"cc5685eb-d585-4711-bf50-2ebe9760cfcb","added_by":"auto","created_at":"2026-05-15 16:11:33","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":75245,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePredictors of early and sustained remission\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFigure 1 legend: Firth-penalised logistic regression models for early and sustained remission. (A) Association between patient- and treatment-related variables and early remission (t\u003csub\u003eR1\u003c/sub\u003e, 6 months after immunotherapy initiation). (B) Association with sustained remission (t\u003csub\u003eR2\u003c/sub\u003e, 6 months after complete discontinuation of immunotherapy). Dots represent Firth-penalised log odds ratios (log OR), and horizontal lines show 95% confidence intervals (CIs). The vertical dashed line indicates no association (log OR = 0). Continuous predictors (age and delay to immunotherapy) were standardised (z-scored). Green CIs indicate a statistically significant positive association with remission (95% CI entirely \u0026gt; 0); red CIs indicate a statistically significant negative association (95% CI entirely \u0026lt; 0); grey CIs indicate no clear association (95% CI crosses 0). For each model, the area under the receiver operating characteristic curve (AUC) and its 95% bootstrap confidence interval are reported on the right-hand side. AUC values are shown in bold when discrimination is acceptable (AUC \u0026gt; 0.70) and the 95% bootstrap CI lies entirely above chance (lower bound \u0026gt; 0.50).\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9245619/v1/233092d43525c9eaeeb724ba.jpg"},{"id":109405436,"identity":"750ab352-c90a-4f57-9b3b-dbe35db4f66b","added_by":"auto","created_at":"2026-05-17 13:18:05","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":85801,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSuggested first-line immunotherapy protocol based on neurological involvement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFigure 2 legend: We propose a first-line immunotherapy protocol based on clinical and radiological involvement. For cases of isolated tonic-dystonic seizures (i.e. motor cortex involvement), we recommend the following steps: 1) high-dose intravenous methylprednisolone at 1000 mg per day for 3 to 5 days; 2) switch to oral prednisone at a dosage of 1mg/kg per day. This dosage should be maintained until tonic-dystonic seizures have resolved, which typically takes about 3 to 6 weeks; 3) once the seizures have disappeared, gradually taper off the prednisone over a period of 4 to 6 months. In cases of isolated or associated mesial temporal lobe involvement – such as mesial temporal lobe seizures, limbic cognitive impairment, or MRI/PET hippocampal lesions – we recommend adding intravenous immunoglobulin (IVIg) to the corticosteroid protocol described above. The recommended dosage for IVIg is 2g/kg per month, administered over 3 to 5 days, for a duration of 4 to 6 months. Oral prednisone should be maintained at a dosage of 1mg/kg per day until a significant reduction of mesial temporal lobe seizure frequency and/or resolution of confusion, after which a slow tapering can begin. We do not recommend the systematic addition of second-line immunotherapy.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9245619/v1/2dcb7891a1efc4cf876d264e.jpg"},{"id":109406340,"identity":"7a285419-c423-4c3e-95fd-c9827e64809c","added_by":"auto","created_at":"2026-05-17 13:27:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":387717,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9245619/v1/87e774c2-de6d-4f37-bdfb-066e02dda2b4.pdf"},{"id":109405607,"identity":"84620555-bdf2-4500-b125-99c56030fa0d","added_by":"auto","created_at":"2026-05-17 13:19:21","extension":"pptx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":38135,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFig1.pptx","url":"https://assets-eu.researchsquare.com/files/rs-9245619/v1/e58e517c1c79e4f241b4afb1.pptx"},{"id":109405553,"identity":"4fd82042-1a4f-481b-957f-9fd1eceb5158","added_by":"auto","created_at":"2026-05-17 13:18:56","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":19423,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarytables.docx","url":"https://assets-eu.researchsquare.com/files/rs-9245619/v1/ff5e9e01b5934419150e0e62.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Immunotherapy-related factors associated with early and sustained remission in anti-LGI1 encephalitis","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eLeucine-rich, glioma-inactivated 1 (LGI1) is a glycoprotein involved in a trans-synaptic multiprotein complex including ADAM22 (A Disintegrin And Metalloproteinase 22) and ADAM23, which regulates Kv1.1 channels and the synaptic expression of AMPA receptors.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e IgG autoantibodies directed against LGI1 are responsible for autoimmune encephalitis targeting both frontal and mesial temporal lobes, respectively causing faciobrachial tonic-dystonic seizures, and mesial temporal lobe seizures and/or limbic cognitive impairment.\u003csup\u003e\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eEarly administration of immunotherapy is now recommended to manage these clinical manifestations, including seizures that are usually refractory to antiseizure medications.\u003csup\u003e\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e However, while delayed or suboptimal immunotherapy may lead to neurological sequelae \u0026ndash; mainly hippocampal sclerosis with cognitive disorders and/or drug-resistant epilepsy \u0026ndash; there is still no consensus on the early management of anti-LGI1 encephalitis. A small clinical trial highlighted the superiority of intravenous immunoglobulin (IVIg) over placebo in controlling all types of seizures and improving cognitive impairment.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e A retrospective study compared the efficacy of corticosteroids (intravenous, oral, or both) and IVIg as single acute immunotherapies.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Corticosteroids were associated with a better chance of seizure freedom and functional and cognitive improvement. Favourable outcomes were reported after prolonged corticosteroids without steroid-sparing maintenance immunotherapy in an uncontrolled, retrospective study.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e Consistent with these observations, a recent multicentre cohort study found that intravenous pulsed methylprednisolone was associated with favourable functional outcomes at 12 months.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eNo prospective studies have investigated the benefits of additional second-line immunotherapies that might be considered for anti-LGI1 encephalitis, such as rituximab or cyclophosphamide. A German registry has suggested that rituximab may lower relapse rates.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e In line with this, an Australian cohort reported that rituximab, after adjustment for concomitant immunotherapies, was associated with a markedly prolonged time to first clinical relapse in anti-LGI1 encephalitis.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Furthermore, a recent prospective cohort study has identified an association between persistent cognitive disorders and the lack of early rituximab use.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e In these studies, no detailed first-line immunotherapy protocol was reported prior to the introduction of rituximab. It would be valuable to determine the need for a second-line treatment following a standardized first-line strategy.\u003c/p\u003e \u003cp\u003eIn this study, we aimed to evaluate immunotherapy-related factors associated with early and sustained remission.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cp\u003e \u003cb\u003ePatient selection and data collection\u003c/b\u003e \u003c/p\u003e \u003cp\u003eWe retrospectively screened all patients with encephalitis and anti-LGI1 antibodies treated at the Piti\u0026eacute;-Salp\u0026ecirc;tri\u0026egrave;re Hospital (Paris, France) and the Hospices Civils de Lyon (French Reference Centre for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Lyon, France), between August 15th, 2005, and February 19th, 2022. Detection of anti-LGI1 antibodies was performed in serum and/or cerebrospinal fluid (CSF) samples using indirect immunofluorescence, ELISA (Euroimmun\u0026reg;, Germany), and cell-based assays as previously described \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. We selected patients who received at least one line of immunotherapy (see flow chart in Supplementary Fig.\u0026nbsp;1). Patients with intercurrent disorders causing seizures or rapidly progressive cognitive disorders were excluded to strictly analyse the effects of immunotherapy on the course of encephalitis.\u003c/p\u003e \u003cp\u003eWe only included patients for whom the entire medical chart was available in order to accurately define the timing of the different outcomes. Clinical and neurological data were retrospectively collected. Functional consequences were graded using the modified Rankin Scale (mRS) at the onset and last follow-up. Brain MRIs were reviewed by a neuroradiologist (NS).\u003c/p\u003e \u003cp\u003eUnder the applicable French regulatory framework for retrospective observational studies, written informed consent was not required, and patients were informed about the use of their anonymised data. For patients treated at Piti\u0026eacute;-Salp\u0026ecirc;tri\u0026egrave;re Hospital, the study complied with the CNIL framework (French data protection authority; No. 2211991). For patients treated at the Hospices Civils de Lyon, the study was also approved by the Institutional Review Board of the Hospices Civils de Lyon (IRB 00013204). All procedures were conducted in accordance with relevant guidelines and regulations and with the Declaration of Helsinki.\u003c/p\u003e \u003cp\u003e \u003cb\u003eRemission criteria and time points\u003c/b\u003e \u003c/p\u003e \u003cp\u003eWe established a composite set of remission criteria (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Remission was evaluated at two time points: six months after the initiation of immunotherapy for \u0026lsquo;early\u0026rsquo; remission (t\u003csub\u003eR1\u003c/sub\u003e) and six months after the discontinuation of all immunotherapy drugs for \u0026lsquo;sustained\u0026rsquo; remission (t\u003csub\u003eR2\u003c/sub\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003elegend: Remission was certain if all five criteria were met. If biological and radiological controls were not available, clinical remission was defined as follows: criteria 1\u0026ndash;3 were met and clinical stability or improvement was noticed six months later (while immunotherapy had been discontinued).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eResolution or absence of tonic-dystonic seizures\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSignificant reduction of mesial temporal lobe seizure frequency (\u0026ldquo;very much improved\u0026rdquo; according to the Clinical Global Impression \u0026ndash; Improvement [CGI-I] scale) and no focal to bilateral tonic-clonic seizures nor status epilepticus (in patients with appropriate and well-conducted antiseizure medications)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eResolution of confusion and spatiotemporal disorientation, and significant improvement of cognitive disorders (if available, improvement of \u0026ge;\u0026thinsp;5 points in the MMSE score). Persistent visuospatial dysfunction, verbal memory impairment or dysexecutive syndrome are potential sequelae, which do not necessarily reflect an active encephalitis.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDisappearance of anti-LGI1 antibodies in blood and CSF\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDisappearance of hippocampal swelling on brain MRI and/or hypermetabolism(s) on brain FDG-PET\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eRelapse criteria\u003c/b\u003e \u003c/p\u003e \u003cp\u003eWe established relapse criteria in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Short-term relapse was defined as occurring during immunotherapy drug tapering (e.g., corticosteroids) or within six months after complete discontinuation, and long-term relapse as occurring more than six months after discontinuation.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003elegend: Relapse was defined as follows: 1 major criterion or 2 minor criteria\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eMajor criterion\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRecurrence or appearance of tonic-dystonic seizures\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eMinor criteria\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRecurrence of symptoms suggesting involvement of the limbic system not explained by another affection: rapidly progressive and significant cognitive disorders (loss of \u0026ge;\u0026thinsp;5 points in the MMSE score) and/or significant increase in the mesial temporal lobe seizure frequency (\u0026ldquo;very much worse\u0026rdquo; according to the Clinical Global Impression \u0026ndash; Improvement [CGI-I] scale)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReappearance of anti-LGI1 antibodies in blood or CSF and/or unexplained hyponatremia\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReappearance of hippocampal swelling on brain MRI and/or hypermetabolism on brain FDG-PET\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eStatistical Analyses\u003c/b\u003e \u003c/p\u003e \u003cp\u003eWe analysed early (tR1) and sustained (tR2) remission as two distinct binary outcomes. For each outcome, associations with candidate therapeutic and clinical variables were assessed using univariable Firth\u0026rsquo;s penalised logistic regression (one model per predictor) to obtain bias-reduced estimates in the context of small samples and potential separation. No correction for multiple testing was applied, as this was an exploratory analysis aimed at identifying candidate predictors for subsequent investigation.\u003c/p\u003e \u003cp\u003eContinuous predictors (age and time to immunotherapy) were z-standardised (mean-centred and scaled by the sample standard deviation), so odds ratios (ORs) reflect the change in odds of remission per 1-standard-deviation (SD) increase. Baseline disability was summarised by the modified Rankin Scale (mRS; 0\u0026ndash;6) entered per 1-point increase; all other predictors were analysed as binary variables. Models were fitted on complete cases for the outcome\u0026ndash;predictor pair, so the number of observations could vary across analyses.\u003c/p\u003e \u003cp\u003eWe prespecified that models would not be fitted when fewer than 10 complete observations were available, or when either the outcome or the predictor showed no variability; such associations were reported as not estimable. Effect sizes are reported as ORs, computed as OR\u0026thinsp;=\u0026thinsp;exp(β), where β is the Firth\u0026rsquo;s penalised regression coefficient. 95% confidence intervals (CIs) for ORs were derived from the profile penalised likelihood rather than Wald intervals.\u003c/p\u003e \u003cp\u003eBecause ORs are not directly comparable across predictors of different measurement scales (e.g. per 1-SD for continuous variables vs binary contrasts), we additionally computed the area under the receiver operating characteristic curve (AUC) for each univariable model to provide a standardised measure of association. When feasible, 95% CIs for AUC were obtained by nonparametric class-stratified bootstrap (1,000 resamples) using pROC; if ROC estimation failed, AUC was computed using the rank-based formulation equivalent to the Mann\u0026ndash;Whitney U (Wilcoxon rank-sum) statistic, and CIs were derived using the same class-stratified bootstrap scheme. A fixed random seed was used to ensure reproducibility.\u003c/p\u003e \u003cp\u003eThe delay between disease onset and initiation of immunotherapy was compared between patients with and without neurological sequelae (epilepsy and/or cognitive impairment) at last follow-up using the Wilcoxon-Mann-Whitney test.\u003c/p\u003e \u003cp\u003eAll analyses were performed in R (version 4.5.1; R Foundation for Statistical Computing, Vienna, Austria).\u003c/p\u003e"},{"header":"3. Results","content":"\u003cp\u003e \u003cb\u003eStudy patients\u003c/b\u003e \u003c/p\u003e \u003cp\u003eWe included 42 patients with anti-LGI1 encephalitis. Median age at onset was 64.5 years [56.3\u0026ndash;73.0], and 27/42 (64.3%) were male (Table\u0026nbsp;3). At presentation, most patients had cognitive impairment (37/42, 88.1%) and mesial temporal lobe seizures (34/42, 81.0%); faciobrachial dystonic seizures were observed in 28/42 (66.7%), and psychiatric symptoms in 21/42 (50.0%). Median [Q1-Q3] baseline mRS was 3 [2.3\u0026ndash;3.0]. Immunotherapy was initiated after a median delay of 4 months [1.0\u0026ndash;6.8] from first symptoms. Most patients received corticosteroids (35/42, 83.3%), often as high-dose intravenous methylprednisolone followed by oral prednisone, and a large majority received IVIg (34/42, 81.0%). A \u0026lsquo;full corticosteroid protocol\u0026rsquo;, defined as high-dose intravenous methylprednisolone (typically 1,000 mg/day) followed by oral prednisone at 1 mg/kg/day with subsequent monthly tapering, was administered in 17/42 patients (40.5%).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eTable 3. Clinical features, therapeutics and outcome of patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable 3 legend: mRS: modified Rankin Scale; IV: intravenous; NA: not applicable; NS: non-significant; Q1: first quartile; Q3: third quartile\u003c/p\u003e\n\u003cp\u003e*Second-line therapies refer here to rituximab and/or cyclophosphamide.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"529\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003cp\u003en=42\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDemographic characteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eAge at onset, median [Q1;Q3], years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e64.5 [56.3;73.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eFemale, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e15 (35.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eClinical symptoms at onset\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eCognitive impairment, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e37 (88.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003ePsychiatric symptoms, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e21 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eFaciobrachial dystonic seizures, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e28 (66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eMesial temporal lobe seizures, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e34 (81.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003emRS, median [Q1;Q3]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e3 [2.3;3]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eImmunotherapy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eTime to initiation, median [Q1;Q3], months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e4 [1;6.8]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eCorticosteroids (CS), n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e35 (83.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 387px;\"\u003e\n \u003cp\u003eIV methylprednisolone (MP), n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e28 (66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 369px;\"\u003e\n \u003cp\u003e1000mg/day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e21 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 387px;\"\u003e\n \u003cp\u003eOral CS, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e30 (71.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 369px;\"\u003e\n \u003cp\u003e1mg/kg/day, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e27 (64.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 387px;\"\u003e\n \u003cp\u003eIV MP and oral CS, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e23 (54.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 370px;\"\u003e\n \u003cp\u003e1000mg/day and 1mg/kg/day, respectively, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e17 (40.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eIV immunoglobulin, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e34 (81.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eRituximab, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e18 (42.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eCyclophosphamide, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e17 (40.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003ePlasma exchange, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e2 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eMycophenolate mofetil, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e6 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eAzathioprine, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1 (2.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eClinical remission\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eEarly remission, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e31 (73.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eSustained remission, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e35/39 (89.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRelapse\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eShort-term relapse, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e3 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eLong-term relapse, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e5/39 (12.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEvolution\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eFollow-up, median [Q1;Q3], years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e3.4 [2.2;5.5]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003emRS at last follow-up, median [Q1;Q3]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1.0 [1.0;2.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"top\" style=\"width: 529px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNeurological sequelae at last follow-up\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eCognitive impairment, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e21 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eDrug-resistant epilepsy, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e6/41 (14.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eHippocampal atrophy, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e30/38 (78.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdverse events\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eSerious adverse events, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e11 (26.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e \u003cp\u003eSecond-line therapies included rituximab (18/42, 42.9%) and cyclophosphamide (17/42, 40.5%).\u003c/p\u003e \u003cp\u003e \u003cb\u003eTherapeutic factors associated with remission\u003c/b\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eEarly remission (t\u003csub\u003eR1\u003c/sub\u003e)\u003c/strong\u003e \u003cp\u003eSix months after initiation of immunotherapy, 31/42 patients (73.8%) fulfilled the predefined criteria for early remission. In univariable Firth\u0026rsquo;s penalised logistic regression models, only two treatment-related variables showed clear associations with early remission (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003eA and Supplementary Table\u0026nbsp;1). First, the full corticosteroid protocol was strongly associated with early remission (odds ratio [OR] 7.45, 95% confidence interval [CI] 1.47\u0026ndash;74.96, p\u0026thinsp;=\u0026thinsp;0.01; AUC 0.71, 95% CI 0.59\u0026ndash;0.82). Second, exposure to cyclophosphamide was associated with lower odds of early remission (OR 0.15, 95% CI 0.03\u0026ndash;0.61, p\u0026thinsp;=\u0026thinsp;0.007; AUC 0.73, 95% CI 0.58\u0026ndash;0.87), indicating a statistically significant negative association. For all other immunotherapy-related variables (intravenous methylprednisolone alone, oral prednisone alone, any corticosteroids, IVIg, rituximab, plasma exchanges, long-term oral immunosuppression, and delay to immunotherapy) and patient-related factors (age, sex, baseline mRS), the 95% CIs for the ORs all crossed 1.0, and AUCs remained modest (typically 0.49\u0026ndash;0.64) with 95% CIs crossing 0.5, indicating no robust association with early remission.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eSustained remission (t\u003csub\u003eR2\u003c/sub\u003e)\u003c/strong\u003e \u003cp\u003eAmong the 39 patients with sufficient follow-up to evaluate t\u003csub\u003eR2\u003c/sub\u003e, 35 (89.7%) achieved sustained remission six months after complete discontinuation of immunotherapy. In this context of a very high event rate and a small number of failures (4/39, 10.3%), none of the tested variables showed a statistically robust association with sustained remission in univariable Firth models (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003eB and Supplementary Table\u0026nbsp;2).\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eNeurological sequelae at last follow-up\u003c/b\u003e \u003c/p\u003e \u003cp\u003eAt last follow-up (median 3.4 years [2.2\u0026ndash;5.5]), overall disability was low, with a median mRS of 1.0 [1.0\u0026ndash;2.0] (Table\u0026nbsp;3). Disability was primarily attributable to cognitive impairment, which persisted in 21/42 patients (50.0%). Drug-resistant epilepsy was present in 6/41 patients (14.6%), and hippocampal atrophy was identified in 30/38 (78.9%).\u003c/p\u003e \u003cp\u003eA longer delay between disease onset and initiation of immunotherapy was associated with neurological sequelae (epilepsy and/or cognitive impairment): median 4.0 months [3.0\u0026ndash;7.3] in patients with sequelae vs. 1.0 month [1.0\u0026ndash;5.0] in those without sequelae (p\u0026thinsp;=\u0026thinsp;0.04).\u003c/p\u003e \u003cp\u003e \u003cb\u003eAdverse events\u003c/b\u003e \u003c/p\u003e \u003cp\u003eSerious adverse events were reported in 11 patients (26.2%) and included infectious complications (in 3 patients who received both rituximab and cyclophosphamide), steroid-induced diabetes (n\u0026thinsp;=\u0026thinsp;2), osteoporosis (n\u0026thinsp;=\u0026thinsp;2), severe cutaneous adverse drug reactions (n\u0026thinsp;=\u0026thinsp;2), cardiovascular events (n\u0026thinsp;=\u0026thinsp;2) and significant weight gain (n\u0026thinsp;=\u0026thinsp;1).\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eIn this study, we evaluated immunotherapy-related factors associated with early and sustained remission using Firth\u0026rsquo;s penalised logistic regression. Three main findings emerged. First, most patients achieved early (73.8%) and sustained (89.7%) remission under the immunotherapy strategies used in clinical practice. Second, a full corticosteroid protocol \u0026ndash; high-dose intravenous methylprednisolone followed by oral prednisone at 1 mg/kg/day \u0026ndash; was strongly associated with higher odds of early remission. Third, exposure to cyclophosphamide was associated with lower odds of early remission, but this association should be interpreted cautiously, as cyclophosphamide was preferentially used in more severe or refractory cases. No factor showed a statistically robust association with sustained remission, largely because only four patients failed to reach t\u003csub\u003eR2\u003c/sub\u003e.\u003c/p\u003e \u003cp\u003eOur results support a central role for sufficiently intensive corticosteroid therapy in achieving rapid disease control in anti-LGI1 encephalitis. Previous studies have shown that corticosteroids are more effective than IVIg alone in improving seizures and functional outcomes in the acute phase\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e, that they can reduce the risk of future relapses\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e, and that prolonged corticosteroid courses may lead to favourable long-term outcomes without maintenance immunotherapy.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e Additional studies have also suggested that corticosteroids administered as intravenous pulses are associated with fewer long-term seizures and favourable functional outcomes.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eWe extend these findings and suggest that a \u0026ldquo;full\u0026rdquo; corticosteroid protocol, rather than corticosteroid exposure per se, is the treatment component most strongly associated with early remission. Clinically, this argues against prematurely tapering corticosteroids or using submaximal doses in this indication, although our observational design precludes firm causal conclusions.\u003c/p\u003e \u003cp\u003eIn contrast, we did not observe a clear association between the use of rituximab or cyclophosphamide and early or sustained remission. Registry data have suggested that rituximab may reduce the risk of relapse in autoimmune encephalitis\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e, and early rituximab use has been associated with better cognitive outcomes in anti-LGI1 encephalitis.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e However, these studies did not detail the underlying first-line immunotherapy protocol. In our cohort, second-line agents were probably introduced in more severe or refractory cases, which introduces strong confounding by indication and limits the interpretability of their apparent effects. The absence of a detectable association with remission in our models should therefore not be interpreted as evidence of inefficacy, but rather as reflecting limited power and clinical heterogeneity.\u003c/p\u003e \u003cp\u003eWe also confirmed that anti-LGI1 encephalitis is usually a monophasic autoimmune disorder with a relatively low relapse risk. Only 12.8% of patients experienced long-term relapse, and most patients achieved sustained remission after withdrawal of immunotherapy, in line with previous series reporting rare relapses but frequent hippocampal atrophy and persistent cognitive impairment.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e In our study, longer delays to immunotherapy were associated with neurological sequelae, underscoring the need for early recognition and prompt treatment. Taken together, these data argue for an approach combining early diagnosis, intensive first-line corticosteroid therapy with a prolonged taper, and careful long-term follow-up.\u003c/p\u003e \u003cp\u003eBased on our findings and on published evidence, we propose a pragmatic first-line immunotherapy strategy tailored to the pattern of neurological involvement (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003e). High-dose intravenous methylprednisolone followed by oral prednisone at 1 mg/kg/day should be considered the backbone of treatment, maintained until clear clinical improvement, with a slow taper over several months. In cases with mesial temporal lobe involvement \u0026ndash; such as mesial temporal lobe seizures, limbic cognitive impairment, or hippocampal MRI/PET lesions \u0026ndash; adding IVIg may help to protect particularly vulnerable hippocampal structures. Second-line agents such as rituximab or cyclophosphamide should be reserved for severe, refractory, or relapsing cases after careful risk\u0026ndash;benefit assessment, especially in older patients at increased risk of treatment-related complications.\u003c/p\u003e \u003cp\u003eThis study has several limitations. Its retrospective, non-randomized design and modest sample size inherently limit statistical power and increase the risk of residual confounding. We relied on univariable Firth models, prioritizing robust estimation over multivariable adjustment; as a result, we cannot fully disentangle the independent effects of correlated treatment decisions. Confounding by indication is a major concern, particularly for second-line therapies that were preferentially used in more severe cases. In addition, remission and relapse were defined using composite criteria that combined clinical, biological, and imaging data; although these definitions were prespecified and applied systematically, retrospective assessment of cognitive outcomes was limited by the absence of standardized neuropsychological testing in all patients.\u003c/p\u003e \u003cp\u003eDespite these limitations, our work provides clinically relevant information for the management of anti-LGI1 encephalitis. It suggests that early remission may be more likely in patients who receive a full, high-dose corticosteroid protocol, and it reinforces the need to minimize delays to immunotherapy initiation. Prospective, multicentre studies with standardized treatment pathways and long-term cognitive follow-up will be needed to confirm these associations and to clarify the optimal timing and indications for second-line immunotherapies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cem\u003eFunding:\u003c/em\u003e this work was supported by a public grant overseen by the Agence Nationale de la Recherche (ANR) as part of the \u0026ldquo;Investissements d\u0026rsquo;Avenir\u0026rdquo; ANR-10-IAIHU-06 and ANR-18-RHUS-0012, and grants from the Fondation de l\u0026rsquo;Assistance Publique-H\u0026ocirc;pitaux de Paris (EPIRES \u0026ndash; Marie Laure PLV Merchandising). This study was also performed within the framework of the LABEX CORTEX of the Universit\u0026eacute; Claude Bernard Lyon 1, within the program \u0026quot;Investissements d\u0026apos;Avenir\u0026quot; (ANR-11-LABX-0042) operated by the ANR.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDisclosure of conflicts of interest:\u003c/em\u003e V. Navarro reports fees from Boards with UCB Pharma, Angelini Pharma, and Jazz Pharma. The remaining authors have no conflicts of interest.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEthical approval:\u003c/em\u003e We confirm that we have read the Journal\u0026rsquo;s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eData availability:\u003c/em\u003e The datasets used and analysed during the current study are available from the corresponding author on reasonable request.\u0026nbsp;\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eL.C. and V.N. conceived the study. L.C. and D.G. collected the data. L.C. and M.H. performed the statistical analyses. N.S. reviewed brain MRIs. L.C. drafted the manuscript. J.H., S.R. and V.N. critically revised the manuscript. All authors reviewed the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBaudin, P., Cousyn, L. \u0026amp; Navarro, V. The LGI1 protein: molecular structure, physiological functions and disruption-related seizures. \u003cem\u003eCell. Mol. Life Sci.\u003c/em\u003e \u003cb\u003e79\u003c/b\u003e, 16 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFels, E. et al. Role of LGI1 protein in synaptic transmission: From physiology to pathology. \u003cem\u003eNeurobiol. Dis.\u003c/em\u003e \u003cb\u003e160\u003c/b\u003e, 105537 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIrani, S. R. et al. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. \u003cem\u003eAnn. Neurol.\u003c/em\u003e \u003cb\u003e69\u003c/b\u003e, 892\u0026ndash;900 (2011).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNavarro, V. et al. Motor cortex and hippocampus are the two main cortical targets in LGI1-antibody encephalitis. \u003cem\u003eBrain\u003c/em\u003e \u003cb\u003e139\u003c/b\u003e, 1079\u0026ndash;1093 (2016).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGadoth, A. et al. Expanded phenotypes and outcomes among 256 LGI1/CASPR2-IgG-positive patients. \u003cem\u003eAnn. Neurol.\u003c/em\u003e \u003cb\u003e82\u003c/b\u003e, 79\u0026ndash;92 (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIrani, S. R. et al. Faciobrachial dystonic seizures: the influence of immunotherapy on seizure control and prevention of cognitive impairment in a broadening phenotype. \u003cem\u003eBrain\u003c/em\u003e \u003cb\u003e136\u003c/b\u003e, 3151\u0026ndash;3162 (2013).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThompson, J. et al. The importance of early immunotherapy in patients with faciobrachial dystonic seizures. \u003cem\u003eBrain\u003c/em\u003e \u003cb\u003e141\u003c/b\u003e, 348\u0026ndash;356 (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFeyissa, A. M. et al. Antiepileptic drug therapy in autoimmune epilepsy associated with antibodies targeting the leucine-rich glioma-inactivated protein 1. \u003cem\u003eEpilepsia Open.\u003c/em\u003e \u003cb\u003e3\u003c/b\u003e, 348\u0026ndash;356 (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ede Bruijn, M. A. A. M. et al. Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABA \u003csub\u003eB\u003c/sub\u003e R encephalitis. \u003cem\u003eNeurology\u003c/em\u003e \u003cb\u003e92\u003c/b\u003e, e2185\u0026ndash;e2196 (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDubey, D. et al. Randomized Placebo-Controlled Trial of Intravenous Immunoglobulin in Autoimmune LGI1/CASPR2 Epilepsy. \u003cem\u003eAnn. Neurol.\u003c/em\u003e \u003cb\u003e87\u003c/b\u003e, 313\u0026ndash;323 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRodriguez, A. et al. LGI1 antibody encephalitis: acute treatment comparisons and outcome. \u003cem\u003eJ. Neurol. Neurosurg. Psychiatry\u003c/em\u003e. \u003cb\u003e93\u003c/b\u003e, 309\u0026ndash;315 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlkabie, S. \u0026amp; Budhram, A. Prolonged Corticosteroids Without Maintenance Immunotherapy for Treatment of Anti-LGI1 Encephalitis. \u003cem\u003eNeurol. Neuroimmunol. Neuroinflammation\u003c/em\u003e. \u003cb\u003e10\u003c/b\u003e, e200115 (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSeery, N. et al. Acute and Long-Term Immune-Treatment Strategies in Anti-LGI1 Antibody\u0026ndash;Mediated Encephalitis. \u003cem\u003eNeurol. Neuroimmunol. Neuroinflammation\u003c/em\u003e. \u003cb\u003e12\u003c/b\u003e, e200412 (2025).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThaler, F. S. et al. Rituximab Treatment and Long-term Outcome of Patients With Autoimmune Encephalitis: Real-world Evidence From the GENERATE Registry. \u003cem\u003eNeurol. Neuroimmunol. Neuroinflamm\u003c/em\u003e. \u003cb\u003e8\u003c/b\u003e, e1088 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMu\u0026ntilde;oz-Lopetegi, A. et al. Neurological, psychiatric, and sleep investigations after treatment of anti-leucine-rich glioma-inactivated protein 1 (LGI1) encephalitis in Spain: a prospective cohort study. \u003cem\u003eLancet Neurol.\u003c/em\u003e \u003cb\u003e23\u003c/b\u003e, 256\u0026ndash;266 (2024).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMu\u0026ntilde;iz-Castrillo, S. et al. Clinical and Prognostic Value of Immunogenetic Characteristics in Anti-LGI1 Encephalitis. \u003cem\u003eNeurol. Neuroimmunol. Neuroinflamm\u003c/em\u003e. \u003cb\u003e8\u003c/b\u003e, e974 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCampetella, L. et al. Predictors and Clinical Characteristics of Relapses in LGI1-Antibody Encephalitis. \u003cem\u003eNeurol. Neuroimmunol. Neuroinflammation\u003c/em\u003e. \u003cb\u003e11\u003c/b\u003e, e200228 (2024).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLin, N. et al. Long-term seizure outcomes in patients with anti-Leucine-rich glioma-inactivated 1 encephalitis. \u003cem\u003eEpilepsy Behav.\u003c/em\u003e \u003cb\u003e122\u003c/b\u003e, 108159 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuery, D. et al. Long-term evolution and prognostic factors of epilepsy in limbic encephalitis with LGI1 antibodies. \u003cem\u003eJ. Neurol.\u003c/em\u003e \u003cb\u003e269\u003c/b\u003e, 5061\u0026ndash;5069 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShen, C. H. et al. Seizures and risk of epilepsy in anti-NMDAR, anti-LGI1, and anti-GABABR encephalitis. \u003cem\u003eAnn. Clin. Transl. Neurol.\u003c/em\u003e \u003cb\u003e7\u003c/b\u003e, 1392\u0026ndash;1399 (2020).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"LGI1 antibodies, First-line immunotherapy, Early management, Corticosteroid protocol","lastPublishedDoi":"10.21203/rs.3.rs-9245619/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9245619/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eWhile delayed or suboptimal immunotherapy may lead to neurological sequelae, there is still no consensus on the early management of anti-LGI1 encephalitis. We aimed to identify immunotherapy-related factors associated with early and sustained remission in patients with anti-LGI1 encephalitis.\u003c/p\u003e \u003cp\u003eWe retrospectively included 42 patients with anti-LGI1 encephalitis who received at least one line of immunotherapy. Early remission was assessed 6 months after immunotherapy initiation and sustained remission 6 months after discontinuation of all immunotherapy drugs, using predefined composite criteria. Univariable Firth\u0026rsquo;s penalised logistic regression estimated odds ratios (ORs) with 95% confidence intervals (CIs).\u003c/p\u003e \u003cp\u003eOverall, 31/42 patients (73.8%) achieved early remission and 35/39 (89.7%) sustained remission. A \u0026ldquo;full corticosteroid protocol\u0026rdquo;, defined as high-dose intravenous methylprednisolone followed by oral prednisone at 1 mg/kg/day with subsequent monthly tapering, was strongly associated with early remission (OR 7.45, 95% CI 1.47\u0026ndash;74.96, p\u0026thinsp;=\u0026thinsp;0.01). In contrast, cyclophosphamide exposure was associated with lower odds of early remission (OR 0.15, 95% CI 0.03\u0026ndash;0.61, p\u0026thinsp;=\u0026thinsp;0.007), probably reflecting confounding by indication. No variable showed a clear association with sustained remission, with only 4/39 patients failing to remit.\u003c/p\u003e \u003cp\u003eEarly remission was more frequent in patients who received an intensive corticosteroid regimen. These findings support the importance of first-line corticosteroids and should be confirmed in larger, prospective studies.\u003c/p\u003e","manuscriptTitle":"Immunotherapy-related factors associated with early and sustained remission in anti-LGI1 encephalitis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-15 16:11:18","doi":"10.21203/rs.3.rs-9245619/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"235978951200861831005057735126948125880","date":"2026-05-17T23:01:09+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-05-06T14:07:05+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-21T01:43:58+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-04-08T09:36:14+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-06T11:46:04+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2026-04-06T11:05:49+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e6a12aaf-3e41-49fc-b4d1-66ee6742796c","owner":[],"postedDate":"May 15th, 2026","published":true,"recentEditorialEvents":[{"type":"reviewerAgreed","content":"235978951200861831005057735126948125880","date":"2026-05-17T23:01:09+00:00","index":62,"fulltext":""},{"type":"reviewersInvited","content":"6","date":"2026-05-06T14:07:05+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":67678745,"name":"Biological sciences/Immunology"},{"id":67678746,"name":"Health sciences/Neurology"},{"id":67678747,"name":"Biological sciences/Neuroscience"}],"tags":[],"updatedAt":"2026-05-15T16:11:19+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-15 16:11:18","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9245619","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9245619","identity":"rs-9245619","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}