MSMilan2023 – Paper Poster - Session 2

P400/515

Inclusion of optic nerve,v temporal lobe and corpus callosum involvement in dissemination in space criteria for multiple sclerosis

Michael Foster¹, Giuseppe Pontillo¹, Indran Davagnanam², Sara Collorone¹, Ferran Prados^1,3,4, Baris Kanber^1,3, Marios Yiannaikas¹, Lola Ogunbowale⁵, Ailbhe Burke⁵, claudia wheeler-kingshott^1,6, Olga Ciccarelli^1,7, Wallace Brownlee^1,7, Frederik Barkhof^1,2,3,7,8, Ahmed Toosy¹

¹University College London, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, London, United Kingdom, ²University College London, Department of Brain Repair & Rehabilitation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, London, United Kingdom, ³University College London, Centre for Medical Imaging Computing, Department of Medical Physics and Biomedical Engineering, Faculty of Engineering Science, London, United Kingdom, ⁴Universitat Oberta de Catalunya, Barcelona, Spain, ⁵Moorfields Eye Hospital NHS Foundation Trust, Strabismus and Neuro-Ophthalmology Service, London, United Kingdom, ⁶University of Pavia, Department of Brain and Behavioural Sciences, Pavia, Italy, ⁷NIHR University College London Hospitals Biomedical Research Centre, London, United Kingdom, ⁸Vrije Universiteit Amsterdam, Department of Radiology and Nuclear Medicine, Amsterdam UMC, Amsterdam, Netherlands

Introduction: Magnetic resonance imaging (MRI) is instrumental in the early diagnosis of multiple sclerosis (MS), enabling timely treatment start. Despite being characteristic locations of MS lesions, the optic nerve (ON), temporal lobe (TL), and corpus callosum (CC) are not included as independent compartments to demonstrate dissemination in space (DIS) in the 2017 McDonald criteria.

Objectives/Aims: To investigate the effect of including ON, TL, and CC involvement in DIS criteria for the diagnosis of MS in people with clinically isolated syndrome.

Methods: Participants were scanned within 3 months of a first demyelinating event on 3T MRI with standard brain, spinal cord, and ON imaging protocols and followed up at 6, 12, 36, and 60 months. Three experienced neuroradiologists reviewed baseline scans in consensus to assess DIS according to 2017 McDonald criteria and modified versions: ON (DIS+ON), TL (DIS+TL) or CC (DIS+CC) as a fifth compartment (requiring 2/5 regions) or all simultaneously (DIS+ON+TL+CC, any 3 of 7); dissemination in time (DIT) was determined on post-contrast imaging. Performance of these criteria was evaluated against conversion to MS according to 2017 McDonald criteria (relapse, new T2 lesion, oligoclonal bands) at any time during follow-up.

Results: We recruited 84 patients (53F, 32.8±7.1 years, mean follow-up 31 months): 66 (79%) had optic neuritis. At baseline, 73 had ON lesions, 64 TL lesions, and 52 CC lesions; 45 had at least one enhancing lesion. 55 were diagnosed with MS over follow-up. DIS criteria were 89% sensitive (95% CI 78-96), 62% specific (42-79) and 80% accurate (70-88) in diagnosing MS. Performances for modified criteria were: DIS+ON sensitivity 98% (90-100), specificity 21% (8-40), accuracy 71% (61-81); DIS+TL sensitivity 95% (85-99), specificity 41% (24-61), accuracy 76% (66-85); DIS+CC sensitivity 93% (82-98), specificity 59% (39-76), accuracy 81% (71-89); DIS+ON+TL+CC, sensitivity 96% (87-100), specificity 45% (27-64), accuracy 79% (68-87). With DIT, performances were: DIS/DIT sensitivity 40% (26-54), specificity 100% (86-100), accuracy 59% (47-70); DIS+ON/DIT, sensitivity 62% (47-75), specificity 52% (31-72), accuracy 58% (47-70).

Conclusion: The inclusion of ON, TL, and CC in DIS, alone or in combination, yields increased sensitivity in diagnosing MS at the expense of lower specificity; the pattern is preserved when DIS and DIT are considered together. Our results suggest additional compartments should be considered when determining DIS, in particular the ON.

Disclosure of interest: MF is supported by a grant from the MRC (MR/S026088/1).

GP has received research grants from ECTRIMS-MAGNIMS and ESNR.

ID has no relevant disclosures.

SC has no relevant disclosures.

FP has no relevant disclosures.

BK is supported by the NIHR Biomedical Research Centre at UCL and UCLH.

MY has no relevant disclosures.

LO has no relevant disclosures.

AB has no relevant disclosures.

CW receives funding from the MS Society (#77), Wings for Life (#169111), BRC (#BRC704/CAP/CGW), UCL Global Challenges Research Fund (GCRF), MRC (#MR/S026088/1) and Ataxia UK, and is a shareholder in Queen Square Analytics Ltd.

OC is a member of independent DSMB for Novartis, gave a teaching talk on McDonald criteria in a Merck local symposium, and contributed to an Advisory Board for Biogen; she is Deputy Editor of Neurology, for which she receives an honorarium.

WB has received speaker honoraria for educational activities and/or acted as a consultant for Biogen, Janssen, Merck, Novartis, Roche, Sanofi-Genzyme and Viatris.

FB is supported by the NIHR Biomedical Research Centre initiative at UCLH, and he serves on the editorial boards of Radiology, Neurology, Multiple Sclerosis, and Neuroradiology, and is a consultant to Bayer, Biogen, Roche, Merck-Serono, Novartis, Janssen, IXICO and Combinostics.

AT is supported by recent awards from the MRC (MR/S026088/1), NIHR BRC (541/CAP/OC/818837), RoseTrees Trust (A1332 and PGL21/10079) and MSIF; he has received speaker honoraria from Biomedia and Merck and meeting expenses from Biogen Idec and Merck, and was the UK PI for two clinical trials sponsored by MEDDAY pharmaceutical company (MD1003 in optic neuropathy [MS-ON - NCT02220244] and progressive MS [MS-SPI2 - NCT02220244].

P401/1269

Clinically Defined Conversion to SPMS Approaching Objectively Data-driven Incidence in RWE in the Czech Republic in years 2016-2021

Dana Horakova¹, Lukas Sobisek², Zuzana Pocikova², Aneta Mazouchova^3,4, Michal Lauer^3,4, Jiri Drahota^1,3

¹First Faculty of Medicine, Charles University in Prague and General University Hospital, Department of Neurology and Centre of Clinical Neuroscience, Prague, Czech Republic, ²Novartis, s.r.o., Prague, Czech Republic, ³Endowment Fund IMPULS, Prague, Czech Republic, ⁴Prague University of Economics and Business, Department of Economic Statistics, Prague, Czech Republic

Introduction: Secondary progressive multiple sclerosis (SPMS) leads to progressive neurological disability. With the new therapeutic options for SPMS, Siponimod has received reimbursement in the Czech Republic as of 2021. This makes early and correct diagnosis even more important, but it is often made retrospectively with a delay. (Lorscheider et al., 2016) provides a standardized definition of SPMS based on data with the possibility of earlier diagnosis.

Objectives/Aims: To determine the number of newly diagnosed SPMS patients in Czechia and describe their characteristics at SPMS diagnoses before Siponimod reimbursement (years 2016-20) and in year 2021. To describe similarity between Clinical (C) and objective Data-driven (D) diagnosis of SPMS patients’ cohorts.

Methods: We used secondary data of all 17864 followed patients from the Czech national MS registry (ReMuS) during the period 2016-2021. We analysed (i) changes in the number of SPMS patients and their characteristics at SPMS onset (demographic, working status, EDSS, prior ARR, and active disease modifying treatment (DMT) class: platform (P-DMT) and high-efficacy DMT (HET) in years 2016-20, 2021, and (ii) convergence of cohort C to D. The reported incidence (I) and prevalence (P) rate is per 100,000 population.

Results: The number of newly clinically diagnosed SPMS patients (C) in the ReMuS increased from 53 per year in average (I from 0.34 to 0.64) in 2016-2020 to 99 (I 0.94, P 11.05) in 2021. Increasing trend is slowly approaching objectively diagnosed patients (D) (2016-2020: 162 (I from 1.4 to 1.65), 2021: 165 (1.57)). There are no relevant differences in demographics (approx. 65-69 % females, median age 48-51 years); detected change of working patients in D (from 34 % to 50.7 %), but stable in C (44.3 % to 45.7 %); slight change in median EDSS stable for C (5.0 to 5.5), no change in D (6.0); median ARR before SPMS dg decreased in C (0.31 to 0.2) closer to the median for D (0.2); MS duration to SPMS dg extended for D: from 15.2 years to 17.2, but not for C: 16.2 to 15.9.The proportion of DMT at SPMS onset has changed for C as follows: HET 25.1 % to 30.3 %, PDM-T 30.4 to 38.4, for D: HET 26.0 % to 42.4 %, PDM-T 24.7 to 29.1.

Conclusion: Data from the Czech national ReMuS registry show an increasing number of patients with newly diagnosed SPMS between 2016 and 2021. This trend is also evident in the clinically assigned diagnosis. Incidence and prevalence rates are consistent with those reported in the EU.

Disclosure of interest: The study was performed under financial support from Novartis, s.r.o., Czech Republic. Dana Horakova received compensation for travel, speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche, and Teva, as well as support for research activities from Biogen Idec. Jiri Drahota, Aneta Mazouchová and Michal Lauer are employees of the ReMuS registry. Lukas Sobisek, Zuzana Pocikova are employees of Novartis, s.r.o., Czech Republic.

P402/2080

Retinal Optical Coherence Tomography Markers for Dissemination in Time

Gilberto Solorza Buenrostro^1,2,3, Angela Vidal-Jordana⁴, Lilian Aly⁵, Ting-Yi Lin^1,2, Jaume Sastre-Garriga⁴, Wauschkuhn Josephine⁵, Claudia Chien^1,2,3, Susanna Asseyer^1,2,3, Mar Tintoré⁴, Mark Mühlau⁵, Bernhard Hemmer^5,6, Tanja Schmitz-Hübsch^1,2,3, Benjamin Knier⁵, Montalban Xavier⁴, Letizia Leocani⁷, Alexander U. Brandt^1,2, Friedemann Paul^1,2,3, Hanna G. Zimmermann^1,2,3,8

Study Group: International Multiple Sclerosis Visual System Consortium

¹Charité – Universitätsmedizin Berlin, Experimental and Clinical Research Center, Berlin, Germany, ²Max Delbrück Center for Molecular Medicine, Berlin, Germany, ³Charité – Universitätsmedizin Berlin, Neuroscience Clinical Research Center, Berlin, Germany, ⁴Centre d'Esclerosi Mútiple de Catalunya (Cemcat), Neurology Department, Barcelona, Spain, ⁵Klinikum rechts der Isar der Technischen Universität München, Department of Neurology, München, Germany, ⁶Munich Cluster for Systems Neurology (SyNergy), München, Germany, ⁷San Raffaele Hospital, Segrate, Italy, ⁸Einstein Center Digital Future, Berlin, Germany

Introduction: Oligoclonal bands (OB) can be a substitute for dissemination in time (DIT) in the 2017 revision of the McDonald multiple sclerosis (MS) diagnostic criteria. However, the invasive nature of this procedure prompts the search for more convenient options. Retinal optical coherence tomography (OCT) has emerged as a potential alternative, as it has shown associations with future relapses in early MS.

Objectives/Aims: To explore the use of OCT markers for early MS diagnosis.

Methods: Three international MS centers acquired OCT data from 2011 to 2020 from participants experiencing a first demyelinating event suggestive of MS. Optimal cutoffs of peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell and inner plexiform layer thickness (GCIPL) in non-optic neuritis eyes were calculated to predict clinically definite MS (CDMS) using Youden Index. Modified DIT, defined as DIT through MRI and/or OCT measurements below the cutoffs, was calculated (pRNFL modDIT and GCIPL modDIT). Univariate Cox proportional hazard models were used to calculate rates of CDMS conversion.

Results: Among 178 patients (mean age 37.9±8.5 years, 120 female), 134 (75%) fulfilled the 2017 McDonald criteria for relapsing-remitting MS (RRMS) and 60 (34%) were receiving disease-modifying treatment at baseline. Over a mean follow–up time of 4.03 (±1.94) years, 54 (30%) developed CDMS, of which 47 (87%) had RRMS at baseline. The optimal cutoff values for CDMS conversion were pRNFL below 98 µm (Sensitivity 0.72, Specificity 0.51) and GCIPL below 68 µm (Sensitivity 0.68, Specificity 0.46). Both lower pRNFL (HR 2.30 [CI 1.30-4.00], p=0.003) and GCIPL (HR 2.1 [1.20-3.60], p=0.008) were associated with an increased CDMS rate. McDonald 2017 DIT criteria including OB (DIT-2017) (HR 1.8 [0.57-5.90], p=0.310) and DIT based on baseline MRI only (MRI-DIT) (HR 1.3 [0.73-2.30], p=0.387) lacked significant associations with future CDMS. GCIPL modDIT was associated with future CDMS (HR 2.0 [1.10-3.70], p=0.031), while pRNFL modDIT did not reach significance (HR 1.80 [CI 0.98-3.50], p=0.064).

Conclusion: Retinal OCT markers, particularly GCIPL thickness, hold promise for early MS diagnosis. GCIPL modDIT shows a higher rate of future CDMS compared to DIT-2017 or MRI-DIT alone. These findings suggest that OCT could enhance MS diagnostic accuracy by aiding in the identification of DIT in non-optic neuritis cases. However, further research is needed to validate these markers, assess diagnostic accuracy, and refine clinical utility.

Disclosure of interest: GSB: Nothing to disclose.

AVJ has received support for contracts Juan Rodes (JR16/00024) and from Fondo de Investigación en Salud (PI17/02162 and PI22/01589) from Instituto de Salud Carlos III, Spain, and has engaged in consulting and/or participated as a speaker in events organized by Roche, Novartis, Merck, and Sanofi.

LA received travel and research support from Novartis.

TYL: received compensation from ADA Health, unrelated to the presented work.

JSG serves as co-Editor for Europe on the editorial board of Multiple Sclerosis Journal and as Editor-in-Chief in Revista de Neurología, receives research support from Fondo de Investigaciones Sanitarias (19/950), and has served as consultat/speaker for Biogen, Celgene/Bristol Meyers Squibb, Sanofi, Novartis and Merck.

JW: Nothing to disclose.

CC received speaking honoraria from Bayer and research support from Novartis, unrelated to this study. She also serves as a member of the Standing Committee on Science for the Canadian Institutes of Health Research (CIHR).

SA has received speaker honoraria from Alexion, Bayer, and Roche, unrelated to this submitted work.

MT has received compensation for consulting services, speaking honoraria and research support from Almirall, Bayer Schering Pharma, Biogen-Idec, Genzyme, Janssen, Merck-Serono, Novartis, Roche, Sanofi-Aventis, Viela Bio and Teva Pharmaceuticals. Data Safety Monitoring Board for Parexel and UCB Biopharma.

MM is currently supported by the German Research Foundation (DFG SPP2177, Radiomics: Next Generation of Biomedical Imaging – project number 428223038), by the DIFUTURE (Data Integration for Future Medicine) consortium, funded by the German Federal Ministry of Education and Research (BMBF) within the Medical Informatics Initiative (grants 01ZZ1603[A-D] and 01ZZ1804[A-I]), by the National Institutes of Health (grant 1R01NS112161-01), and by the Bavarian State Ministry for Science and Art (Collaborative Bilateral Research Program Bavaria – Quebec: AI in medicine, grant F.4-V0134.K5.1/86/34).

BH has served on scientific advisory boards for Novartis; he has served as DMSC member for AllergyCare, Sandoz, Polpharma, Biocon and TG therapeutics; his institution received research grants from Roche for multiple sclerosis research. He has received honoraria for counseling (Gerson Lehrmann Group). He holds part of two patents; one for the detection of antibodies against KIR4.1 in a subpopulation of patients with multiple sclerosis and one for genetic determinants of neutralizing antibodies to interferon. All conflicts are not relevant to the topic of the study. He is associated with DIFUTURE (Data Integration for Future Medicine) [BMBF 01ZZ1804[A-I]]. Bernhard Hemmer received funding for the study from the European Union’s Horizon 2020 Research and Innovation Program [grant MultipleMS, EU RIA 733161] and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology [EXC 2145 SyNergy – ID 390857198].

TSH is funded by the institution from Celgene/BMS und Roche Pharma. She receives speakers’ honoraria from Bayer AG and Biogen.

BK received travel support and speaking honoraria from Novartis and Teva. He was funded by the Else Kröner Fresenius-Stiftung (Else Kröner Fresenius Exzellenzstipendium 2019_EKES.09), the Gemeinnützige Hertie Foundation (medMS program) and received a research award from Novartis.

XM has received speaking honoraria and travel expenses for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Abbvie, Actelion, Alexion, Biogen, Bristol-Myers Squibb/Celgene, EMD Serono, Genzyme, Hoffmann-La Roche, Immunic, Janssen Pharmaceuticals, Medday, Merck, Mylan, Nervgen, Novartis, Sandoz, Sanofi-Genzyme, Teva Pharmaceutical, TG Therapeutics, Excemed, MSIF and NMSS.

LL received honoraria for consulting services from Merck, Roche, Biogen and for speaking activities from Teva and research support from Merck, Biogen, Novartis; travel support from Merck, Roche, Biogen, Almirall.

AUB is cofounder and holds shares of medical technology companies Motognosis GmbH and Nocturne GmbH. He is named as inventor on several patents and patent applications describing methods for retinal image analyses, motor function analysis, multiple sclerosis serum biomarkers and myelination therapies utilizing N-glycosylation modification. He is co-founder of IMSVISUAL. AUB is now full-time employee and holds stocks and stock options of Eli Lilly and Company. His contribution to this work is his own and does not represent a contribution from Eli Lilly.

FP served on the scientific advisory boards of Novartis and MedImmune; received travel funding and/or speaker honoraria from Bayer, Novartis, Biogen, Teva, Sanofi-Aventis/Genzyme, Merck Serono, Alexion, Chugai, MedImmune, and Shire; is an associate editor of Neurology: Neuroimmunology & Neuroinflammation; is an academic editor of PLoS ONE; consulted for Sanofi Genzyme, Biogen, MedImmune, Shire, and Alexion; received research support from Bayer, Novartis, Biogen, Teva, Sanofi-Aventis/Geynzme, Alexion, and Merck Serono; and received research support from the German Research Council, Werth Stiftung of the City of Cologne, German Ministry of Education and Research, Arthur Arnstein Stiftung Berlin, EU FP7 Framework Program, Arthur Arnstein Foundation Berlin, Guthy-Jackson Charitable Foundation, and NMSS.

HGZ received research grants and speaking honoraria from Novartis

P403/2243

Towards a unified approach to multiple sclerosis and radiological isolated syndromes (RIS): revising RIS diagnostic criteria

Andreu Vilaseca¹, Willem Calderon², Sofia Sceppacuercia², Luciana Midaglia¹, Pere Carbonell¹, Luca Bollo¹, Neus Mongay-Ochoa¹, Carmen Tur¹, Georgina Arrambide¹, Joaquin Castillo-Justribo¹, Jordi Rio¹, Ingrid Galán¹, Alvaro Cobo Calvo¹, Breogán Rodríguez¹, Ana Zabalza¹, Cristina Auger², Alex Rovira Cañellas², Xavier Montalban¹, Angela Vidal-Jordana¹

¹Multiple Sclerosis Ccentre of Catalonia-Vall Hebron University Hospital, Barcelona, Spain, ²Dept. of Radiology-Vall Hebron University Hospital, Magnetic Resonance Unit, Barcelona, Spain

Introduction: Radiological Isolated Syndrome (RIS) identifies asymptomatic patients presenting with incidental findings in MRI of demyelinating lesions typical of multiple sclerosis (MS). Despite its growing relevance, there is still a lack of consensus on which diagnostic criteria should be used.

Objectives/Aims: We aim to evaluate the diagostic performance of different RIS criteria, including the recently published 2023 RIS criteria.

Methods: Observational study including all patients referred to our Centre with suspected RIS. After an anamnesis and centralized MRI reading, all patients with at least 1 typical MS lesion were included. Developing MS typical symptoms during follow-up was defined as primary outcome and new T2 lesion in radiological follow-up as secondary outcome. We analyzed the performance of various proposed criteria, including the 2009 and 2023 RIS criteria, 2017 DIS criteria, and McDonald MS criteria. As the 2023 RIS criteria incorporates follow-up information, we assessed their performance using only baseline information (2023 RIS baseline criteria: fulfilment 2009 RIS criteria or ⩾1 brain typical lesion in ⩾1 DIS region + fulfilment of oligoclonal bands (OB) and spinal cord lesions).

Results: 122 patients initially referred for RIS evaluation; 88 (62 females, mean age 49.2 years, SD 12.0) were finally included. Twenty-two (25.0%) patients developed MS symptoms after a mean time of 30.7 months (SD 34.5). When evaluating the primary outcome, the 2017 DIS criteria showed a higher sensitivity (S) and a lower specificity (E) compared to the 2009 RIS criteria (S 0.82 vs 0.59, E 0.64 vs 0.36). When OB or contrast- enhancing lesions were included to the 2017 DIS criteria, specificity improved (0.64 and 0.90, respectively). The 2017 McDonald criteria (combining DIS with DIT at baseline and/or OB) displayed a sensitivity of 0.50 and a specificity of 0.65. The 2023 RIS criteria showed a high sensitivity (0.94) with a moderate specificity (0.50). However, when only baseline information (2023 RIS baseline) was used, the diagnostic performance was similar to the 2017 DIS criteria (S 0.83 vs 0.82, E 0.46 vs 0.36). Similar results were observed in secondary outcome.

Conclusion: While the newer 2023 RIS criteria showed a high sensitivity with a moderate specificity, our results suggest that their diagnostic performance is similar to 2017 DIS criteria when only baseline characteristics were considered. Thus, using the 2017 DIS criteria to establish RIS diagnosis appears reasonable and could simplify the process of RIS diagnosis.

Disclosure of interest: Andreu Vilaseca has received a Rio Hortega grant (CM22/00247) by Institute of Health Carlos III (ISCIII).

Willem Calderon reports no disclosures.

Sofia Sceppacuercia reports no disclosures.

Luciana Midaglia reports no disclosures.

Pere Carbonell-Mirabent’s yearly salary is supported by a grant from Biogen to Fundació privada Cemcat for statistical analysis

Luca Bollo’s research is supported by a one-year stipend endowed by the NMSS/AAN John Dystel Prize for Multiple Sclerosis Research awarded to Prof. Xavier Montalban in 2022.

Neus Mongay-Ochoa has a predoctoral grant Rio Hortega, from the Instituto de Salud Carlos III (CM21/00018). She also has received speaking honoraria and travel expenses from Merck and Roche.

Carmen Tur is currently being funded by a Junior Leader La Caixa Fellowship (fellowship code is LCF/BQ/PI20/11760008), awarded by “la Caixa” Foundation (ID 100010434). She has also received the 2021 Merck’s Award for the Investigation in MS, awarded by Fundación Merck Salud (Spain) and a grant awarded by the Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia e Innovación de España (PI21/01860). In 2015, she received an ECTRIMS Post-doctoral Research Fellowship and has received funding from the UK MS Society. She is a member of the Editorial Board of Neurology and Multiple Sclerosis Journal. She has also received honoraria from Roche and Novartis and is a steering committee member of the O’HAND trial and of the Consensus group on Follow-on DMTs.

Georgina Arrambide has received compensation for consulting services, participation in advisory boards or speaking honoraria from Merck, Roche, and Horizon Therapeutics; and travel support for scientific meetings from Novartis, Roche, and ECTRIMS. G. Arrambide is editor for Europe of the Multiple Sclerosis Journal – Experimental, Translational and Clinical; a member of the executive committee of the International Women in Multiple Sclerosis (iWiMS) network, and a member of the European Biomarkers in MS (BioMS-eu) consortium steering committee. She is a recipient of grants PI19/01590 and PI22/01570, awarded by the Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia e Innovación de España.

Joaquín Castilló reports no disclosures.

Jordi Rio has received speaking honoraria and personal compensation for participating on Advisory Boards from Biogen-Idec, Genzyme, Janssen, Merck- Serono, Novartis, Teva, Roche, and Sanofi-Aventis.

Ingrid Galan reports no disclosures.

Alvaro Cobo-Calvo has received a grant from Instituto de Salud Carlos III, Spain; JR19/00007.

Breogan Rodriguez-Acevedo has received speaking honoraria from Merck and honoraria for consulting services from Novartis.

Ana Zabalza has a predoctoral grant Rio Hortega, from the Instituto de Salud Carlos III, Spain (CM22/00237), received travel expenses for scientific meetings from Biogen-Idec, Merck Serono and Novartis; speaking honoraria from Eisai; and a study grant from Novartis.

Cristina Auger reports no disclosures.

Mar Tintoré has received compensation for consulting services, speaking honoraria and research support from Almirall, Bayer Schering Pharma, Biogen-Idec, Genzyme, Janssen, Merck-Serono, Novartis, Roche, Sanofi-Aventis, Viela Bio and Teva Pharmaceuticals. Data Safety Monitoring Board for Parexel and UCB Biopharma.

Jaume Sastre-Garriga serves as co-Editor for Europe for the Multiple Sclerosis Journal and as Editor-in-Chief of Revista de Neurología, receives research support from Fondo de Investigaciones Sanitarias (19/950 and 22/750) and in the last twelve months has served as a consultant/speaker for BMS, Roche, Sanofi, Janssen, and Merck.

Manolo Comabella has received compensation for consulting services and speaking honoraria from Bayer Schering Pharma, Merk Serono, Biogen-Idec, Teva Pharmaceuticals, Sanofi-Aventis, and Novartis.

Alex Rovira serves/ed on scientific advisory boards for Novartis, Sanofi-Genzyme, Synthetic MR, TensorMedical, Roche, and Biogen, and has received speaker honoraria from Bayer, Sanofi-Genzyme, Merck-Serono, Teva Pharmaceutical Industries Ltd, Novartis, Roche, Bristol-Myers and Biogen, is CMO and co-founder of TensorMedical, and receives research support from Fondo de Investigación en Salud (PI19/00950 and PI22/01589) from Instituto de Salud Carlos III, Spain.

Xavier Montalban has received speaking honoraria and travel expenses for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Abbvie, Actelion, Alexion, Biogen, Bristol-Myers Squibb/Celgene, EMD Serono, Genzyme, Hoffmann-La Roche, Immunic, Janssen Pharmaceuticals, Medday, Merck, Mylan, Nervgen, Novartis, Sandoz, Sanofi-Genzyme, Teva Pharmaceutical, TG Therapeutics, Excemed, MSIF and NMSS.

Angela Vidal-Jordana has received support has received support for contracts Juan Rodes (JR16/00024) and from Fondo de Investigación en Salud (PI17/02162 and PI22/01589) from Instituto de Salud Carlos III, Spain, and has engaged in consulting and/or participated as speaker in events organized by Roche, Novartis, Merck, and Sanofi.

P404/2247

Uncovering alternative diagnoses in patients with suspected multiple sclerosis: a study from teh prospective Barcelona CIS cohort

Andreu Vilaseca¹, Mar Tintoré¹, Pere Carbonell¹, Marta Rodríguez-Barranco¹, Maria Jesus Arevalo¹, Cristina Auger², Luca Bollo¹, René Carvajal¹, Joaquin Castillo-Justribo¹, Alvaro Cobo Calvo¹, Manuel Comabella¹, Victoria Fernández¹, Ingrid Galán¹, Claudia Guio-Sanchez¹, Luciana Midaglia¹, Neus Mongay-Ochoa¹, Carlos Nos¹, Susana Otero-Romero^1,3, Agustín Pappolla¹, Jordi Rio¹, Breogán Rodríguez¹, Jaume Sastre-Garriga¹, Sofia Sceppacuercia¹, Paula Tagliani¹, Carmen Tur¹, Angela Vidal-Jordana¹, Javier Villacieros-Alvarez¹, Ana Zabalza¹, Alex Rovira Cañellas¹, Xavier Montalban¹, Georgina Arrambide¹

¹Multiple Sclerosis Centre of Catalonia - Vall Hebron University Hospital, Barcelona, Spain, ²Dept. of Radiology, Neuroradiology-Vall Hebron University Hospital, Barcelona, Spain, ³Dept. of Preventive Medicine-Vall Hebron University Hospital, Barcelona, Spain

Introduction: Multiple sclerosis (MS) causes a wide range of symptoms that can often mimic those of other neurological conditions. As a result diagnosing MS requires careful consideration of clinical presentation, laboratory tests and neuroimaging.

Objectives/Aims: In this study, we aim to describe the proportion and types of alternative diagnoses in patients initially suspected to have a clinically isolated syndrome (CIS) suggestive of MS.

Methods: Study based on the Barcelona CIS cohort with prospective enrolment of patients under age 50 presentING with a first symptom considered suggestive of MS seen within 3 months of first attack. Following a comprehensive diagnostic workup and longitudinal followup, a subset of patients was ultimately determined to have a diagnosis other than MS. A descriptive analysis was performed focusing on topographical neurological syndrome and aetiologies of alternative diagnosis.

Results: Between November 1994 and February 2023 we prospectively collected data from 1537 patients with CIS. Of these, 1468 met the study inclusion criteria. Following a comprehensive diagnostic work-up, 1368 patients were diagnosed with MS according to the 2017 McDonald criteria, with an inflammatory-demyelinating disease that suggested MS but did not meet the criteria or had no final diagnosis. However, in 100 cases (6.8%), an alternative diagnosis was identified. Sixty-five (65.0%) were women and mean age was 34.5 years. Baseline brain MR was available for this assessment in 90 (90.0%) patients and spinal cord MR in 64 (64.0%). Following the diagnostic work-up, optic neuropathy was the most common neurological syndrome (37, 37.0%), followed by spinal cord syndrome (16,16.0%) and functional syndrome (15,15.0%). The commonest etiology was other immune-mediated diseases (41, 41.0%) followed by functional disorder (15,15.0%) and vascular disease (10,10.0%). Considering patients with at least one suggestive inflammatory-demyelinating lesion on baseline MR (26 (28.3%) patients), 16 (61.5%) had other immune-mediated neurologic diseases (including 10 MOGAD), and 5 (19.2%) had vascular disease. None of the patients with an alternative diagnosis met the 2017 McDonald criteria for multiple sclerosis.

Conclusion: In conclusion, alternative diagnoses are relatively uncommon in patients presenting with symptoms suggestive of MS. It is noteworthy that a significant proportion of them are ultimately diagnosed with other immune-mediated diseases. Other main diagnoses include functional, or vascular diseases.

Disclosure of interest: Disclosures: The study was NOT supported by any commercial entity, government agency, etc

Authors’ Disclosures:

Andreu Vilaseca has received a Rio Hortega grant (CM22/00247) by Institute of Health Carlos III (ISCIII).

Mar Tintoré has received compensation for consulting services, speaking honoraria and research support from Almirall, Bayer Schering Pharma, Biogen-Idec, Genzyme, Janssen, Merck-Serono, Novartis, Roche, Sanofi-Aventis, Viela Bio and Teva Pharmaceuticals. Data Safety Monitoring Board for Parexel and UCB Biopharma.

Angela Vidal-Jordana has received support has received support for contracts Juan Rodes (JR16/00024) and from Fondo de Investigación en Salud (PI17/02162 and PI22/01589) from Instituto de Salud Carlos III, Spain, and has engaged in consulting and/or participated as speaker in events organized by Roche, Novartis, Merck, and Sanofi.

Sofia Sceppacuercia reports no disclosures.

Luciana Midaglia reports no disclosures.

Pere Carbonell-Mirabent’s yearly salary is supported by a grant from Biogen to Fundació privada Cemcat for statistical analysis

Luca Bollo’s research is supported by a one-year stipend endowed by the NMSS/AAN John Dystel Prize for Multiple Sclerosis Research awarded to Prof. Xavier Montalban in 2022.

Neus Mongay-Ochoa has a predoctoral grant Rio Hortega, from the Instituto de Salud Carlos III (CM21/00018). She also has received speaking honoraria and travel expenses from Merck and Roche.

C. Nos has received compensation for participating on steering committee of clinical trials from Hoffmann-La Roche, and funding for registration in scientific meetings from Novartis.

S. Otero-Romero has received speaking and consulting honoraria from Genzyme, Biogen-Idec, Novartis, Roche, Excemed and MSD; as well as research support from Novartis.

A. Papolla is a 2023 McDonald Fellowship awardee at Cemcat.

P. Tagliani has received travel expenses for scientific meetings from Roche.

V. Fernández is a 2022 ECTRIMS clinical fellow at Cemcat.

C. Guío is a 2022 ECTRIMS clinical fellow at Cemcat.

J. Villacieros-Álvarez has received grant FI21/00282 from the Instituto de Salud Carlos III, Spain.

R Carvajal has received consulting services, speaking honoraria from Roche, Novartis, BIIB-Colombia, Merck, Sanofi and this project was supported by ECTRIMS Fellowship training awardee 2021–2022.

Carmen Tur is currently being funded by a Junior Leader La Caixa Fellowship (fellowship code is LCF/BQ/PI20/11760008), awarded by “la Caixa” Foundation (ID 100010434). She has also received the 2021 Merck’s Award for the Investigation in MS, awarded by Fundación Merck Salud (Spain) and a grant awarded by the Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia e Innovación de España (PI21/01860). In 2015, she received an ECTRIMS Post-doctoral Research Fellowship and has received funding from the UK MS Society. She is a member of the Editorial Board of Neurology and Multiple Sclerosis Journal. She has also received honoraria from Roche and Novartis and is a steering committee member of the O’HAND trial and of the Consensus group on Follow-on DMTs.

Joaquín Castilló reports no disclosures.

Jordi Rio has received speaking honoraria and personal compensation for participating on Advisory Boards from Biogen-Idec, Genzyme, Janssen, Merck- Serono, Novartis, Teva, Roche, and Sanofi-Aventis.

Ingrid Galan reports no disclosures.

Alvaro Cobo-Calvo has received a grant from Instituto de Salud Carlos III, Spain; JR19/00007.

Breogan Rodriguez-Acevedo has received speaking honoraria from Merck and honoraria for consulting services from Novartis.

Ana Zabalza has a predoctoral grant Rio Hortega, from the Instituto de Salud Carlos III, Spain (CM22/00237), received travel expenses for scientific meetings from Biogen-Idec, Merck Serono and Novartis; speaking honoraria from Eisai; and a study grant from Novartis.

Cristina Auger reports no disclosures.

Jaume Sastre-Garriga serves as co-Editor for Europe for the Multiple Sclerosis Journal and as Editor-in-Chief of Revista de Neurología, receives research support from Fondo de Investigaciones Sanitarias (19/950 and 22/750) and in the last twelve months has served as a consultant/speaker for BMS, Roche, Sanofi, Janssen, and Merck.

Manolo Comabella has received compensation for consulting services and speaking honoraria from Bayer Schering Pharma, Merk Serono, Biogen-Idec, Teva Pharmaceuticals, Sanofi-Aventis, and Novartis.

Alex Rovira serves/ed on scientific advisory boards for Novartis, Sanofi-Genzyme, Synthetic MR, TensorMedical, Roche, and Biogen, and has received speaker honoraria from Bayer, Sanofi-Genzyme, Merck-Serono, Teva Pharmaceutical Industries Ltd, Novartis, Roche, Bristol-Myers and Biogen, is CMO and co-founder of TensorMedical, and receives research support from Fondo de Investigación en Salud (PI19/00950 and PI22/01589) from Instituto de Salud Carlos III, Spain.

Xavier Montalban has received speaking honoraria and travel expenses for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Abbvie, Actelion, Alexion, Biogen, Bristol-Myers Squibb/Celgene, EMD Serono, Genzyme, Hoffmann-La Roche, Immunic, Janssen Pharmaceuticals, Medday, Merck, Mylan, Nervgen, Novartis, Sandoz, Sanofi-Genzyme, Teva Pharmaceutical, TG Therapeutics, Excemed, MSIF and NMSS.

Georgina Arrambide has received compensation for consulting services, participation in advisory boards or speaking honoraria from Merck, Roche, and Horizon Therapeutics; and travel support for scientific meetings from Novartis, Roche, and ECTRIMS. G. Arrambide is editor for Europe of the Multiple Sclerosis Journal – Experimental, Translational and Clinical; a member of the executive committee of the International Women in Multiple Sclerosis (iWiMS) network, and a member of the European Biomarkers in MS (BioMS-eu) consortium steering committee. She is a recipient of grants PI19/01590 and PI22/01570, awarded by the Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia e Innovación de España.

P405/908

Kappa free light chains for multiple sclerosis diagnosis: 10-year data

Domizia Vecchio¹, Chiara Puricelli², Eleonora Virgilio¹, Giorgio Bellomo², Ilaria Crespi², Paola Naldi¹, Roberto Cantello¹, Umberto Dianzani², cristoforo comi¹

¹University of Piemonte Orientale, Neurology Unit, Department of Translational Medicine, Novara, Italy, ²University of Piemonte Orientale, Clinical Biochemistry, Department of Translational Medicine, Novara, Italy

Introduction: Cerebrospinal fluid (CSF) kappa free light chains (KFLC) are becoming a diagnostic biomarker for multiple sclerosis (MS).

Objectives/Aims: To compare the efficiency of KFLC to that of oligoclonal bands (OB) in diagnosing MS, radiological and clinical isolated syndromes (RIS-CIS).

Methods: We collected 802 patients (59% females) in 10 years, who underwent CSF analysis for intrathecal synthesis in the diagnostic work-up, and they were classified according to their diagnosis as: 296 MS, 170 with other neurological inflammatory (including 28 RIS-CIS), and 336 non-inflammatory diseases (excluding lymphoproliferative and infective diagnosis). KFLC index cut off was 5.

Results: KFLC index was significantly higher in MS patients compared to those with other neurological diseases (mean ±standard deviation: 68.6±154.1 versus 4.7±12.4; p<0.001), and showed high sensitivity (91% equal to OB) and moderate specificity (85% if compared to 90% of OB) in diagnosing MS. A KFLC index above 5 was demonstrated in 4/28 RIS-CIS and 6/27 MS cases with no OB.

Conclusion: The KFLC index confirmed the accuracy in MS diagnosis in this large Italian cohort, adding information also in the RIS-CIS population and those patients with no OB.

Disclosure of interest: all authors have nothing to disclose

P406/2254

Should we wait to see dissemination in time to diagnose multiple sclerosis in patients with clinically isolated syndromes and typical lesions?

Georgina Arrambide¹, Mar Tintoré¹, Pere Carbonell¹, Marta Rodríguez-Barranco¹, Maria Jesus Arevalo¹, Helena Ariño¹, Cristina Auger¹, Luca Bollo¹, Joaquin Castillo-Justribo¹, Alvaro Cobo Calvo¹, Manuel Comabella¹, Victoria Fernández¹, Claudia Guio-Sanchez¹, Ingrid Galán¹, Delon La Puma¹, Luciana Midaglia¹, Neus Mongay-Ochoa¹, Carlos Nos¹, Susana Otero-Romero¹, Agustín Pappolla¹, Jordi Rio¹, Breogán Rodríguez¹, Jaume Sastre-Garriga¹, Sofia Sceppacuercia¹, Paula Tagliani¹, Carmen Tur¹, Angela Vidal-Jordana¹, Andreu Vilaseca¹, Javier Villacieros-Alvarez¹, Ana Zabalza¹, Alex Rovira Cañellas¹, Xavier Montalban¹

¹Multiple Sclerosis Centre of Catalonia-Vall Hebron University Hospital, Barcelona, Spain

Introduction: Dissemination in time (DIT) is one key concept to diagnose MS but occurs in other diseases. Besides, MS can be diagnosed with typical lesions fulfilling dissemination in space (DIS) plus oligoclonal bands (OB); and some studies show that by natural history, most subjects with clinically isolated syndromes (CIS) and typical lesions develop DIT. Furthermore, DIT may be influenced by disease-modifying therapy (DMT).

Objectives/Aims: Thus, our aim was to assess the frequency of DIT at baseline and follow-up in CIS.

Methods: Study based on a CIS inception cohort. We selected 503 subjects with a follow-up ⩾10 years and ⩾1 typical MS lesion on baseline brain or spinal cord (SC) MRI. We assessed the proportion fulfilling the 2017 McDonald criteria components individually and in combination, at baseline and during follow-up, and calculated the number of patients who started a DMT before MRI DIT and before 2017 McDonald MS.

Results: Of 503 patients, 349 (69.4%) were women; median (min-max) age was 30.4 (10.0-49.9) years. OB were positive in 332/437 (76.0%). Baseline brain and SC MRIs were abnormal in 490 (94.4%) and 101/255 (39.6%). Contrast-enhancing lesions (CEL) on brain and SC were present in 167/405 (41.2%) and 26/116 (22.4%). Median follow-up was 17.9 (10.0-27.9) years during which 360 (71.6%) initiated DMT: interferon (IFN) Beta or glatiramer acetate (GA) in 289 (80.3%), clinical trials (CT) in 45 (12.5%), orals in 18 (5.0%), monoclonal antibodies (Mab) in 5 (1.4%) and other in 3 (0.8%). At baseline, 336 (66.8%) fulfilled DIS, 197 (39.2%) DIT, 231 (45.9%) DIS + OB, 169 (33.6%) DIS + DIT and 284 (56.5%) McDonald MS. At last follow-up, 383 (76.1%) had a second attack; 439 (87.3%) fulfilled MRI DIS, 103/503 (20.5%) after baseline; 447 (88.9%) MRI DIT, 250/503 (49.7%) after baseline; 307 (61.0%) DIS + OB; 420 (83.5%) DIS + DIT; and 461 (91.7%) McDonald MS. Median (Q1-Q3) times to DIT and first DMT were 0.98 (0.29-1.57) and 1.17 (0.51-4.28) years. Of the 360 who initiated DMT, 83 (23.1%) did before MRI DIT; 10 (12.0%) have not fulfilled MRI DIT at last follow-up (n=7 IFN/GA, n=3 CT). DMTs were started before McDonald MS in 51 (14.2%); 1 (2.0%) on GA has not fulfilled McDonald MS.

Conclusion: In CIS patients with ⩾1 typical MS lesions, 56.5% fulfil the diagnostic criteria at baseline and most will fulfil the criteria during follow-up if not treated or treated with IFN Beta or GA.

Disclosure of interest: G. Arrambide has received speaking honoraria, compensation for consulting services or participation in advisory boards from Merck, Roche and Horizon Therapeutics; travel support for scientific meetings from Novartis, Roche, and ECTRIMS; is editor for Europe of the Multiple Sclerosis Journal – Experimental, Translational and Clinical; is a member of the International Women in Multiple Sclerosis (iWiMS) network executive committee; and is a member of the European Biomarkers in MS (BioMS-eu) consortium steering committee.

M. Tintore has received compensation for consulting services, speaking honoraria and research support from Almirall, Bayer Schering Pharma, Biogen-Idec, Genzyme, Janssen, Merck-Serono, Novartis, Roche, Sanofi-Aventis, Viela Bio and Teva Pharmaceuticals. Data Safety Monitoring Board for Parexel and UCB Biopharma

P. Carbonell-Mirabent’s yearly salary is supported by a grant from Biogen to Fundació privada Cemcat for statistical analysis.

H. Ariño has received a grant from Instituto de Salud Carlos III, Spain; JR22/00072.

C. Auger has received speaking honoraria from Novartis, Biogen and Stendhal.

A. Cobo-Calvo has received a grant from Instituto de Salud Carlos III, Spain; JR19/00007.

M. Comabella has received compensation for consulting services and speaking honoraria from Bayer Schering Pharma, Merck Serono, Biogen-Idec, Teva Pharmaceuticals, Sanofi-Aventis and Novartis.

V. Fernández is a 2022 ECTRIMS clinical fellow at Cemcat.

C. Guío is a 2022 ECTRIMS clinical fellow at Cemcat.

L. Midaglia has received honoraria for consulting services and speaking honoraria from Roche and Novartis.

N. Mongay has been awarded a Rio Hortega predoctoral grant from Instituto de Salud Carlos III (CM21/00018).

C. Nos has received compensation for participating on steering committee of clinical trials from Hoffmann-La Roche, and funding for registration in scientific meetings from Novartis.

S. Otero-Romero has received speaking and consulting honoraria from Genzyme, Biogen-Idec, Novartis, Roche, Excemed and MSD; as well as research support from Novartis.

A. Pappolla has received funding travel from Roche and speaking honoraria from Novartis. He performed an ECTRIMS Clinical Training Fellowship program during 2021, and is currently performing an MSIF-ARSEP Fellowship program.

J. Río has received speaking honoraria and personal compensation for participating on Advisory Boards from Biogen-Idec, Genzyme, Janssen, Merck- Serono, Novartis, Teva, Roche, and Sanofi-Aventis.

B. Rodríguez-Acevedo has received honoraria for consulting services from Wellspect.

J. Sastre-Garriga has received compensation for consulting services and speaking honoraria from Almirall, Bayer, Biogen, Celgene, Sanofi, Merck, Novartis, Roche, Bial, Biopass and Teva, is member of the editorial committee of Multiple Sclerosis Journal, and director of Revista de Neurología.

P. Tagliani has received travel expenses for scientific meetings from Roche.

C. Tur is currently being funded by a Junior Leader La Caixa Fellowship (fellowship code is LCF/BQ/PI20/11760008), awarded by “la Caixa” Foundation (ID 100010434). She has also received the 2021 Merck’s Award for the Investigation in MS, awarded by Fundación Merck Salud (Spain) and a grant awarded by the Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia e Innovación de España (PI21/01860). In 2015, she received an ECTRIMS Post-doctoral Research Fellowship and has received funding from the UK MS Society. She is a member of the Editorial Board of Neurology and Multiple Sclerosis Journal. She has also received honoraria from Roche and Novartis and is a steering committee member of the O’HAND trial and of the Consensus group on Follow-on DMTs.

A. Vidal-Jordana has received support has received support for contracts Juan Rodes (JR16/00024) and from Fondo de Investigación en Salud (PI17/02162 and PI22/01589) from Instituto de Salud Carlos III, Spain, and has engaged in consulting and/or participated as speaker in events organized by Roche, Novartis, Merck, and Sanofi.

A. Vilaseca has a predoctoral grant Rio Hortega, from the Instituto de Salud Carlos III, Spain

J. Villacieros-Álvarez has received grant from Instituto de Salud Carlos III, Spain; FI21/00282.

A. Zabalza has a predoctoral grant Rio Hortega, from the Instituto de Salud Carlos III, Spain (CM22/00237), received travel expenses for scientific meetings from Biogen-Idec, Merck Serono and Novartis; speaking honoraria from Eisai; and a study grant from Novartis.

A. Rovira serves/ed on scientific advisory boards for Novartis, Sanofi-Genzyme, Synthetic MR, TensorMedical, Roche, and Biogen, and has received speaker honoraria from Bayer, Sanofi-Genzyme, Merck-Serono, Teva Pharmaceutical Industries Ltd, Novartis, Roche, Bristol-Myers and Biogen, is CMO and co-founder of TensorMedical, and receives research support from Fondo de Investigación en Salud (PI19/00950) from Instituto de Salud Carlos III, Spain.

X. Montalban has received speaking honoraria and travel expenses for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Abbvie, Actelion, Alexion, Biogen, Bristol-Myers Squibb/Celgene, EMD Serono, Genzyme, Hoffmann-La Roche, Immunic, Janssen Pharmaceuticals, Medday, Merck, Mylan, Nervgen, Novartis, Sandoz, Sanofi-Genzyme, Teva Pharmaceutical, TG Therapeutics, Excemed, MSIF and NMSS.

M. Rodríguez-Barranco, L. Bollo, M. Castilló, I. Galán, D. Lapuma, and S. Sceppacuercia report no disclosures.

P407/431

Atypical Idiopathic Inflammatory Demyelinating Lesions in 38 Japanese Patients: Radiological Features, distinct from Multiple Sclerosis, were maintained during longitudinal analysis

Yuriko Aratake^1,2, Kenji Yoshinaga^2,3, Chihiro Fujii^2,4, Takayuki Kondo^1,2

¹Kyoto university graduate school, Neurology, Kyoto, Japan, ²Kansai Medical University Medical School, Neurology, Osaka, Japan, ³Kyoto University, Integrated Neuroanatomy&Neuroimaging, Kyoto, Japan, ⁴Kyoto Prefectural University of Medicine, Neurology, Kyoto, Japan

Introduction: Typical and significant cerebral lesions for the diagnosis of multiple sclerosis (MS) include periventricular ovoid, subcortical, and juxtacortical lesions, supported by nodular, ring or open ring enhancements in the active phase. However, the International Panel on MS Diagnosis has not yet concluded whether patients with atypical presentations can be diagnosed with possible MS. Hence, patients with atypical idiopathic inflammatory demyelinating lesions (AIIDLs), which are not typical MS lesions and insufficient for an MS diagnosis, pose diagnostic and treatment challenges.

Objectives/Aims: We aimed to know whether subsequent lesions of AIIDLs are MS-typical or not during follow-up.

Methods: We analysed 38 patients with AIIDLs. Based on their initial brain images, we classified them as having multiple spotty lesions (MSLs; n=18), disseminated encephalomyelitis-like lesions (DEMLs; n=14), leukoencephalopathy-like lesions (LELs; n=3), and tumefactive lesion (TL; n=3). We followed them longitudinally to estimate whether new lesions exhibited MS-typical characteristics based on locations, morphologies, central vein signs and/or enhancing patterns.

Results: After a mean disease duration of 11 years, 25 patients presented new lesions. Lesions of 22 cases (12 MSLs, 7 DEMLs, 1 LELs, and 2 TL) were MS-atypical. Lesions of the remaining 3 cases (2 MSLs and 1 LELs) were classified as MS-typical; however, disease-modifying therapies were effective in only one LELs case. Four MSLs, 7 DEMLs, 1 LELs, and 1 TL case presented no new lesions. In 2 MSLs and 2 DEMLs cases, the initially observed lesions exhibited a marked reduction, which rarely happens in typical MS cases.

Conclusion: Our study showed that 92.5% of AIIDLs cases maintained radiologically MS-atypical presentations. Together with our previous reports on cerebrospinal fluid analysis (Front Neurol, 2022) and treatment strategies (Front Neurol, 2021), this suggests that the pathophysiology of AIIDLs may differ from that of typical MS, and therapeutic options should be individually considered.

Disclosure of interest: Name:nothing to disclose.

P408/1779

DECISIve - DiagnosE using the Central veIn SIgn

Christopher Allen¹, Hari Pai¹, Emma Tallantyre², Klaus Schmierer³, Robert Dineen¹, Deborah Fitzsimmons⁴, Roshan das Nair^1,5,6, Paul Morgan¹, Chris Partlett⁷, Nikos Evangelou¹

¹Mental Health and Clinical Neurosciences Academic Unit, School of Medicine, University of Nottingham, Nottingham, United Kingdom, ²Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, United Kingdom, ³Blizard Institute, Queen Mary University of London, London, United Kingdom, ⁴Swansea Centre for Health Economics, Swansea University, Swansea, United Kingdom, ⁵Institute of Mental Health, Nottinghamshire Healthcare NHS Foundation Trust, Nottingham, United Kingdom, ⁶Health Division, SINTEF, Trondheim, Norway, ⁷Clinical Trials Unit, Faculty of Medicine & Health Sciences, University of Nottingham, Nottingham, United Kingdom

Introduction: Due to the revised 2017 McDonald diagnostic criteria, many more people undergo lumbar punctures as part of their Multiple Sclerosis (MS) diagnostic journey. This results in discomfort and additional costs. Patients often report they find the lumbar puncture painful, and it can cause unintended complications requiring hospitalisations or time off work to recover. Brain lesions with a central vein, detected with T2* MRI are thought to be characteristic of MS. The Central Vein Sign (CVS) supports the diagnosis of MS when over 40% of eligible MRI lesions have a visible central vein. The authors will present the final results from DECISIve – DiagnosE using the Central veIn SIgn (Clinical Trials reference: NCT04024969) at ECTRIMS 2023.

Objectives/Aims: To investigate whether T2* MRI is a more sensitive diagnostic test than lumbar puncture with oligoclonal band examination, in people at first clinical presentation with possible MS.

Methods: A multicentre prospective single group superiority diagnostic accuracy study. Participants presenting with typical clinically isolated syndrome requiring a lumbar puncture to meet the 2017 McDonald diagnostic criteria for MS were enrolled. Trial participants had an eight-minute T2* MRI scan sequence in addition to their lumbar puncture. The final clinical diagnosis is established after at least 18 months of follow up.

Results: Of 113 participants recruited, we were able to include 49 in a preliminary analysis. The sensitivity of the CVS to confirm a diagnosis of MS is 94% and lumbar puncture with oligoclonal band examination is 84% (McNemar test; p=0.453).

Conclusion: The DECISIve interim analysis has shown that the sensitivity of the CVS is higher than testing for oligoclonal bands by lumbar puncture for the diagnosis of multiple sclerosis. We expect that the full DECISIve dataset will have sufficient power to confirm whether there is a clinically meaningful difference or not. There is only a single discordant result between CVS with a threshold of 40% and the ‘rule of six’, suggesting this could be rapidly implemented in clinical practice. Further analysis will include comparing the accuracy, speed, costs, and acceptability of the different tests and aim to establish if most lumbar punctures can be replaced by a slightly longer MRI scan.

Disclosure of interest: Christopher Martin Allen has received grant income from the National Institute for Health Research.

Hari Venkatesh Pai has nothing to disclose.

Emma Tallantyre has received honorarium for consulting work from Biogen, Janssen, Merck, Novartis, and Roche. She has received travel grants to attend or speak at educational meetings from Biogen, Merck, Roche, Takeda and Novartis.

Klaus Schmierer is a member of the MAGNIFY-MS steering committee and MS Global Advisory Network (Merck KGaA), and Chief Investigator of ChariotMS, supported by the National Institute of Health Research EME programme, MS Society of Great Britain & Northern Ireland, National MS Society (US), Barts Charity, and Merck KGaA. Further research support from Biogen and Novartis. Speaking honoraria from, and/or served in an advisory role for, Biogen, Merck, Novartis, Roche, Sanofi-Genzyme. Remuneration for teaching activities from Medscape and MS Academy.

Robert Dineen has has received research support from UK National Institute of Health Research.

Deborah Fitzsimmons has nothing to disclose.

Roshan Das Nair has nothing to disclose.

Paul Morgan has nothing to disclose.

Christopher Partlett has nothing to disclose.

Nikos Evangelou has served as a member of advisory boards for Biogen, Merck, Novartis, and Roche and has received grant income from the United Kingdom Multiple Sclerosis Society, Medical Research Council, Patient-Centered Outcomes Research Institute, and National Institute for Health Research.

christopher.allen@nottingham.ac.uk

P409/1023

Long-Term Comparative Efficacy of Inebilizumab in the AQP4+ Subpopulation from the N-MOmentum Open-Label Extension Versus Azathioprine and Immunosuppressive Therapies and Versus Placebo in Patients with NMOSD

Bruce Cree¹, Beatrice Suero², Sarah Walsh², Romain Marignier³, John Lindsey⁴, Ho Jin Kim⁵, Dewei She⁶, Daniel Cimbora⁶, Kristina Patterson⁶, Friedemann Paul⁷

¹UCSF Weill Institute for Neurosciences, San Francisco, United States, ²Eversana, Burlington, Ontario, Canada, ³Pierre Wertheimer Hospital, Bron, France, ⁴UTHealth Houston (The University of Texas Health Science Center at Houston), Houston, United States, ⁵Research Institute and Hospital of National Cancer Center, Goyang, South Korea, ⁶Horizon Therapeutics, Deerfield, United States, ⁷Max Delbrück Center for Molecular Medicine, Berlin, Germany

Introduction: Inebilizumab (INEB), an anti-CD19 B cell-depleting antibody, is approved for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults seropositive for aquaporin-4 antibody (AQP4⁺). N-MOmentum (NCT02200770) consisted of a 28-week randomized-controlled period (RCP) and an optional open-label extension (OLE) (>2 years) in which all participants received treatment with INEB.

Objectives/Aims: To evaluate the long-term comparative efficacy of INEB over N-MOmentum OLE vs azathioprine and other immunosuppressive therapies (AZA/IST) and vs PBO in participants with NMOSD.

Methods: Two historical comparator groups (HCGs) derived using data from published NMOSD studies were used to evaluate the comparative efficacy of INEB (N=208) over the OLE. The first group consisted of participants who received AZA/IST (N=132), and the second group consisted of participants who received PBO only (N=106). Hazard ratios (HR) for INEB vs HCGs were estimated using a Cox proportional hazards (PH) regression. Time to NMOSD attack was analysed using parametric and flexible survival (spline) models that were fit to INEB and HCGs. Model selection was determined by testing the PH and accelerated failure time assumptions as well as assessing Akaike’s information criterion/Bayesian information criterion, visual fit, estimated attack-free survival at 4 years, and clinical validation.

Results: The HR for time to NMOSD attack for the N-MOmentum PBO group compared to the PBO groups was 1·15; (95% CI: 0.67–1.91; P value = 0.58). The HRs for time to NMOSD attack for INEB vs AZA/IST and PBO groups were 0.29 (95% CI: 0.17, 0.42; P < 0.001) and 0.15 (95% CI: 0.10, 0.21; P < 0.001), respectively. A time-varying spline with two internal knots and normal linear predictor provided the best fit. At 4 years, the model estimated an attack-free survival of 77% (95% CI: 71, 83) for INEB, 36% (95% CI: 27, 46) for AZA/IST, and 12% (95% CI: 7, 20) for PBO. Results indicate a greater difference in efficacy for INEB vs PBO compared to AZA/IST vs PBO, suggesting a significant reduction in risk of attack for INEB vs both AZA/IST and PBO.

Conclusion: INEB was associated with a statistically significant improvement in time to onset of an NMOSD attack and provided a long-term attack-free survival benefit over the OLE compared to the relative short-term benefit observed with AZA/IST. That the PBO treated group from the RCT had a similar attack risk as the historical PBO controls supports the validity of using historical datasets for these comparisons.

Disclosure of interest: B.A.C. Cree reports personal fees for consulting from Alexion, Atara, Autobahn, Avotres, Biogen, Boston Pharma, EMD Serono, Gossamer Bio, Hexal/Sandoz, Horizon, Immunic AG, Neuron23, Novartis, Sanofi, Siemens, TG Therapeutics and Therini and received research support from Genentech.

B. Suero, S. Walsh reports personal fees for consulting from Horizon Therapeutics for this project (as part of EVERSANA).

R. Marignier reports personal fees for consulting from Alexion, Horizon Therapeutics, Roche, and UCB.

J.W. Lindsey reports personal compensation for speaking or consulting for Banner Life Sciences, Biogen, Celgene, EMD Serono, Genentech, Genzyme, Mapi Pharmaceuticals, and TG Therapeutics; is participating in clinical trials funded by Anokion, Atara, Biogen, EMD Serono, and Genentech; and has received research funding from Genentech and the National MS Society.

H.J. Kim has received a grant from the National Research Foundation of Korea; consultancy/speaker fees or research support from Alexion, AprilBio, Altos Biologics, Biogen, Celltrion, Daewoong Pharmaceutical, Eisai, GC Pharma, HanAll Biopharma, Handok, Horizon Therapeutics (formerly Viela Bio), Kolon Life Science, MdImune, Merck Serono, Mitsubishi Tanabe Pharma, Novartis, Roche, Sanofi Genzyme, Teva-Handok, and UCB; and is a co-editor for the Multiple Sclerosis Journal and an associate editor for the Journal of Clinical Neurology.

F. Paul has received research support, speaker honoraria, and travel reimbursement from Bayer, Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, and Teva; is supported by the German Research Council (DFG Exc 257) and the German Competence Network for Multiple Sclerosis; has received travel reimbursement from the Guthy-Jackson Charitable Foundation; and serves on the steering committee of the OCTIMS study, sponsored by Novartis.

D. She, D. Cimbora, K.R. Patterson are employees of Horizon Therapeutics and own stock.

P410/2057

Meningococcal infections in eculizumab- or ravulizumab- treated patients with neuromyelitis optica spectrum disorder: a clinical and real-world pharmacovigilance update across indications

Sami Fam¹, Brian Werneburg¹, Shirali Pandya¹, Becky Parks¹, Yasmin Mashhoon¹, Kerstin Allen¹, Glen Frick¹, Alex Zodiatis¹, Vidya Chitikireddi¹, Hua Zhang¹, Guido Sabatella¹, Arshad Mujeebuddin¹

¹Alexion, AstraZeneca Rare Disease, Boston, United States

Introduction: Terminal complement inhibiting therapies (C5ITs) for rare hematological and neurological diseases, such as neuromyelitis optica spectrum disorder (NMOSD), are associated with increased Neisseria meningitidis (Nm) infection risk. Robust risk mitigation measures include vaccination, drug safety programs, and patient safety cards. Pharmacovigilance analysis of exposure-adjusted incidence and mortality data for Nm infections is ongoing.

Objectives/Aims: Here, we evaluate Nm infection and mortality rates in eculizumab- or ravulizumab-treated patients using clinical and real-world data, with a focus on data collected from NMOSD patients.

Methods: A cumulative search of the Alexion safety database was conducted for eculizumab (Mar 2007–Oct 2022) and ravulizumab (Dec 2018–Jun 2022) across indications, using the MedDRA High Level Term of Neisseria infection. Only cases associated with Nm were included.

Results: For eculizumab- or ravulizumab-treated patients, respectively: cumulative clinical trial Nm infection rates are ~ 0.30 and 0.21 cases per 100 patient-years (PY), Nm mortality rates are ~ 0.00 and 0.03 cases per 100 PY; cumulative post-marketing reporting rates for Nm infections are stable at ~ 0.24 and 0.08 cases per 100 PY, Nm mortality rates are ~ 0.03 and 0.02 cases per 100 PY. In the real-world, Nm infection rates in eculizumab-treated patients decreased over 15 years (0.57 to 0.24 per 100 PY); mortality rates remained stable (0.00 to 0.03 per 100 PY). Updated cumulative clinical trial incidence values for eculizumab and ravulizumab, as well as updated cumulative post-marketing reporting rates for ravulizumab will be presented for NMOSD and other indications. Two cases of Nm infection were reported in the primary treatment period of the CHAMPION-NMOSD ravulizumab trial; details on those cases will be presented. No additional cases have been reported to date in the long-term extension of the trial.

Conclusion: Even though cumulative exposure to eculizumab increased over time, partly because of the addition of rare neurological indications, Nm infection rates steadily decreased and mortality rates remained stable. Ravulizumab-treated patients have comparable rates. Infection awareness, existing risk mitigation strategies, and availability of vaccines effectively reduced the risk of Nm infections in C5IT-treated patients, underlining the importance of adhering to those measures.

Disclosure of interest: All authors are employees of, and hold stock in, Alexion, AstraZeneca Rare Disease

P411/725

Relapse and Non-Relapse Hospitalizations in Neuromyelitis Optica Spectrum Disorders

Sathya Narasimhan¹, Danielle Kei Pua¹, Kathryn Holroyd², Farrah Mateen^3,4, Michael Levy^3,4, Shamik Bhattacharyya^1,4

¹Brigham and Women's Hospital, Neurology, Boston, United States, ²Yale School of Medicine, New Haven, United States, ³Massachusetts General Hospital, Boston, United States, ⁴Harvard Medical School, Boston, United States

Introduction: Hospitalization burden in neuromyelitis optica spectrum disorders (NMOSD) occurs for inflammatory relapses, infectious complications, symptom management, and other medical complications.

Objectives/Aims: To determine frequency and characteristics of hospitalization in a cohort of patients with NMOSD.

Methods: In a multi-center U.S. healthcare system (Mass General Brigham comprising 9 hospitals), electronic medical records were queried for more than one diagnosis code of neuromyelitis optica from 2005 to 2021. Patients were included if they met international consensus diagnostic criteria for NMOSD and had neurology evaluation. Demographics, disease details, treatments, and hospitalization details were collected and analyzed.

Results: 125 adult patients met inclusion criteria (81% seropositive for anti-aquaporin-4; 80.8% female; predominantly of white (64%) and black (15%) races) with an average age at first attack of 42.8 (SD 16.8) years. From diagnosis, patients on average had 5.2 (SD 4.0) years of follow-up and were treated with mean of 1.6 (SD 0.9) NMOSD-directed therapies. Patients on average had 3.5 (SD 2.8) relapses during follow-up (annualized relapse rate of 1.1 (SD 1.6)) of which at least 54.7% required hospitalization. Patients were hospitalized 3.4 (SD 3.1) times on average: 81.5% of hospitalizations were for relapses and 19.7% were for non-relapses. Relapse hospitalizations were on average 7.9 (SD 6.9) days long, and 27.7% had complications, most frequently infections (51.2%). Among NMOSD approved medications, 2 of 6 patients relapsed on eculizumab, 1 of 3 patients on inebilizumab, and 0 of 3 patients on satralizumab. Non-relapse hospitalizations were on average 8.7 (SD 10.8) days, and 32.2% had complications, of which 56.2% were due to infections. On last follow up, 93.6% patients were on treatment (67.9% were on rituximab) with 7 (6.3%) patients off disease modifying therapy and 7 (6.3%) patients on multi-therapy. There were 10 deaths in the cohort of which only 1 was NMOSD-related.

Conclusion: NMOSD results in lengthy hospitalizations both for relapses and non-relapses frequently complicated by infections. While disease modifying therapies may prevent relapses, further investigation is needed for optimal prevention of non-relapse hospitalizations.

Disclosure of interest: Sathya Narasimhan: Nothing to disclose

Danielle K Pua: Nothing to disclose

Kathryn Holroyd: Nothing to disclose

Farrah Mateen: Dr. Mateen has received personal compensation from Horizon Therapeutics, Genentech, TG Therapeutics, EMD Seronon; honorarium for editorial services from Neurology; research support from Genentech, NIH, Sumaira Foundation, EMD Serono, Biogen

Michael Levy: Dr. Levy has received personal compensation from Mitsubishi Pharma, UCB Pharma, Sanofi, Alexion Pharmaceuticals, Horizon, Genentech; honorarium for editorial services from Elsevier; research support from NIH

Shamik Bhattacharyya: Dr. Bhattacharyya has received personal compensation from Alexion Pharmaceuticals; honorarium for editorial services from Continuum and UpToDate; research support from Alexion Pharmaceuticals, UCB, NIH, and Massachusetts Consortium on Pathogen Readiness.

P412/1736

Referral bias impacts cohorts of neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein antibody associated disease

Miguel Leal Rato¹, Eoin O’Sullivan², Sarah Cooper³, Leonora Fisniku⁴, Christopher Halfpenny⁵, Roswell Martin⁶, Sebastian Luppe⁶, Jeremy Hobart⁷, Waqar Rashid⁸, Cheryl Hemingway⁹, Ruth Dobson¹⁰, Sithara Ramdas¹¹, Maria Isabel Leite¹², Ruth Geraldes¹², Jacqueline Palace¹²

¹Hospital Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Serviço de Neurologia, Departamento de Neurociências e Saúde Mental, Lisbon, Portugal, ²King's College Hospital, Eye Department, London, United Kingdom, ³University Hospitals Sussex, Sussex, United Kingdom, ⁴Cambridge University Hospitals, Cambridge, United Kingdom, ⁵University Hospitals Southampton, Southampton, United Kingdom, ⁶Gloucestershire Royal Hospitals NHS Trust, Gloucester, United Kingdom, ⁷Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, United Kingdom, ⁸St George's University Hospitals NHS Foundation Trust, London, United Kingdom, ⁹Great Ormond Street Hospital, Department of Neurology, London, United Kingdom, ¹⁰Wolfson Institute of Population Health, Queen Mary University of London, Preventive Neurology Unit, London, United Kingdom, ¹¹Childrens Hospital, John Radcliffe Hospital, Department of Paediatric Neurology, Oxford, United Kingdom, ¹²Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom

Introduction: Published cohorts of neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD) derive from a variety of service set ups, including centres serving their local/regional community and specialised centres covering wider regions or whole countries.

Objectives/Aims: We set out to assess and compare the characteristics of local, regional and national cohorts of NMOSD and MOGAD.

Methods: Patients from the Oxford national NMO database were grouped into ‘local’ (Oxfordshire), ‘regional’ (Oxfordshire and its catchment area comprising the 4 surrounding counties), and ‘national’ patients (all patients local, regional and from elsewhere). Demographic and clinical differences between groups were assessed using univariate analyses.

Results: From 720 patients (331 patients had MOGAD, 333 had aquaporin-4 antibody–positive NMOSD (AQP4-NMOSD), and 56 had seronegative NMOSD), 48 (6.7%) were local and 109 (15.1%) were regional patients. The proportion of patients with antibody-associated disease versus seronegative was similar across cohorts (45.9 to 60% with MOGAD; 33 to 46.3% with AQP4-NMOSD; and 5.5 to 7.8% with seronegative NMOSD). There were no significant differences in age, sex, or onset clinical phenotype; a higher proportion of white race AQP4-NMOSD patients were present in the local cohort than in the national cohort (81% v. 50%). Despite no significant differences in follow-up time, more monophasic MOGAD disease was present in in the local and regional versus national cohorts (76% and 68% v. 57.1%), and national MOGAD patients had a higher number of relapses than local patients both before and after referral.

Conclusion: This is the first study assessing the impact of referral bias in cohorts of MOGAD or NMOSD. The racial difference in the AQP4-NMOSD cohorts is probably due to the variation in the population demographics rather than a referral bias. The over representation of relapsing v. monophasic MOGAD patients in the national cohort likely reflects a true referral bias, either because monophasic MOGAD may be underdiagnosed in outlying non specialist hospitals or because more challenging relapsing patients are more likely to be referred into the specialist centre. It is reassuring that other characteristics did not differ, suggesting that other than a risk for overestimation of relapsing MOGAD patients comparisons across NMOSD and MOGAD cohorts may be reasonable, even across different health care set ups where the diagnostic definition is the same.

Disclosure of interest: Miguel Leal Rato has received support for attending meetings and/or travel grants from Sanofi, Novartis, Merck, and Boehringer Ingelheim. Eoin O’Sullivan has received honoraria from UCB and Roche. Sarah Cooper has nothing to disclose. Leonora Fisniku has received support for scientific meetings and/or honorariums for advisory work from Biogen, Teva, Novartis, Sanofi, Merck and Roche. Critopher Halfpenny has received honoraria and funding to attend meetings from Roche and Biogen. Roswell Martin has received support for attendance at conferences and speaker fees from Biogen, Roche, Eisai, Novartis and Teva. Sebastian Luppe has received support for scientific meetings from Biogen and Sanofi Genzyme. Jeremy Hobart has received consulting fees, honoraria, support to attend meetings, research support or clinical service support from: Acorda, Bayer Schering, Biogen Idec, BMS, F. Hoffmann-La Roche, Janssen, Merck Serono, Novartis, Oxford PharmaGenesis, Sanofi-Genzyme, Teva. Waqar Rashid has received support for scientific meetings and courses and for advisory work from Biogen Idec, Merck, Novartis, Sanofi, Janssen and Bristol Myers and Squibb. Cheryl Hemingway reports grant support from the MRC, MS Society and Vasculitis UK; she serves as a consultant to Novartis, Biogen-IDEC, Roche, UCB, and Sanofi; she participated on data safety monitoring boards Wellcome SURE IDMC. Ruth Dobson works within the PNU, which is part funded by Barts Charity; has received honoraria for advisory boards and/or educational activities from Biogen, Teva, Sanofi, Merck, Janssen, Novartis, Sandoz and Roche; and research support from Biogen, Merck. Sithara Ramdas has received speaker honorarium from Roche and Novartis; advisory board honorarium from Sarepta, Argenx, Roche and Novartis. Maria Isabel Leite has received funding from the NHS National Specialised Commissioning Group for Neuromyelitis optica and the NIHR Oxford Biomedical Research Centre; and speaker honoraria or travel grants from Biogen Idec, Novartis, and the Guthy-Jackson Charitable Foundation. Ruth Geraldes has received support for scientific meetings and courses from the EAN, Bayer, Biogen, Merck and Novartis; and honoraria for advisory work from Wolfson College. Jacqueline Palace has received support for scientific meetings and honorariums for advisory work from Merck Serono, Novartis, Chugai, Alexion, Roche, Medimmune, Argenx, UCB, Mitsubishi, Amplo, Janssen; grants from Alexion, Roche, Medimmune, Amplo biotechnology; patent ref P37347WO and license agreement Numares multimarker MS diagnostics; shares in AstraZeneca; acknowledges partial funding by Highly specialised services NHS England. The remaining authors have no disclosures to report.

P413/130

Misdiagnosis of Neuromyelitis Optica Spectrum Disorder as Multiple Sclerosis: Multi-institutional database analysis in the United States

Ka-Ho Wong¹, Abigail Sorenson¹, Heewong Hwang¹, Sama Noroozi¹, Trieste Francis¹, Sarah Germaine¹, Melissa Wright¹, Jonathan Galli¹, Robert Kadish¹, Julia Klein¹, M. Mateo Paz Soldan¹, John Greenlee¹, John Rose¹, Tammy Smith¹, Stacey L. Clardy¹

¹University of Utah, Neurology, Salt Lake City, United States

Introduction: Neuromyelitis Optica Spectrum Disorder (NMOSD) is an antibody-mediated inflammatory disease of the central nervous system (CNS) that targets the optic nerves, spinal cord, and certain brain regions. NMOSD patients may be misdiagnosed with the more common condition of MS, given some shared signs and symptoms. Misdiagnosed NMOSD patients may be exposed to MS DMTs that can worsen the morbidity associated with NMOSD.

Objectives/Aims: Ascertain the frequency at which NMOSD is misdiagnosed as Multiple Sclerosis (MS), and consequent inappropriate use of FDA-approved disease-modifying therapies (DMTs) for MS, in a national cohort.

Methods: Preliminary de-identified data was obtained by TriNetX, a health research network providing access to electronic medical records that includes sixty-one healthcare organizations (HCOs) in the US. Patients with the ICD-10 code of NMO (G36.0) were queried from the database between 2008-2022.

Results: 7768 unique patients were identified with NMO in the TriNetX database, and of those, 3617 patients had an ICD-10 code for both NMO and MS. 2352 patients were excluded (<3 visits), of the final 1265 patients; 75.7% are female, median age is 49 years, and 55% are white. The 1265 patients were classified into 3 categories: NMO patients misdiagnosed as MS (n=308), MS patients misdiagnosed as NMO (n=189), and patients diagnosed with MS and NMO interchangeably over time (n=768).

Conclusion: Black race was the most commonly misdiagnosed in NMOSD patients, and the Midwest region has the highest incidence rate of misdiagnosis. Many NMOSD patients were misdiagnosed with MS in this national population, and almost one-quarter of misdiagnosed patients were prescribed an FDA-approved MS DMT.

Disclosure of interest: The study was funded by Sumaira Foundation Spark Grant.

P414/2019

Frequency and phenotype of aquaporin-4-IgG and coexistent autoimmune encephalitis (neuronal and glial) antibody biomarkers: a laboratory-based analysis of over 6,000 tests

Laura Cacciaguerra¹, Binxia Yang¹, Shruti P. Agnihotri², Nusrat Ahsan^3,4, Karen S. Fernandez⁵, Rebecca L. Massey², Erin McLeod², William Meador², Wendy G. Mitchell^3,4, Jacqueline Nicholas⁶, May Lin, Amy Quek⁷, Thomas Shoemaker⁸, Kurt Sieloff⁶, Vanessa Sui², Emmanuelle Waubant⁹, Eoin Flanagan^1,10, Andrew McKeon^1,10, Sean Pittock^1,10, Amy Kunchok¹¹

¹Mayo Clinic, Department of Neurology and Center for MS and Autoimmune Neurology, Rochester, United States, ²University of Alabama at Birmingham School of Medicine, UAB Department of Neurology, Birmingham, United States, ³Children's Hospital Los Angeles, Division of Neurology, Department of Pediatrics, Los Angeles, United States, ⁴Keck School of Medicine at the University of Southern California, Department of Neurology, Los Angeles, United States, ⁵Valley Children's Healthcare, Division of Hematology/Oncology, Cancer and Blood Disorders Center, Stanford Medicine, Madera, United States, ⁶Riverside Methodist Hospital, OhioHealth Multiple Sclerosis Center, Columbus, United States, ⁷Yong Loo Lin School of Medicine, National University of Singapore, Division of Neurology, Department of Medicine, Singapore, Singapore, ⁸Rush University Medical Center, Department of Neurological Sciences, Chicago, United States, ⁹University of California San Francisco, Department of Neurology, San Francisco, United States, ¹⁰Mayo Clinic, Laboratory Medicine and Pathology, Rochester, United States, ¹¹Cleveland Clinic, Mellen Centre for Multiple Sclerosis and Department of Neurology, Cleveland, United States

Introduction: It is well-known that aquaporin-4-IgG seropositive (AQP4+) neuromyelitis optica spectrum disorders (NMOSD) patients often have coexistent organ- and non-organ-specific autoantibodies associated with clinical syndromes. It is less clear if this also applies to neuronal and glial autoantibodies targeting the CNS.

Objectives/Aims: To determine the clinical and radiological features of AQP4+ patients with coexistent neural autoantibodies and their frequency.

Methods: We interrogated the Neuroimmunology Laboratory database for AQP4+ patients between 2007-2022 (n=6,839) whose serum and CSF samples were tested for neuronal or glial-IgG markers of encephalitis.

Results: We identified 21 AQP4-IgG+ patients (7[33%] pediatric) with co-existent neural-IgGs and available clinical and radiological data. Of these, 10(48%) were NMDA-R-IgG+, 2(10%) GFAP-IgG+, and 9(43%) had both. Patients with isolated NMDA-R-IgG and double positivity (NMDA-R/GFAP-IgGs) had a similar rate of encephalopathy (5/9[57%] vs 7/8[88%], p=0.29), brainstem/cerebellar syndromes (not area postrema, 4/10[40%] vs 3/8[38%], p>0.99), seizures (1/10[10%] vs 1/8[13%], p>0.99), psychiatric manifestations (2/10[20%] vs 5/8[63%], p=0.15) and tumors (1/9[11%] vs 5/9[56%], p=0.13). Radiological features were also similar, with lesions/enhancement in the basal ganglia (5/8[63%] vs 3/9[43%], 0.62), temporal lobe (1/8[13%] vs 3/9[43%], p=0.28), and diencephalon (2/8[25%] vs 1/7[14%], p>0.99). These features were less common in a Mayo Clinic AQP4-IgG+NMOSD control cohort (n=311, p<0.001). Both patients with GFAP-IgG alone had longitudinally-extensive spinal cord lesions. One had concomitant psychiatric manifestations. The frequency of co-existent neuronal and glial-IgGs was evaluated in a subgroup of AQP4-IgG+ tested between 2018-2021 in whom the physician ordered a comprehensive autoimmune encephalitis evaluation. There were 121 AQP4-IgG+ tested in serum (children 30, adults 91) and four adults had co-existent GAD65-IgG (1) and MOG-IgG (3). There were 123 AQP4-IgG+ tested in CSF (children 34, adults 89), 22 had co-existent neural-IgGs including GFAP-IgG (9), NMDA-R-IgG (8), NMDA-R-IgG and GFAP-IgG (3, 1 with also AMPA-R-IgG), NMDA-R-IgG/MOG-IgG (1), PCA-1-IgG (1). NMDA-R-IgG was most frequent in children (6/8[80%], and GFAP-IgG in adults (9/14[64%]).

Conclusion: AQP4-IgG+ patients rarely have co-existent encephalitis and CSF positivity for neural antibodies. When identified nearly all are either NMDA-R-IgG, GFAP-IgG, or both.

Disclosure of interest: Laura Cacciaguerra received speaker and consultant honoraria from ACCMED, Roche, BMS Celgene, Sanofi and travel support for conferences by Merck Serono.

Binxia Yang reports no disclosures.

Shruti P. Agnihotri’s institution received fundings from a grant by Genentech/Roche.

Nusrat Ahsan reports no disclosures.

Karen S. Fernandez reports no disclosures.

Rebecca L. Massey reports no disclosures.

William R. Meador reports no disclosures.

Erin McLeod reports no disclosures.

Wendy G. Mitchell reports no disclosures.

Jacqueline A. Nicholas reports research grants from Biogen, Novartis, PCORI, Genentech, and University of Buffalo; consulting activities for EMD Serono, Genentech, Greenwich Biosciences, Novartis, and TG Therapeutics; and speaking honoraria from BMS, EMD Serono, Horizon, and TG Therapeutics.

Amy M.L. Quek reports no disclosures.

Thomas Shoemaker reports no disclosures.

Vanessa Sui reports no disclosures.

Emmanuelle Waubant reports no disclosures.

Eoin P. Flanagan was a site primary investigator in a randomized clinical trial on Inebilizumab in neuromyelitis optica spectrum disorder run by Medimmune/Viela-Bio/Horizon Therapeutics, has received funding from the NIH (R01NS113828), and is a member of the medical advisory board of the MOG project. Dr. Flanagan is an editorial board member of the Journal of the Neurological Sciences and Neuroimmunology Reports, and a patent has been submitted on DACH1-IgG as a biomarker of paraneoplastic autoimmunity.

Andrew McKeon reports grants from the National Institutes of Health (grants RO1NS126227 and U01NS120901); consulting fees from Janssen and Roche (all paid to Mayo Clinic); and had a patent for MAP1B antibody issued, a patent for Septins 5, 7, GFAP, PDE10A, KLCHL11 antibodies pending, a patent for Septin antibodies licensed, and a patent for MAP1B antibodies with royalties paid.

Sean J. Pittock reports grants, personal fees, and non-financial support from Alexion Pharmaceuticals; grants, personal fees, and non-financial support from MedImmune /Viela Bio; and personal fees for consulting from Genentech, Roche, UCB, and Astellas. He has two patents issued (8889102; application 12-678350; Neuromyelitis Optica Autoantibodies as a Marker for Neoplasia; and 9891219B2; application 12-573942; Methods for Treating Neuromyelitis Optica [NMO] by Administration of Eculizumab to an individual that is Aquaporin-4 [AQP4]-IgG Autoantibody positive). Sean J. Pittocl also has patents pending for IgGs to the following proteins as biomarkers of autoimmune neurological disorders: septin-5, kelch-like protein 11, GFAP, PDE10A, and MAP1B.

Amy Kunchok has received personal compensation for scientific advisory boards and consulting for Genentech, Horizon therapeutics, and EMD Serono.

P415/558

The Relationship of Social and Environmental Factors with Relapses in Neuromyelitis Optica Spectrum Disorder Patients

Justin Abbatemarco¹, Albert Aboseif², Carol Swetlik¹, Julie Widmar¹, Tucker Harvey^1,3, Scott Husak^1,3, Amy Kunchok¹, Deborah M. Miller¹, Devon Conway¹

¹Cleveland Clinic Mellen Center, Cleveland, United States, ²Cleveland Clinic Main Campus, Cleveland, United States, ³Cleveland Clinc, Department of Quantitative Health Sciences, Cleveland, United States

Introduction: Neuromyelitis Optica Spectrum Disorder (NMOSD) is known to have a higher prevalence among non-white individuals. Less is known about the relationship between clinical outcomes, race, and social determinants of health (SDoH).

Objectives/Aims: To investigate the relationship between demographic, environmental, and treatment factors with NMOSD relapses.

Methods: We conducted a retrospective cohort study evaluating adult patients with NMOSD confirmed at a tertiary neuroimmunology center. Relevant variables were collected, including self-identified race, age at diagnosis and disease-modifying therapy (DMT) use. SDoH were captured using the Area Deprivation Index (ADI), a validated measure of neighborhood-level disadvantage (analyzed in tertiles), and urban-rural living status. Relapses were determined by chart review and the annualized relapse rates (ARR) were calculated. Negative binomial regression models assessed relevant associations with ARR while controlling for sex, and age of symptom onset.

Results: 158 NMOSD patients (94.9% aquaporin-4 antibody positive) were identified, a majority of whom were White (56.3%), and female (89.9%), with a mean age of 46 years (standard deviation [SD] 17.6) at diagnosis. Mean duration of follow-up at our center was 7.42 years (SD 7.10). Patients in the top ADI tertile (most deprived cohort) had higher annualized relapse rates (ARR; 0.59, SD 1.32) than those in the bottom tertiles (ARR 0.41, SD 0.90), though this difference was not significant (p = 0.35). There was no difference in DMT use based on neighborhood deprivation (p = 0.34), but White patients used DMT an average of 80.9% during of our follow-up period while non-White patients were only on therapy 65.5% of the time (p = 0.003). In an age- and sex-adjusted model, ARR did not significantly differ by ADI, however, non-White NMOSD patients had an estimated ARR that was 1.72 times greater than White patients (95% CI 1.100 – 2.692, p = 0.009). There was no relationship between urban-rural living status and relapses (p = 0.73).

Conclusion: There was no clear relationship between ARR and neighborhood-level disadvantage or urban-rural living status. Increased ARR was seen in non-White patients and was not explained by measured SDoH but there was a clear discrepancy in DMT use by race, which may help to explain this discrepancy. Other societal and biological causes may also contribute, so further efforts should investigate the impact of race on NMOSD patients and underlying reasons for the observed disparities.

Disclosure of interest: JRA: Served on scientific advisory boards for of EMD Serono, Genentech, Horizon; has received research support from Horizon Therapeutics

AA: nothing to disclose

CS: nothing to disclose

JW: nothing to disclose

TH: nothing to disclose

SH: nothing to disclose

AK: has received compensation for consulting and scientific advisory boards for Genentech, Horizon therapeutics and EMD Serono.

DMM: Inventor of the technology underlying the Multiple Sclerosis Performance Test which has been licensed to Qr8 and Biogen. She is entitled to any compensation that results in royalties it accrues. She serves as a consultant to Osmotica Pharmaceuticals.

DC: Has received research support paid to his institution from EMD Serono, Horizon Therapeutics, Novartis, and Biogen. He has received consulting fees from Novartis and Alexion and speaking fees from Biogen.

P416/358

Unilateral optic disc swelling in older adults: MOGAD versus NAION

Nanthaya Tisavipat¹, Hadas Stiebel-Kalish^2,3, Dahlia Palevski², Omer Bialer², Heather Moss^4,5, Pareena Chaitanuwong^5,6, Tanyatuth Padungkiatsagul⁷, Amanda Henderson^8,9, Elias Sotirchos⁸, Shonar Singh⁹, Sean Pittock^1,10, Eoin Flanagan^1,10, John Chen^1,11

¹Mayo Clinic, Neurology, Rochester, United States, ²Rabin Medical Center and Sackler School of Medicine, Tel Aviv University, Neuro-Ophthalmology Division, Department of Ophthalmology, Petah Tikva, Israel, ³Felsenstein Medical Research Center, Tel Aviv University, Petah Tikva, United States, ⁴Stanford University, Neurology, Palo Alto, United States, ⁵Stanford University, Ophthalmology, Palo Alto, United States, ⁶Rajavithi Hospital, Ophthalmology, Bangkok, Thailand, ⁷Faculty of Medicine Ramathibodi Hospital, Mahidol University, Ophthalmology, Bangkok, Thailand, ⁸Johns Hopkins University, Neurology, Baltimore, United States, ⁹Johns Hopkins University, Ophthalmology, Baltimore, United States, ¹⁰Mayo Clinic, Laboratory Medicine and Pathology, Rochester, United States, ¹¹Mayo Clinic, Ophthalmology, Rochester, United States

Introduction: Optic neuritis (ON) in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) can occur at any age and is treated with high dose corticosteroids. In older adults, non-arteritic ischemic optic neuropathy (NAION) is the most common cause of acute optic neuropathy and has no effective treatment. Optic disc swelling is a shared prominent feature of MOGAD-ON and NAION, creating a diagnostic dilemma which can delay treatment of MOGAD-ON.

Objectives/Aims: To determine differentiating features between MOGAD-ON and NAION in older adults.

Methods: We conducted a case-control study (1:1) in 5 tertiary-care centers in the US, Europe, and Asia. MOGAD patients who presented at the age of >45 with an onset attack of unilateral ON were compared to age- and sex-matched NAION controls.

Results: 85 MOGAD-ON patients presenting at age >45 were identified. 65 (76%) had unilateral ON. The median age of onset was 56 (IQR 50-61), 71% were female, and 77% were White. Compared to age- and sex-matched NAION, MOGAD-ON patients were less likely to have crowded optic disc (35% vs 83%, p<0.001; median cup-to-disc ratio 0.3 vs 0.1, p<0.001), dyslipidemia (31% vs 72%, p<0.001), obstructive sleep apnea (19% vs 45%, p=0.003), or a history of smoking (5% vs 17%, p=0.039). The frequency of diabetes, hypertension, obesity, prior cardiovascular disease, or phosphodiesterase 5 inhibitor use were similar. MOGAD-ON more commonly had a subacute onset (progression beyond 48 hours: 48% vs 25%, p=0.021), preceding headache (48% vs 22%, p=0.003), and eye pain (80% vs 22%, p<0.001) which was more likely to be moderate-severe and increased with eye movement. Vision loss in MOGAD-ON was more severe at nadir (median logMAR 1.0 vs 0.4, p=0.005) but recovery was better (median logMAR 0.1 vs 0.3, p<0.001). MOGAD-ON less commonly had altitudinal visual field defect (14% vs 74%, p=0.005), disc edema (66% vs 100%, p<0.001), and segmental disc edema (8% vs 37%, p=0.002). On optical coherence tomography within 2 weeks of onset, the retinal nerve fiber layer (RNFL) thickness was lower in MOGAD (median 114 vs 208 mm, p<0.001; median increment from the unaffected eye 25 vs 102 mm, p<0.001).

Conclusion: In older adults with unilateral optic neuropathy, subacute onset, headache, eye pain, poor visual acuity at nadir with good recovery, and less RNFL swelling suggested MOGAD-ON. While crowded optic disc and sectoral disc edema favoured NAION, these features could be present in MOGAD-ON.

Disclosure of interest: Dr. Tisavipat has no relevant disclosures.

Dr. Stiebel-Kalish received travel funding and/or speaker honoraria from Roche, but this was not relevant to the study.

Dr. Palevski has no relevant disclosures.

Dr. Bialer has no relevant disclosures.

Dr. Moss received funding from NIH for the project P30EY026877 to prevent blindness.

Dr. Henderson has served on advisory boards for Horizon Therapeutics, but this was not relevant to this study.

Dr. Chaitanuwong has no relevant disclosures.

Dr. Padungkiatsagul has no relevant disclosures.

Dr. Sotirchos reports scientific advisory boards and/or consulting for Alexion, Viela Bio, Horizon Therapeutics, Genentech and Ad Scientiam, and speaking honoraria from Alexion, Viela Bio and Biogen, but were not relevant to this study.

Dr. Singh has no relevant disclosures.

Dr. Pittock has served on advisory boards for Genentech, Inc., Sage Therapeutics, Inc., Astellas, Prime Therapeutics, UCB, Roche/Genentech, Alexion, MedImmune/Viela Bio, Arialys Therapeutics, and F. Hoffman/LaRoche AG; has received research supports from Grifols, NIH, Viela Bio/MedImmune/Horizon, Alexion Pharmaceuticals, F. Hoffman/LaRoche/Genentech, NovelMed, AstaZeneca; has received intellectual property interests from a discovery or technology relating to health care. These were not relevant to the study.

Dr. Flanagan has served on advisory boards for Alexion, Genentech, Horizon Therapeutics and UCB; has received research support from UCB; has received speaker honoraria from Pharmacy Times; received royalties from UpToDate; was a site primary investigator in a randomized clinical trial on Inebilizumab in neuromyelitis optica spectrum disorder run by Medimmune/Viela-Bio/Horizon Therapeutics; has received funding from the NIH (R01NS113828); is a member of the medical advisory board of the MOG project; is an editorial board member of the Journal of the Neurological Sciences and Neuroimmunology Reports. A patent has been submitted on DACH1-IgG as a biomarker of paraneoplastic autoimmunity. These were not relevant to the study.

Dr. Chen is a consultant to Horizon and UCB, but this was not relevant to the study.

P417/1359

Comparison of Vision-Related Quality of Life in AQP4+ NMOSD and MOGAD

Adnan A. Gassan¹, Andrea Konig², Rosane Nisenbaum³, Mark S. Freedman⁴, Liesly Lee³, Ruth Ann Marrie⁵, Jennifer McCombe⁶, Jonathan Micieli³, Sarah Morrow⁷, Natalie Parks⁸, Penelope Smyth⁶, Dalia L. Rotstein³

¹Royal College of Surgeons in Ireland, Dublin, Ireland, ²Unity Health Toronto, Toronto, Canada, ³University of Toronto, Toronto, Canada, ⁴University of Ottawa, Ottawa, Canada, ⁵University of Manitoba, Winnipeg, Canada, ⁶University of Alberta, Edmonton, Canada, ⁷Western University, London, Canada, ⁸Dalhousie University, Halifax, Canada

Introduction: Aquaporin-4 antibody positive neuromyelitis spectrum disorder (AQP4+ NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD) are both associated with vision loss due to optic neuritis (ON), although this is felt to be more severe in NMOSD. The validated National Eye Institute Visual Function Questionnaire (NEI-VFQ) may be used to evaluate patients’ perceptions of how vision impairment affects their lives.

Objectives/Aims: To compare vison-related quality of life in AQP4+ NMOSD and MOGAD using the NEI-VFQ.

Methods: Participants with AQP4+ NMOSD and MOGAD, 18 years of age and older, were enrolled through the Canadian NMOSD and other atypical demyelinating diseases cohort study (CANOPTICS) at six Canadian centres and consented to enter the patient-reported outcomes sub-study. NEI-VFQ was completed by the participants at study entry. We compared composite VFQ scores and subscale scores in all of those with NMOSD versus MOGAD, those with history of any ON, and those with history of bilateral simultaneous ON. We used a linear regression model to evaluate the association of NEI-VFQ composite score with disease type (NMOSD versus MOGAD), age, sex, disease duration, history of unilateral ON, history of bilateral ON, and visual functional system score (FSS).

Results: There were 58 NMOSD participants, 49 (84.5%) female, mean age 48.6 (14.8) years, and 42 MOGAD participants, 27 (64.3%) female, mean age 45.2 (15.1) years. Thirty-five (60.3%) with NMOSD had history of any ON and 11 (19.0%) of bilateral ON. For MOGAD, 30 (71.4%) had history of any ON and 14 (33.3%) of bilateral ON. Mean (SD) VFQ composite scores were 82.2 (17.9) in NMOSD and 83.7 (17.6) in MOGAD for the full cohort; 75.0 (19.9) in NMOSD and 80.4 (18.7) in MOGAD for those with any history of ON; and 70.2 (25.6) in NMOSD and 74.9 (21.8) in MOGAD for bilateral ON. Composite scores did not differ significantly between participants with NMOSD and MOGAD in the full cohort or ON sub-groups. History of bilateral ON (β=-13.2, p=0.0008) and visual FSS (β=-4.9, p<0.0001) were significant predictors of VFQ composite score.

Conclusion: In this Canadian multi-centre cohort, vision related-quality of life was impaired in both NMOSD and MOGAD, without significant differences observed in scores, despite neurologists’ views of MOGAD as being more benign. Frequency of ON, and particularly bilateral ON, in MOGAD, and the impact of bilateral ON on vision-related quality of life, may help to explain these findings.

Disclosure of interest: A. Gassan has nothing to disclose.

A. Konig has nothing to disclose.

R. Nisenbaum has nothing to disclose.

M.S. Freedman has received research or educational grants from Sanofi-Genzyme Canada. He has received honoraria or consultation fees from Alexion, Atara Biotherapeutics, Bayer Healthcare, Beigene, BMS (Celgene), EMD Inc., Hoffman La-Roche, Janssen (J&J), Merck Serono, Novartis, Sanofi-Genzyme, and Teva Canada Innovation. He has served as a member of an advisory board or board of directors for Alexion, Atara Biotherapeutics, BayerHealthcare, Beigene, BMS (Celgene), Celestra, Hoffman La-Roche, Janssen (J&J), McKesson, Merck Serono, Novartis, Sanofi-Genzyme. He has participated in a speaker’s bureau for Sanofi-Genzyme and EMD Serono.

L. Lee is a co-investigator on studies receiving funding from Novartis, Roche Canada and Sanofi Canada.

R.A. Marrie receives research funding from: CIHR, Multiple Sclerosis Society of Canada, Multiple Sclerosis Scientific Research Foundation, Crohn’s and Colitis Canada, National Multiple Sclerosis Society, CMSC, the Arthritis Society and the US Department of Defense, and is a co-investigator on studies receiving funding from Biogen Idec and Roche Canada

J. McCombe has received consulting fees from Roche, Biogen, Novartis and Genzyme.

J. Micieli

S.A. Morrow in the last 3 years, has served as an advisory board member or received consulting fees from Biogen Idec; BMS/Celgene; EMDSerono; Novartis; Roche; Sanofi. She has participated in a speaker’s bureau for Biogen Idec; BMS/Celgene; EMDSerono; Novartis; Roche; Sanofi. She has received research support from Biogen Idec; EMDSerono, Novartis, Roche; Sanofi Genzyme. She has participated as a site investigator in clinical trials sponsored by Bristol Myers Squibb/Celgene; EMDSerono; Novartis; Roche; Sanofi.

N.E. Parks has received honoraria and consulting fees from Biogen, Bristol Myers Squibb, EMD Serono, Novartis, Roche, and Sanofi Genzyme.

P. Smyth has received research funding from MS Society of Canada. She is a co-investigator on studies receiving funding from Biogen Idec. She has received honoraria and consulting fees from Novartis, Roche, Sanofi-Genzyme, EMD Serono, Biogen-Idec, Genzyme, and Bristol-Myers Squibb.

D.L. Rotstein has received research support from MS Canada, the National MS Society, CMSC, University of Toronto Division of Neurology, and Roche Canda. She has received speaker or consultant fees from Alexion, Biogen, EMD Serono, Novartis, Roche, and Sanofi Aventis.

P418/208

Myelin Oligodendrocyte Glycoprotein (MOG) Antibody Disease and MOG Testing Landscape in Canada

Jodie Burton¹, Saerom Youn², Abdullah Al-Ani³, Fiona Costello⁴

¹University of Calgary, Clinical Neurosciences, Community Health Sciences, Calgary, Canada, ²University of Calgary, Calgary, Canada, ³University of Calgary, Surgery (Ophthalmology), Calgary, Canada, ⁴University of Calgary, Clinical Neurosciences, Surgery (Ophthalmology), Calgary, Canada

Introduction: The story of Myelin Oligodendrocyte Glycoprotein Antibody Disease (MOGAD), a more recently recognized central nervous system demyelinating disease that is distinct from Multiple Sclerosis (MS) and Neuromyelitis Optica Spectrum Disorder (NMOSD), continues to be written. Newly discovered presentations improve our ability to identify and treat patients, but we do not have a formal grasp of the Canadian experience.

Objectives/Aims: We aimed to identify all patients in Alberta tested for MOG (and aquaporin-4 or AQP4) since the MOG assay became cell-based in 2017, with objectives including of evaluating prevalence of MOGAD and NMOSD, the demographics of the disease in our province, common phenotypes and titers, trends in monitoring/retesting, and common mimics.

Methods: In Alberta, essentially all MOG assays (fixed, cell-based) are performed by MitogenDx through Alberta Precision Labs. A data pull of all tests identified as NMO, neuromyelitis optica, AQP4, aquaporin-4, MOG, and myelin oligodendrocyte glycoprotein, was undertaken from July 2017 (when MOG became a cell-based assay) through October 2022. Results were statistically analyzed with Microsoft® Excel and GraphPad Prism v9.5.1

Results: There were 7654 assays in 3304 people (6947 serum, 706 cerebrospinal fluid). Mean age was 39.9y (0.75-95.85y, IQR 23.07y). There were 47 AQP4 positive results in 39 patients of 3266 tested (1.4% positive, mean age 46.0y, 33F:6M) and 162 MOG positive patients in 3135 tested (5.2% positive, mean age 37.8y, 87F:75M). The mean age of MOG- patients was 41.1y (p=0.017). Only 64 (39.5%) MOG positive patients were re-tested, 19 of whom sero-reverted. MOG positive phenotypes were predominantly recurrent/bilateral optic neuritis (46/162), optic neuritis (33/162), longitudinally extensive transverse myelitis and/or transverse myelitis (46/162). Of the 87/162 weak positive MOG patients, 16 received a diagnosis of MOGAD, while over half had an unrelated final diagnosis if any.

Conclusion: MOG patient demographics in Canada resemble those seen in other populations, with positive test patients significantly younger than negative ones. Positivity rates have increased over time owing in part to greater recognition, although recommended retesting is not performed frequently. Unsurprisingly, weak titers remain a challenge, requiring clinical context and assay refinement.

Disclosure of interest: Dr. Burton has participated in advisory boards and received honoraria for speaking engagements from Roche, Novartis, Biogen and Alexion.

P419/647

Clinical feature and disease outcome in patients with myelin oligodendrocyte glycoprotein antibody-associated disorder: a Chinese study

Jingzi ZhangBao¹, Wenjuan Huang¹, Chao Quan¹

¹Huashan Hospital, Shanghai Medical College, Fudan University, Department of Neurology, Shanghai, China

Introduction: Myelin oligodendrocyte glycoprotein antibody (MOG-ab) -associated disorder (MOGAD) is currently considered a distinct entity of demyelinating disease of the central nervous system. Factors associated with a relapsing type, frequent relapses, and poor disability outcome in MOGAD are not consistently defined.

Objectives/Aims: To identify factors associated with relapse risk and disability in myelin oligodendrocyte glycoprotein antibody (MOG-ab)-associated disorder (MOGAD).

Methods: Between 2016 and 2021, 186 patients with MOGAD were included in the study. Factors associated with a relapsing course, annualized relapse rate (ARR), recurrent relapses under different maintenance treatments, and unfavorable disability outcome were analyzed.

Results: MOGAD affects females (53.8%) slightly more often than males. After a median disease duration of 51.0 months, 60.2% (112/186) relapsed, with an overall ARR of 0.5. The ARR (0.6 vs 0.4, p=0.049), median Expanded Disability Status Scale (EDSS) score (1 [range 0-9.5] vs 1 [range 0-3.5], p=0.005) and Visual Functional System Score (VFSS) (0 [range 0-6] vs 0 [range 0-3], p=0.023) at last visit were higher in adults than in children, and time to first relapse was shorter in adults than in children (4.1[range 1.0-111.0] vs 12.2 [range 1.3-266.8] months, p=0.001). MOG-ab persistence over 1 year was associated with a relapsing course (odds ratio [OR] 7.41, 95% confidence interval [CI] 2.46-22.33, p=0.000), while timely maintenance therapy was associated with a lower ARR (p=0.008). More than 4 attacks (OR=4.86, 95%CI 1.65-14.28, p=0.004) and poor recovery from the first attack (OR=75.28, 95%CI 14.45-392.05, p=0.000) were associated with an unfavorable outcome (EDSS score⩾2 including VFSS⩾2).

Conclusion: The results underscored the importance of timely maintenance treatment to prevent further relapses, especially in adult patients with persistently positive MOG-ab and unsatisfactory recovery from the onset attack.

Disclosure of interest: Jingzi ZhangBao: nothing to disclose.

Wenjuan Huang: nothing to disclose.

Chaoquan: nothing to disclose.

P420/1429

Diagnosis of Epilepsy Following MOGAD in Paediatric Patients

Karla Salazar^1,2, Jonathan Yarimi^1,2, Varun Kannan^1,2, Victoria Hardwick^1,2, Nikita Shukla^1,2, Tim Lotze^1,2, Kristen Fisher^1,2

¹Baylor College of Medicine, Houston, United States, ²Texas Children's Hospital, Houston, United States

Introduction: Myelin Oligodendrocyte glycoprotein antibody disease (MOGAD) is associated with multiple clinical presentations including encephalitis, acute disseminated encephalomyelitis (ADEM), optic neuritis, transverse myelitis, and others. Seizures may be present in patients with MOGAD, but little is known regarding the development of an epilepsy diagnosis following MOGAD.

Objectives/Aims: To define clinical characteristics of a cohort of paediatric patients with MOGAD who were subsequently diagnosed with epilepsy.

Methods: Patients under age 18 who met the 2023 diagnostic criteria for MOGAD were included in a retrospective analysis. Clinical and demographic data points were collected. Patients who continued to have unprovoked seizures after acute presentation were labelled with epilepsy. Acute symptomatic seizures were defined as seizures during initial presentation but none further after discharge. Magnetic Resonance Imaging (MRI) findings were categorized into 4 phenotypes: ADEM, tumefactive, FLAIR-hyperintense Lesions in Anti-MOG related Encephalitis with Seizures (FLAMES), and other.

Results: Of 88 MOGAD patients, 21 presented with acute symptomatic seizure (24%). Seven patients (33% of those with seizure at onset, 8% of overall cohort) went on to receive a diagnosis of epilepsy, of which three had drug resistant epilepsy. Initial presentation of status epilepticus was more common in those who were given an epilepsy diagnosis (71.4%) in comparison to those with solely acute symptomatic seizures (28.5%). Epilepsy diagnosis was more frequently seen in those presenting with FLAMES (42.8%) and tumefactive MOG (28.6%), and additionally more frequent in comparison to those of the same clinical phenotype presenting with acute symptomatic seizures (50% and 66.7% respectively). Comparatively, 8 patients (20%) with ADEM presented with acute symptomatic seizures, but only one patient (2.5%) was given an epilepsy diagnosis.

Conclusion: This study highlights the need for further investigation of paediatric MOGAD to determine predictors of epilepsy diagnosis. Our study suggests a 33% risk of epilepsy diagnosis if presenting with acute symptomatic seizures. In addition, those with MRI findings of FLAMES and tumefactive MOG may be at further increased risk in comparison to other clinical phenotypes. This limited data can help provide possible guidance in epilepsy risk for paediatric MOGAD patients and families.

Disclosure of interest: Karla Salazar: nothing to disclose

Jon Yarimi: nothing to disclose

Varun Kannan: nothing to disclose

Victoria Hardwick: nothing to disclose

Nikita Shukla: nothing to disclose

Tim Lotze: nothing to disclose

Kristen Fisher: nothing to disclose

P421/1709

The Neutrophil-to-lymphocyte ratio is a marker of acute inflammation but does not predict relapses or disease severity in a UK cohort of people with MOGAD and NMOSD

Maha Salman¹, Athanasios Papathanasiou², Aimee Hibbert², Bruno Gran^2,3, Cris Constantinescu³, Nikos Evangelou^2,3, Radu Tanasescu^2,3

¹School of Medicine, University of Nottingham, Nottingham, United Kingdom, ²Nottingham University Hospitals, Department of Neurology, Nottingham, United Kingdom, ³School of Medicine, University of Nottingham, Academic Clinical Neurology, Nottingham, United Kingdom

Introduction: Neutrophil-to-lymphocyte ratio (NLR) is a blood marker of systemic inflammation. Two studies from China have recently proposed NLR as biomarker of disease severity in people with oligodendrocyte glycoprotein associated disease (MOGAD) and neuromyelitis optica spectrum disorder (NMOSD), with higher NLR in NMOSD compared to MOGAD.

Objectives/Aims: To assess if NLR predicts relapse risk and worse disability in a group of patients with MOGAD and NMOSD from the East Midlands of England.

Methods: We extracted demographic, clinical and biology data of people with MOGAD and NMOSD aquaporin4 IgG positive, attending the NMOSD/MOGAD specialist clinic at the Queen’s Medical Centre in Nottingham, UK. We compared NLR in relapse and remission, and how NLR correlates with relapse rate, risk of early relapses (<6 months, considered marker of risk of recurrence in MOGAD), disease course (monophasic vs relapsing), and disability accumulation (EDSS). Two-tailed student t-test, Mann-Whitney U test, Chi-Square or Fisher's exact tests were used for detecting the differences. Receiver operator curve (ROC) analysis was used to assess the ability of NLR to distinguish between MOGAD and NMOSD aquaporin4 IgG positive. Binary logistic regression analysis was used to evaluate potential risk factors for disease recurrence. Estimates of the probability of relapse were obtained using a univariate Cox Proportional Hazards model.

Results: We collected data of 28 patients with MOGAD (16 women; average age 33.4y; 13 relapsing MOGAD) and 37 patients with NMOSD AQP4IgG+(33 women; average age 45y) with a mean duration of follow-up of 8.6y (median 7.5y) and 9.8y (median 6.8y) respectively. NLR was higher in relapse than in remission in both MOGAD and NMOSD, but did not differentiate between the two conditions. NLR at disease onset had no predictive value in discerning the event of relapse < 6 months from onset. NLR at diagnosis (at first attack) or in remission had no association with the event of first relapse after diagnosis, number of relapses and disability accumulation for any of the two conditions, and could not differentiate between monophasic and relapsing forms of MOGAD.

Conclusion: NLR is merely a marker of acute inflammation in MOGAD and NMOSD and cannot serve as predictor for risk of relapse or disability accumulation.

Disclosure of interest: Radu Tanasescu received support from the UK MRC (CARP MR/T024402/1).

The other authors have nothing to disclose related to this work.

P422/95

Coping Strategies of NMOSD and MOGAD Affected Persons with a Sociological and Psychological Focus (CoMMOnsense)

Anna Walz¹, Daria Tkachenko¹, Julian Reza Kretschmer¹, Martin W. Hümmert¹, Tanja Zimmermann², Corinna Trebst¹

Study Group: Neuromyelitis optica study group (NEMOS)

¹Hannover Medical School, Department of Neurology, Hannover, Germany, ²Hannover Medical School, Department of Psychosomatics and Psychotherapy, Hannover, Germany

Introduction: Neuromyelitis optica spectrum disorders (NMOSD) and MOG antibody associated diseases (MOGAD) are rare autoimmune mediated diseases of the central nervous system, which can lead to permanent physical limitations as well as psychological distress. A reduced quality of life, depression and emotional distress are common. How patients and their partners cope with the disease is still unclear. However, it is already known from oncology and transplantation medicine that the way of coping with the disease is changeable and relevant for the health outcome.

Objectives/Aims: The identification of risk factors for efficient coping with the disease in order to be able to offer assistance in coping with the disease in the clinical setting.

Methods: This is an ongoing prospective, multicenter, two-armed study in the form of a questionnaire survey. The survey includes disease specific data extracted from the Neuromyelitis optica study group (NEMOS) registry (Expanded Disability Status Scale (EDSS), duration of disease, etc.) and psychosocial (depression, anxiety, fear of progression, etc.) aspects as well as individual coping strategies (Hamburg Coping Inventory) and dyadic coping strategies (Dyadic Coping Inventory). In addition to data collection in Hannover, recruitment in other German centers of the NEMOS group will take place in the course of the project. Simultaneously, socio-demographic and disease-related data from the NEMOS register will be linked with the newly collected coping data of this study.

Results: By March 2023, a total of 41 patients had been recruited in Hannover. Of these, 23 patients had a confirmed MOGAD (40.43 +/- 14.55 years; 56.5% female) and 18 patients had a NMOSD (53.5 +/- 15.5 years; 72.2% female). In the psychosocial parameters, the Hannover sample showed a depression score (PHQ-9) of (10.22 +/- 6.28) and an anxiety score (GAD-7) of (7.83 +/- 4.42) in MOGAD patients. In NMOSD patients, depression (PHQ-9) scored (6.17 +/- 4.2) and anxiety (GAD-7) (5.56 +/- 4.49).

Conclusion: The CoMMOnsense study addresses the unmet need for knowledge on the topic of disease management in patients with the rare disease of NMOSD and MOGAD. Depending on the coping type, a new clinical approach can be adapted for our patients.

Disclosure of interest: AW: has nothing to disclose.

DT: has nothing to disclose.

JRK: has nothing to disclose.

MWH: received research support from Myelitis e. V.

TZ: has nothing to disclose.

CT: has received honoraria for consultation and expert testimony from Alexion Pharma Germany GmbH, and Roche Pharma GmbH. None of this interfered with the current report.

P423/1106

Assessing the performance of cell based assays for MOGAD in the real world setting of a resource poor region - Impact of the international MOGAD diagnostic criteria

Lekha Pandit¹, Anitha D'Cunha², Chaithra Malli², Akshatha Sudhir²

¹Nitte University, Center For Advanced Neurological Research, Mangalore, India, ²Nitte University, Mangalore, India

Introduction: Diagnostic criteria for MOGAD includes a typical clinical phenotype, clear positive MOG antibody( IgG) titer by cell based assay (CBA) and additional clinical and MRI features if assay titers are low. In resource poor settings, commercial fixed CBA (FCBA) alone is available with testing in 1:10 dilution. Additional dilutions required for clear positive titers ( ⩾1:100) adds to the cost of “out of pocket” spending.

Objectives/Aims: To evaluate the performance of FCBA against a live CBA (LCBA) in the background of new criteria, in a real world setting

Methods: From our registry, 257 consecutive patients with a MOGAD phenotype were included. Clinical and MRI features were obtained. Serum samples were anonymized and tested in serial dilutions using both FCBA and “in house” LCBA. Agreement between assays and diagnostic sensitivity was evaluated.

Results: Among paired samples tested on both platforms, 117 were positive and 139 negative for both methodologies (Cohen’s Kappa 0.97 [0.00- 0.01], Spearman correlation coefficient - 0.976, p-<0.001). By FCBA, 87 samples were clear positive and 30 (25.6%) were low positive. Twenty of the latter tested positive in 1:80, 7 in 1:40 and 3 in 1:10 dilutions. In this low titer group, 28 patients satisfied additional clinical and or MRI criteria for MOGAD diagnosis. Inclusion of supportive features improved diagnostic sensitivity by 12% and final diagnosis was comparable between assays. There was good correlation between low titers on FCBA and high titers on LCBA.

Conclusion: Overall there was excellent agreement in performance between FCBA in standard 1:10 serum dilution and LCBA in a real world setting. Careful patient selection and matching for supportive criteria among those with low titers on FCBA, allowed for a cost effective and sensitive diagnosis of MOGAD in our resource poor setting.

Disclosure of interest: Lekha Pandit -Nothing to disclose

Anitha DCunha- Nothing to disclose

Chaithra Malli- Nothing to disclose

Akshatha Sudhir- Nothing to disclose

P424/2362

Depression and Cognition in Multiple Sclerosis: Longitudinal Evidence of a Specific Link to Executive Control

Jordyn Anderson¹, Kathryn Fitzgerald², Ilana Katz Sand¹, James Murrough¹, Tali Sorets³, Stephen Krieger¹, Claire Riley⁴, Michelle Fabian¹, James Sumowski¹

¹Icahn School of Medicine at Mount Sinai, Neurology, New York, United States, ²Johns Hopkins University, Baltimore, United States, ³Feinberg School of Medicine, Northwestern University, New York, United States, ⁴Columbia University Irving Medical Center, New York, United States

Introduction: Depression is highly prevalent in MS and is associated with worse cognition in cross-sectional studies. Prospective longitudinal designs are needed to examine whether cognition and depression co-vary over time within persons with MS. Based on our results at baseline we hypothesized that change in depression would be most strongly related to change in executive control of attention.

Objectives/Aims: To investigate the impact of change in depression on cognition in persons with multiple sclerosis (MS).

Methods: The RADIEMS longitudinal cohort study enrolled 185 people with early relapse-onset MS at baseline (Y0). Current analyses used Y0 and three-year follow up (Y3) data; 165 patients completed all Y3 tasks and were included for analysis. Patients completed the Beck Depression Inventory, Fast Screen (BDI-FS) and were classified as depressed (BDI-FS⩾4) or non-depressed (BDI-FS <4) at Y0 and Y3. Interval depression change was coded as worsened, improved, or stable. Patients were given a battery of cognitive tests used to derive composite scores of cognitive speed (e.g., Decision Speed), executive control (e.g., Stroop Color Word Test), and memory (e.g., Selective Reminding Test), as well as a high-sensitivity cognitive screener (Symbol Digit Modalities Test, SDMT). Analyses used one-way ANOVAs to assess differences in cognitive change across depression groups.

Results: Change in depression status was related to changes in executive control (p=0.002, η_p²=0.07) and executive control adjusted for cognitive speed (p=0.004, η_p²=0.06); worsened depression was linked to worsened executive control, and improved mood was linked to improved executive control. Depression change was not related to changes in cognitive speed (p=0.825, η_p²=0.00), memory (p=0.278, η_p²=0.02), or SDMT (p=0.633, η_p²=0.01). Findings remained when adjusting for interval changes in fatigue and anxiety. We also explored links between changes in executive control and individual symptoms of depression: executive control was most related to loss of pleasure and suicidal thoughts.

Conclusion: Findings support our understanding of depression as a modifiable risk factor within our model of reserve against disability in MS; improved mood may improve cognition. Additionally, results advance our understanding of MS depression as a distinct entity and the nature of its link to cognition, which appears specific to executive control of attention. Results align with a model of MS depression based in dysfunctional reward processing and anhedonia.

Disclosure of interest: Jordyn Anderson: nothing to disclose.

Kathryn Fitzgerald: nothing to disclose.

Ilana Katz Sand: nothing to disclose.

James Murrough: consultation services and/or served on advisory boards for Boehreinger Ingelheim, Clexio Bio-sciences, FSV7, Global Medical Education (GME), Otsuka, and Sage Therapeutics

Tali Sorets: nothing to disclose

Stephen Krieger: consulting or advisory work with Biogen, EMD Serono, Genentech, Genzyme, Mallinckrodt, MedDay, Novartis, Teva, and TG Therapeutics, nonpromotional speaking with Biogen, EMD Serono, Genentech, and Novartis, and grant and research support from Biogen and Novartis.

Claire Riley: personal fees from Teva Neuroscience, personal fees from Genzyme Sanofi, personal fees from Genentech, personal fees from Celgene, personal fees from Biogen Idec, personal fees from EMD Serono

Michelle Fabian: nothing to disclose

James Sumowski: nothing to disclose.

P425/2153

Cognitive phenotypes and response to restorative cognitive rehabilitation in multiple sclerosis: a post-hoc analysis of the RRCR study

Stefano Ziccardi¹, Tom Fuchs², Michael Dwyer², Robert Zivadinov², Hanneke Hulst^3,4, Massimiliano Calabrese¹, Ralph Benedict⁵

¹University of Verona, Neurology Section, Department of Neurosciences, Biomedicine and Movement Sciences, Verona, Italy, ²Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United States, ³Vrije Universiteit Amsterdam, MS Center Amsterdam, Anatomy and Neurosciences, Amsterdam Neuroscience, Amsterdam UMC Location VUmc, Amsterdam, Netherlands, ⁴Leiden University, Institute of Psychology, Health, Medical and Neuropsychology Unit, Leiden, Netherlands, ⁵University of Buffalo, Jacobs School of Medicine and Biomedical Sciences, Department of Neurology and Psychiatry, Buffalo, NY, United States

Introduction: Specific patterns of cognitive deficits can be detected in people with multiple sclerosis (pwMS) (i.e. cognitive phenotypes) and have been suggested to tailor rehabilitation strategies. We recently identified clinical/MRI predictors of response to restorative cognitive rehabilitation (RRCR). However little is known about treatment response in pwMS with different cognitive phenotypes.

Objectives/Aims: To explore a wider range of cognitive outcomes and relationships with baseline neuropsychological performance, in order to identify which pwMS benefit most from treatment considering baseline cognitive phenotypes.

Methods: 51 pwMS were tested before and after a home-based restorative cognitive training (BrainHQ) with the Brief International Cognitive Assessment for MS (BICAMS) and tests from the Delis-Kaplan Executive Function System (DKEFS). A threshold of -1 standard deviations (SD) for z-scores of cognitive tests was considered: pwMS were classified as preserved (all tests above -1SD) or impaired (at least one test below -1SD). Cognitive phenotypes were computed considered performance in three domains of memory, attention/information processing speed, and executive function: single-domain impairment (failed tests in only one domain), bi-domain impairment (failed tests in two domains), or multi-domain impairment (failed tests in all three domains). Regression analyses investigated for each test the association between pre-post intervention change and baseline cognitive performance. Analyses of covariance (ANCOVA) compared pre-post change in each test among pwMS with different cognitive phenotypes, accounting for presence of baseline impairment in that test and for treatment compliance.

Results: pwMS with lower baseline performance in verbal memory (p<0.001) and executive functions (p=0.002, p=0.004, p=0.047) tests exhibited higher improvement within those tests after cognitive training. Single-domain impaired pwMS showed the highest improvement after rehabilitation in the DKEFS card sorting test subscores (p<0.001, p=0.04), with a significantly greater benefit than multi-domain impaired pWMS.

Conclusion: Results highlight the importance of an early neuropsychological approach to identify slight cognitive alterations that can be treated before the impairment is excessively broad and hardly recoverable. The identification of cognitive phenotypes may help clinicians provide a prompt cognitive rehabilitation to pwMS best suited for treatment and thus to maximize the training effect.

Disclosure of interest: Stefano Ziccardi and Tom A. Fuchs have nothing to disclose.

Michael G. Dwyer received grant support from Novartis, Bristol Myers Squibb, Mapi Pharma, Merck Serono, Keystone Heart Ltd., Protembis GmbH, and V-Wave Ltd., and consulting fees Bristol Myers Squibb, Merck Serono, and Keystone Heart Ltd.

Robert Zivadinov has received personal compensation from Bristol Myers Squibb, EMD Serono, Sanofi, Janssen, Sanofi, 415 Capital, Filterlex and Mapi Pharma for speaking and consultant fees. He received financial support for research activities from Novartis, Bristol Myers Squibb, EMD Serono, Octave, Mapi Pharma, CorEvitas, Protembis and V-WAVE Medical.

Hanneke E. Hulst is an editor of the Multiple Sclerosis Journal controversies sections, receives research support from the Dutch MS Research Foundation and the Dutch Research Council. She has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Novartis, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, MedDay and Merck BV.

Massimiliano Calabrese received honoraria for research or speaking and funds for travel from Roche, Sanofi-Genzyme, Merck-Serono, Biogen Idec, Teva and Novartis Pharma.

Ralph H. B. Benedict received research support from Biogen, Bristol Meyers Squibb, Novartis, National Institute of Health, and National Multiple Sclerosis Society; consultant fees from Bristol Meyers Squibb, Novartis, Roche, Sanofi; speaking fees from Bristol Meyers Squibb, EMD Serono; royalties for Psychological Assessment Resources.

P426/2272

Social cognition deficits are present in multiple sclerosis since the time of diagnosis and rely on specific neural substrates

Stefano Ziccardi¹, Helen Genova^2,3, Maddalena Guandalini¹, Agnese Tamanti¹, Elisa Colato¹, Massimiliano Calabrese¹

¹University of Verona, Neurology Section, Department of Neurosciences, Biomedicine and Movement Sciences, Verona, Italy, ²Kessler Foundation, East Hanover, NJ, United States, ³Rutgers University, New Jersey Medical School, Newark, NJ, United States

Introduction: Cognitive and affective symptoms in multiple sclerosis (MS) can be independently impaired and have different pathways of progression. Cognitive alterations have been described since the earliest MS stages; by contrast, social cognition (SC) domain has never been investigated in the first year from MS diagnosis.

Objectives/Aims: To evaluate social cognition and to unravel its neural bases in newly diagnosed MS patients.

Methods: 70 MS patients underwent at the time of diagnosis both a SC assessment (median months between diagnosis and cognitive evaluation = 0 [range 0-12]) and a 3T MRI scan (median months between diagnosis and MRI = 0 [range 0-6]). The SC protocol included a facial emotion recognition test (Test of Facial Emotion Recognition – Kessler Foundation; TOFER-KF), a theory of mind test (Reading the Mind in the Eyes test; RME), and a measure of empathy (Empathy Quotient; EQ). For each SC task, we divided the sample in lower performers and higher performers, based on scores below or above the average of the sample. We also tested two matched reference samples: 31 relapsing-remitting MS patients with a longer MS course, and 38 healthy controls (HCs). FreeSurfer and FSL-FIRST were used to analyze the 3T MRI metrics and to calculate cortical thicknesses (CTh) and volumes of brain regions/structures from the T1 weighted images. Statistical analyses were conducted using t-tests/Mann-Whitney tests, depending on normality distribution.

Results: MS patients at diagnosis performed significantly lower than HCs in TOFER-KF (global: p<0.001; happiness: p=0.041, anger: p=0.007, fear: p<0.001, disgust: p=0.004), and in RME (p=0.005). Interestingly, no significant difference was found in all SC measures between patients at diagnosis and with a longer MS course. Compared to lower performers, higher performers in TOFER-KF showed greater volume of amygdala (p=0.032) and caudate (p=0.036); higher performers in RME showed greater CTh in lingual gyrus (p=0.006), cuneus (p=0.024), isthmus cingulate (p=0.038), and greater volumes of putamen (p=0.016), pallidum (p=0.029), amygdala (p=0.032); higher performers in EQ showed lower total intracranial volume (p=0.039), lower cuneus CTh (p=0.042), and lower putamen volume (p=0.007).

Conclusion: SC deficits are present since the time of diagnosis in MS patients and remain persistent along the MS course. Results also highlighted that specific basal ganglia, limbic structures, and parieto-occipital areas play a significant role in the pathogenesis of these alterations.

Disclosure of interest: Stefano Ziccardi, Helen M. Genova, Maddalena Guandalini, Agnese Tamanti and Elisa Colato have nothing to disclose.

Massimiliano Calabrese received honoraria for research or speaking and funds for travel from Roche, Sanofi-Genzyme, Merck-Serono, Biogen Idec, Teva and Novartis Pharma.

P427/1271

Comparison of Oral, Oral Hands-Free, Tablet-Based Versions of the Symbol Digit Modalities Test (SDMT) for Use in Patients with Impaired Hand Motor Functions

Jiri Motyl¹, Daniela Nova², Michaela Andelova¹, Lucie Friedova¹, Jana Ambrozova², Danuta Sliwkova², Karolina Vodehnalová¹, Dana Horakova¹, Tomas Uher¹

¹First Faculty of Medicine, Charles University and General University Hospital in Prague, Department of Neurology and Center of Clinical Neuroscience, Prague, Czech Republic, ²Centrum Paraple, o.p.s., Prague, Czech Republic

Introduction: Symbol Digit Modalities Test (SDMT) in its oral form of administration is the most sensitive measure to multiple sclerosis (MS)-related cognitive dysfunction. However, the instructions for oral administration are vague (e.g., do not clearly cover the topic of finger tracking) and thus may indirectly affect results of the assessment, most significantly in MS patients with weakened upper-limb functioning.

Objectives/Aims: To compare performance of classical oral, adapted handsfree and tablet-based versions of the SDMT.

Methods: In the SDMT-oral (SDMT-O) participants were asked to finger-track their position in the test, in the SDMT-oral-handsfree (SDMT-O-HF) the administrator tracked the position and pointed it to examinees, and in the CogEval approach we tested administration of the tablet-based equivalent of the SDMT. The study included two cohorts: 1) Healthy controls (HC) longitudinally monitored in the Prague MS center as part of the local normative cohort (study GAUK 1154218). Inclusion criteria included age 18-65 years and absence of other disease or medical condition that can influence cognitive performance. Firstly, HC (N=82, Mean Age=41.1[±10.5]) were assessed by the SDMT-O. At the end of the session (after 30 minutes), a half of the patients (N=37) was assessed by SDMT-O-HF (alternative form) and another half of the patients (N=44) by CogEval. 2) Para or tetra paretic/plegic patients of various etiologies from Paraple center who underwent a psychological examination in 2021 (N=95, Mean Age=45.8[±15.3]). SDMT-O-HF was administered to these patients as a part of their routine assessment. All individual scores were transformed into standardized z-scores accounting for age and education.

Results: The mean z-score for SDMT-O-HF in HC (z=-0.02[±1.08]) was slightly lower (t=2.25, p<0.05) than for SDMT-O (z=0.22[±0.9]). SDMT-O showed comparable results to CogEval (z=0.16[±0.69]; t=0.42, p=0.68). There was a difference (t=-6.21, p<0.001) in mean z-scores on SDMT-O-HF between HC and plegic/paretic population (z=-1.33[±1.09]). In HC, there was a strong positive correlation between SDMT-O and SDMT-O-HF z-scores (r=0.71, p<0.001) and no correlation between SDMT-O and CogEval z-scores (r=0.2, p=0.20).

Conclusion: SDMT-O-HF shows comparable results and functioning to classical SMDT-O administration and can be used in paretic/plegic patients or in bed-side conditions where the classical administration would be compromised. The poor association between SDMT-O and CogEval needs further assessment.

Disclosure of interest: This project was sponsored by GAUK project 1154218; National Institute for Neurological Research (Program EXCELES, ID project No LX22NPO5107) - funded by the European Union-Next Generation EU; Czech Ministry of Health project grants NV22-04-00193, RVO 64165; and Czech Ministry of Education - Cooperation, 1.LF, Neuroscience

Jiri Motyl received compensation for traveling, conference fees and speaker honoraria from Sanofi Genzyme, Biogen, Novartis and Merck.

Daniela Nova has nothing to disclose.

Michaela Andelova received financial support for conference travel from Novartis, Genzyme, Merck Serono, Biogen Idec and Roche.

Lucie Friedova has nothing to disclose.

Jana Ambrozova has nothing to disclose.

Danuta Sliwkova has nothing to disclose.

Karolina Vodehnalova received compensation for traveling, conference fees and consulting fees from Merck, Teva, Sanofi Genzyme, Biogen Idec, Novartis, Roche.

Dana Horakova received compensation for travel, speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche, and Teva, as well as support for research activities from Biogen Idec.

Tomas Uher received financial support for conference travel and honoraria from Biogen Idec, Novartis, Roche, Genzyme and Merck Serono, as well as support for research activities from Biogen Idec and Sanofi.

P428/1163

Quality-of-life changes in newly diagnosed people with Multiple Sclerosis are associated with cognitive reserve: an exploratory and longitudinal study

Manuela Altieri¹, Alvino Bisecco¹, Alessandro D' Ambrosio¹, Valentina Rippa¹, Rocco Capuano¹, Mario Risi¹, Riccardo Maria Borgo¹, Teresa Cuomo², Gioacchino Tedeschi¹, Gabriella Santangelo³, Antonio Gallo¹

¹University of Campania Luigi Vanvitelli, Department of Advanced Medical and Surgical Sciences, Naples, Italy, ²"Umberto I" Hospital, Department of Neurology, Nocera Inferiore, Italy, ³University of Campania Luigi Vanvitelli, Department of Psychology, Caserta, Italy

Introduction: The protective effect of cognitive reserve (CR) on cognition in Multiple Sclerosis (MS) has been confirmed in multiple studies. It is not clear, however, whether high CR may also counteract a decline of quality-of-life (QoL) over time in recently diagnosed people with MS (pwMS), as demonstrated in studies on older healthy adults.

Objectives/Aims: The aim of the study was to evaluate the effect of CR on changes in QoL at three years after the onset.

Methods: 55 newly diagnosed pwMS (women = 58.2%) underwent a neurological and neuropsychological evaluation at baseline (T0; at least 1 month after the onset) and follow-up (T1; at least 3 years from T0). At both time points the evaluation included: Symbol Digit Modalities Test (SDMT), Multiple Sclerosis Quality of Life-54 (MSQoL-54), Beck Depression Inventory II (BDI-II), State-Trait Anxiety Inventory (STAI-Y) to evaluate cognitive status, QoL, depressive and anxiety symptomatology, respectively. A repeated measures MANCOVA with Bonferroni correction for multiple comparison was performed. Within-subject factor was time (T0 vs T1), between-subject factor was CR (categorized in high [>13 years], medium [13 years] and low [<13 years] CR), whereas the dependent variables were each subscore of MSQoL-54. Covariates of the model included: sex, disease duration, EDSS, BDI-II, STAI-Y and SDMT.

Results: The MANCOVA revealed no significant main effects of CR or time on MSQoL-54 scores; however, an interaction effect between CR and time was found (Wilks’ Λ = .22, F_(32,48) = 1.721, p = .043, partial η² = .534). Univariate analysis showed that the CR*time interaction was significant for social function (p = .029), sexual function (p = .011), satisfaction with sexual function (p = .009) and overall QoL (p = .021), meaning that only pwMS with low CR showed a decline of these MSQoL-54 subscales at T1 evaluation.

Conclusion: CR may be a protective factor of QoL decline in newly diagnosed pwMS; low CR seems to be associated with a worse perception of their social and sexual functioning and to a more negative evaluation of one’s overall QoL levels at T1. These findings may support the hypothesis that CR may reflect the individual’s resilience not only to physical and cognitive damage, but also to changes on perception of social and sexual wellness. Future studies may further investigate this issue by including more proxies of CR and other psychological variables (e.g., coping strategies).

Disclosure of interest: Manuela Altieri, Alessandro d’Ambrosio, Valentina Rippa, Rocco Capuano, Mario Risi, Riccardo Maria Borgo, Teresa Cuomo, Gabriella Santangelo: nothing to disclose.

Alvino Bisecco: has received speaker honoraria and/or compensation for consulting service from Biogen, Merck and Genzyme.

Gioacchino Tedeschi: has received compensation for consulting services and/or speaking activities from Biogen, Novartis, Merck, Genzyme, Roche, Teva; and receives research support from Biogen Idec, Merck Serono, and Fondazione Italiana Sclerosi Multipla.

Antonio Gallo: has received honoraria for speaking and travel grants from Merck, Genzyme, Teva, Mylan, Roche and Novartis.

P429/1690

Cognitive Impairment in Multiple Sclerosis: Comparing Dual-Task Performance, Anxiety, Depression and Disability

Özge Sağıcı¹, Asiye Tuba Özdoğar², Cavid Baba³, Serkan Ozakbas³

Study Group: MS Research Group

¹Dokuz Eylul University, Graduate School of Health Science, Izmir, Turkey, ²Van Yüzüncü Yıl University, Department of Physiotherapy, Faculty of Health Sciences, Van, ³Dokuz Eylul University, Faculty of Medicine, Department of Neurology, Izmir, Turkey

Introduction: People with Multiple Sclerosis (MS, pwMS) commonly experience cognitive impairment (CI), which can have a negative impact on their functioning. There are various tests to assess CI in pwMS. The Multiple Sclerosis Neuropsychological Screening Questionnaire (MSNQ) is a self-reported scale that detects CI by evaluating neuropsychological competence. The Brief International Cognitive Assessment in Multiple Sclerosis (BICAMS) is a valid measurement method used to evaluate cognitive functions in pwMS.

Objectives/Aims: This study compares dual-task performance (DTP), anxiety, depression, disease duration (DD), and disability level between cognitively impaired pwMS (as determined by the MSNQ and BICAMS) and cognitively unimpaired pwMS.

Methods: Five-hundred and thirty-one pwMS and age-education level matched 348 healthy controls (HC) were enrolled. Neuropsychological competence was assessed using MSNQ. pwMS with a score of 23 and above on the MSNQ were considered positive for CI, while those below 23 were negative. BICAMS battery includes three subtests: Symbol Digit Modalities Test (SDMT), California Verbal Learning Test-II (CVLT-II), and Brief Visuospatial Memory Test-Revised (BVMT-R). pwMS who were 1.5 standard deviations below the mean score of the HC in at least one of the BICAMS subtests were considered to have CI. pwMS who had CI on BICAMS or MSNQ tests were recorded as cognitively impaired. DTP was evaluated with the Timed Up and Go (TUG) test and included a cognitive task (3 counting backwards from 50) added to the standard TUG test. Disability was assessed with Expanded Disability Status Scale (EDSS), anxiety and depression levels with The Hospital Anxiety and Depression Scale (HAD).

Results: According to the MSNQ and BICAMS, 273 (51.4%) had CI. The cognitively impaired pwMS had higher anxiety (8.72±4.81;5.43±3.91) (p<0.001) and depression (7.04±4.08; 4.17±3.43) (p=0.012) levels and higher disability levels (1.55±1.46; 0.61±1.09) (p<0.001) compared to the cognitively unimpaired pwMS. There was no difference in disease duration and DTP between the groups (p>0.05)

Conclusion: This study showed that CI is important in terms of disability and mood. In the study, a simple cognitive task was given during the DTP. It is possible that more complex cognitive tasks could reveal differences in performance between cognitively impaired and unimpaired pwMS.

Disclosure of interest: Özge Sağıcı: nothing to disclose

Asiye Tuba Özdoğar: nothing to disclose

Cavid Baba: nothing to disclose

Serkan Ozakbas: nothing to disclose

P430/2068

The Impact of Information Processing Speed Deficits on Visuospatial Memory in Multiple Sclerosis: Preliminary Results

Pauline Waskowiak^1,2,3, Suzanne De Jong^1,3, Ilse Nauta^2,3,4, Maureen van Dam^2,3,5, Sanne Driessen^1,3, Menno Schoonheim^2,3,5, Bernard Uitdehaag^2,3,4, Hanneke Hulst⁶, de Jong Brigit^2,3,4, Martin Klein^1,2,3

¹Amsterdam UMC location Vrije Universiteit Amsterdam, Medical Psychology, Amsterdam, Netherlands, ²Amsterdam Neuroscience, Neuroinfection &-inflammation, Amsterdam, Netherlands, ³MS Center Amsterdam, Amsterdam, Netherlands, ⁴Amsterdam UMC location Vrije Universiteit Amsterdam, Neurology, Amsterdam, Netherlands, ⁵Amsterdam UMC location Vrije Universiteit Amsterdam, Anatomy and Neurosciences, Amsterdam, Netherlands, ⁶Health, Medical and Neuropsychology Unit, Leiden University, Leiden, Netherlands

Introduction: People with Multiple Sclerosis (PwMS) often have impaired information processing speed (IPS). On several neuropsychological tests lower IPS may hamper test performance, which might not necessarily be the result of deficits in the domain being tested. For example, lower IPS has been shown to be associated with poorer visuospatial abilities. Regarding memory, however, it is unknown how IPS impairment is associated with the different learning and memory elements of a visuospatial memory test.

Objectives/Aims: To investigate the predictive value of IPS on the separate learning trials, delayed recall, retention, and recognition of the Brief Visuospatial Memory Test-Revised (BVMT-R) in PwMS.

Methods: In total, 100 PwMS (mean age=48.06±10 years; 62% female; MS type=72% relapsing remitting, 15% secondary progressive, 9% primary progressive, 4% unknown; mean disease duration=12.80±8.8 years; median EDSS=4.0 (interquartile range=1.0)) were selected from the MS Center Amsterdam Second Opinion MS and Cognition (SOMSCOG) outpatient clinic database. IPS and visuospatial memory were measured using the Symbol Digit Modalities Test (SDMT) and the BVMT-R, respectively. Hierarchical regression analyses were performed to determine the predictive value of IPS impairment (defined as z-score < -1.5) for the three separate BVMT-R learning trials, delayed recall, retention, and recognition. All models were controlled for age, education, gender, physical disability, disease duration, fatigue, depression, and anxiety.

Results: Performance on SDMT was impaired in 47% (mean SDMT score impaired=52.87 ±8.02 vs. not impaired=37.32 ±10.13). SDMT scores significantly predicted BVMT-R trial 2 (ß=-0.26, p<.05), trial 3 (ß=-0.29, p<.005), delayed recall (ß=-0.35, p<.005), and retention scores (ß=-0.27, p<.005), but not BVMT-R trial 1 (ß=-0.08, p=.433) and recognition scores (ß=-0.15, p=.147). The strength of the prediction increased with each subsequent trial of the BVMT-R and impaired SDMT scores were consistently associated with lower scores on all measures.

Conclusion: Our findings indicate that IPS impairment negatively influences visuospatial learning and memory performance in PwMS, especially after the first learning trial. Moreover, PwMS with IPS impairment seem to retain less visuospatial information after encoding. In a next step, we will investigate whether this phenomenon can also be found in healthy controls.

Disclosure of interest: Pauline T. Waskowiak has no conflicting interests regarding publication of these data.

Suzanne R. de Jong has no conflicting interests regarding publication of these data.

Ilse M. Nauta is supported by the Dutch MS Research Foundation, grant nr. 15-911.

Maureen van Dam has no conflicting interests regarding publication of these data.

Sanne Driessen has no conflicting interests regarding publication of these data.

Menno Schoonheim serves on the editorial board of Neurology and Frontiers in Neurology, receives research support from the Dutch MS Research Foundation, Eurostars-EUREKA, ARSEP, Amsterdam Neuroscience, MAGNIMS and ZonMW (Vidi grant, project number 09150172010056) and has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Celgene/Bristol Meyers Squibb, EIP, Sanofi, MedDay and Merck.

Bernard M. J. Uitdehaag has received research support and/or consultancy fees from Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, Teva and Immunic Therapeutics.

Hanneke E. Hulst is an editor of the Multiple Sclerosis Journal controversies sections, receives research support from the Dutch MS Research Foundation and the Dutch Research Council. She has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Novartis, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, MedDay and Merck BV.

Brigit de Jong reported receiving grants from Dutch MS Research Foundation (project number 15–911) and National MS Foundation. B.A. de Jong is member of the medical advisory board of the Dutch MS Society, chair of the committee for the revision of the guideline on disease modifying therapy and MS for the Netherlands Society of Neurology, and chair of the committee of the Dutch National MS registration of the Netherlands Society of Neurology.

Martin Klein has no conflicting interests regarding publication of these data.

P431/1224

TRACK-MS-An ultrashort screening test to detect cognitive impairment in different subtypes of MS

Daniela Taranu¹, Patrick Fissler², Jill Holbrook¹, Luisa Balz¹, Dorothee Lule¹, Ingo Uttner¹, Hayrettin Tumani¹

¹University of Ulm, Ulm, ²Psychiatric Services Thurgau, Münsterlingen

Introduction: Cognitive impairment is a common symptom in multiple sclerosis. The international current gold standard to screen for cognitive impairment is the BICAMS (Brief International Cognitive Assessment for MS), which takes 20 minutes to administer; a short version is also available (BICAMS short). We validated an even briefer test battery (Track-MS) that takes only 5 minutes to administer and that showed comparable performance to the BICAMS in a pooled group of patients with any form of MS¹_.

Objectives/Aims: We aimed to determine whether our short test battery (Track-MS) performed comparably to the BICAMS and BICAMS-short for subgroups of patients with RRMS, PPMS, or SPMS.

Methods: The study included 88 participants (22 healthy controls [HC], and 22 patients each with RRMS, PPMS, or SPMS). We used the German BICAMS version composed of the VLMT, BVMT-R and SDMT scores; the BICAMS-short, composed of the SDMT and BVMT-R scores; and TRACK-MS test, composed of the COWAT and SDMT scores.

Results: After adjustment for age and education, MS patients scored significantly worse than the healthy controls in all 3 three test batteries, with a higher effect size for the TRACK-MS battery in comparison with the BICAMS and BICAMS-short for all MS types. For TRACK MS, in RRMS patients the effect size was -0.57 SD, CI: -1,22 to 0.08 (p=0.12); for the SPMS patients the effect size was -1.07 SD, CI: -1.70 to -0.44 (p<0.001), and for the PPMS patients the effect size was -1.0 SD, CI: -1.6 to -0.39 (p<0.001). In comparison, for the BICAMS, in RRMS patients the effect size was -0.40 SD, CI: -1,0 to 0.20 (p=0.47), in SPMS patients the effect size was -0.72 SD, CI: -1.30 to -0.14 (p=0.007), and in PPMS patients the effect size was -0.80 SD, CI: -1.40 to -0.23, (p=0.002).

Conclusion: TRACK-MS appears to be a valid and reliable battery in detecting cognitive impairment in different subtypes of MS, with larger effect sizes and a shorter administration time than the current gold standard BICAMS battery.

Taranu, D.; Tumani, H.; Holbrook, J.; Tumani, V.; Uttner, I.; Fissler, P. The TRACK-MS Test Battery: A Very Brief Tool to Track Multiple Sclerosis-Related Cognitive Impairment. Biomedicines 2022, 10, 2975. https://doi.org/10.3390/biomedicines10112975

Disclosure of interest: Taranu, D: nothing to disclose

Fissler, P: nothing to disclose

Holbrook, J: nothing to disclose

Balz, L. : nothing to disclose

Lule, D: nothing to disclose

Uttner, I: nothing to disclose

Tumani, H: received research grants and/or consulting/speaker honoraria from Alexion, Bayer, Biogen, Bristol-Myers Squibb, Celgene, Diamed, Fresenius, Fujirebio, GlaxoSmithKline, Horizon, Janssen-Cilag, Merck, Novartis, Roche, Sanofi Genzyme, TEVA. His research is also funded by Ministry of Education and Research (BMBF), Ministry of Science, Research and Arts Baden Württemberg (MWK-BW), German Society of Multiple Sclerosis (DMSG), DMS-Stiftung, AMSEL-Stiftung, Bayern-DMSG and Chemische Fabrik Karl Bucher GmbH.

P432/1979

Factors affecting motor imagery ability in people with Multiple Sclerosis

Hilal Karakas¹, Turhan Kahraman², Asiye Tuba Özdoğar³, Cavid Baba⁴, Serkan Ozakbas⁴

¹Dokuz Eylul University, Dokuz Eylul University, Graduate School of Health Sciences, Izmir, Turkey, Izmir, Turkey, ²Izmir Katip Celebi University, Department of Physiotherapy and Rehabilitation, Faculty of Health Sciences, Izmir, Turkey, ³Van Yüzüncü Yıl University, Department of Physiotherapy, Faculty of Health Sciences, Van, Turkey, ⁴Dokuz Eylul University, Faculty of Medicine, Department of Neurology, Izmir, Turkey

Introduction: Motor imagery (MI) is a rehabilitation technique that use in neuropsychology in people with multiple sclerosis (MS, pwMS) through alterations in neural networks. It is important to evaluate possible factors affecting MI abilities before its use to increase MI training benefits.

Objectives/Aims: To investigate factors affecting MI ability in pwMS.

Methods: This cross-sectional study included thirty-two pwMS. Visual analog scale (VAS) and PainDETECT Questionnaire (PDQ) were used to assess general and neuropathic pain severity. Kinesthetic and Visual Imagery Questionnaire (KVIQ) was used to assess kinesthetic and visual MI abilities. Hospital Anxiety and Depression Scale (HADS), Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), Multiple Sclerosis International Quality of Life Questionnaire (MusiQoL), Modified Fatigue Impact Scale (MFIS) and Brief International Cognitive Assessment for MS (including Symbol Digit Modalities Test, SDMT; California Verbal Learning Test-II, CVLT-II; The Brief Visuospatial Memory Test-Revised, BVMT-R) were used to assess psychosocial parameters. The Expanded Disability Status Scale (EDSS), disease duration, and age of the participants were recorded.

Results: Out of thirty-two participants 24 (75%) were female with an average age of 37.0±10.8 years and the mean EDSS score was 2.00±1.04. There were significant negative moderate correlations between KVIQ and EDSS (kinesthetic: r= -0.574, p=0.001; visual: r= -0.480, p=0.005), last seven days’ general VAS pain (kinesthetic: r= -0.415, p=0.018; visual: r= -0.500, p=0.023), HADS-depression (kinesthetic: r= -0.450, p=0.01; visual: r= -0.50, p=0.004), MFIS (kinesthetic: r= -0.440, p=0.012; visual: r= -0.449, p=0.010). In addition, there was a significant positive moderate correlation between KVIQ and MusiQoL (kinesthetic: r= 0.531, p=0.002; visual: r= 0.582, p<0.001), BVMT-R (kinesthetic: r= 0.421, p=0.002; visual: r= 0.449, p=0.010). According to the multiple linear regression analysis, EDSS, in the seven-day general VAS pain, HADS-depression, MFIS and MusiQoL and BVMT-R explained 42% of variance in the visual and 32% variance in the kinesthetic MI ability in pwMS.

Conclusion: The study suggests that factors such as EDSS, pain severity, depression, fatigue, quality of life, and visuospatial memory are related to MI ability in pwMS. MI training programs should be individualized and tailored to the specific needs and abilities of each patient by considering these factors that may affect MI ability.

Disclosure of interest: Hilal Karakas: nothing to disclose

Turhan Kahraman: nothing to disclose

Asiye Tuba Özdoğar: nothing to disclose

Cavid Baba: nothing to disclose

Serkan Ozakbas: nothing to disclose

P433/2066

Paediatric Onset of MS: data from the UK MS Register

Elaine Craig¹, Rod Middleton¹, Richard Nicholas²

Study Group: UK MS Register Research Group

¹Swansea University, Population Heath Data Science, Sketty, United Kingdom, ²Imperial College London, Department of Cellular and Molecular Neuroscience, London, United Kingdom

Introduction: The UK Multiple Sclerosis Register (UKMSR) is a disease register with more than 12 years’ worth of Patient Reported Outcome data (PRO) and clinical data from the National Health Service in the UK. We sought to understand if there were any differences in disease severity for those diagnosed with paediatric onset MS (POMS) and those people with MS (pwMS) with Adult Onset Multiple Sclerosis (AOMS) in the UKMSR.

Objectives/Aims: To evaluate the severity of MS in POMS against AOMS.

Methods: Using the online population of the UKMSR we separated them into AOMS (diagnosis age ⩾18yrs) and POMS (<18 yrs). We carried out statistical testing (Mann-Whitney, Chi-Sq) analysing age, time to diagnosis, webEDSS (web Expanded Disability Status Scale), the Multiple Sclerosis Impact Scale physical measure (MSIS-phys), and the MS Walking Scale (MSWS).

Results: 18,925 pwMS were analysed (18,041 AOMS and 884 POMS). The POMS group were found to have a longer time from symptom onset to diagnosis of (all median score [IQR]) 10[2.6-20.3]yrs against 1.7[0.5-5.3] in the AOMS population. Symptom onset to time now was POMS 33.3[21.5-45.3]yrs, AOMS 18.1[11.3-27.0]yrs. Controlling for this confirmed the POMS group had increased disability scores across MSIS-phys, MSWS, and webEDSS (all p<0.001). However, when controlling for time since diagnosis (POMS 18.2[12.1-27.9]yrs, AOMS 14.1[8.3-21.9]yrs), there was no significant difference between POMS and AOMS populations in terms of webEDSS and MSWS. MSIS-phys showed a difference with smaller significance (p = 0.05).

Conclusion: There is a significantly higher disability in the POMS patients, but the disability is no different once controlled for age of diagnosis. An interpretation could be that the disease is present asymptomatically for over a decade in the AOMS population.

Disclosure of interest: EM Craig and R M Middleton have no individual pecuniary interests to declare. The UK MS Register is prirmarily funded by the MS Society. Individual projects have been funded by Merck KgAA, Novartis and Sanofi.

Nicholas, Richard

attended paid advisory boards for Novartis and Roche, vice chair of NICE HTA committee, received funding from the UK MS Society

P434/1123

Brain reserve and physical disability in secondary progressive multiple sclerosis

Yingtong Li¹, Nevin A John^1,2, Floriana De Angelis³, Jonathan Stutters³, Ferran Prados^3,4,5, Arman Eshaghi³, Anisha Doshi³, Alberto Calvi⁶, Thomas Williams³, Domenico Plantone⁷, Thanh Phan^1,2, Frederik Barkhof^3,4,8,9, Jeremy Chataway^3,8

Study Group: MS-SMART Investigators

¹Department of Medicine, School of Clinical Sciences, Monash University, Melbourne, Australia, ²Department of Neurology, Monash Health, Melbourne, Australia, ³Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Institute of Neurology, Faculty of Brain Sciences, University College London, London, United Kingdom, ⁴Centre for Medical Image Computing (CMIC), University College London, London, United Kingdom, ⁵e-Health Center, Universitat Oberta de Catalunya, Barcelona, Spain, ⁶Laboratory of Advanced Imaging in Neuroimmunological Diseases (imaginEM), Fundació de Recerca Clínic Barcelona – Institut d’Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), Barcelona, Spain, ⁷Department of Medicine, Surgery & Neuroscience, University of Siena, Siena, Italy, ⁸National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, United Kingdom, ⁹Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centre, Amsterdam, Netherlands

Introduction: The brain reserve hypothesis posits that larger maximal lifetime brain growth (MLBG) may confer protection against physical disability in multiple sclerosis (MS). Larger MLBG as a proxy for brain reserve, has been associated with reduced progression of physical disability in patients with early MS; however, it is unknown whether this association remains once in the secondary progressive phase of MS (SPMS).

Objectives/Aims: To assess whether larger MLBG is associated with decreased physical disability progression in SPMS.

Methods: We conducted a post-hoc analysis of participants in the MS-Secondary Progressive Multi-Arm Randomisation Trial (NCT01910259), a multi-centre randomised placebo-controlled trial of the neuroprotective potential of 3 agents in SPMS.

Physical disability was measured by Expanded Disability Status Scale (EDSS), 9-hole peg test (9HPT) and 25-foot timed walk test (T25FW) at baseline and 96 weeks. Clinically significant progression was defined as increase in EDSS score of ⩾1.0 if baseline ⩽5.0 or ⩾0.5 if baseline ⩾5.5, or increase in 9HPT or T25FW time of ⩾20%. MLBG was estimated by baseline intracranial volume (ICV), and classified as larger or smaller based on median ICV for sex.

Multivariable logistic and linear regression was used to investigate the association between MLBG and physical disability progression adjusting for age, sex, previous relapse within 2 years, baseline normalised brain volume, baseline normalised T2 lesion volume and percent brain volume change.

Results: 383 participants were followed up over 96 weeks. Mean age was 54.7 years and 256 were female. Median baseline EDSS was 6.0 (range 4.0–6.5). 136 participants demonstrated clinically significant progression in EDSS over 96 weeks.

Adjusted for covariates, larger MLBG was associated with reduced risk of EDSS progression (adjusted odds ratio 0.61, 95% CI: 0.39–0.96; p=0.03), and smaller change in EDSS score over 96 weeks (adjusted mean difference 0.16, 95% CI 0.01–0.31; p=0.04). Larger MLBG was not independently associated with progression as measured by 9HPT or T25FW.

Conclusion: Larger MLBG is independently associated with physical disability progression over 96 weeks as measured by EDSS in SPMS. This suggests that MLBG as a proxy for brain reserve may continue to confer protection against disability when in the secondary progression phase of MS.

Disclosure of interest: YL, FDA, JS, FPC, AE, AD, AC, TW and DP report nothing to disclose.

NJ is an investigator on MS commercial studies sponsored by Biogen, Sanofi-Genzyme and Novartis.

FB is a consultant for Bayer, Biogen-Idec, Teva, Merck, Novartis, Roche, Apitope, IXICO and Lundbeck.

TP has received honoraria from Pfizer/BMS and Bayer.

JC has received support from the EME Programme and Health Technology Assessment Programme (NIHR), the UK MS Society, and the US National MS Society; has been a local principal investigator for trials in MS funded by Receptos, Novartis, Roche, and Biogen Idec; has received an investigator grant from Novartis; and has taken part in advisory boards and consultancy for Roche, Merck, MedDay, Biogen and Celgene.

P435/726

Assessing likelihood of secondary progressive multiple sclerosis in Sweden and Denmark: A federated learning analysis unveiling modestly higher odds in Sweden

Lars Forsberg¹, Jan Hillert¹, Elena Flavia Mouresan¹, Anna Glaser¹, Melinda Magyari^2,3, Luigi Pontieri²

¹Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden, ²Copenhagen University Hospital, The Danish Multiple Sclerosis Registry, Copenhagen, Denmark, ³Copenhagen University Hospital, Danish Multiple Sclerosis Center, Copenhagen, Denmark

Introduction: A recent study reported a higher proportion of Secondary Progressive Multiple Sclerosis (SPMS) patients in Sweden than in Denmark. However, the results were limited to descriptive statistics since data could not be pooled. Therefore, the reasons behind this difference remain unclear. One hypothesis is that it might be linked to differences in age and sex distribution between the two Multiple Sclerosis (MS) populations.

Objectives/Aims: To investigate if the likelihood of being assigned with SPMS remains higher for patients in Sweden compared to Denmark when adjusting for age and sex distribution using a novel federated learning method.

Methods: We used data from MS registries in Sweden and Denmark on patients (i) alive at April 3, 2023 (index date); (ii) clinically assigned relapsing remitting MS (RRMS) or SPMS, and (iii) with complete data on birth date and MS onset date. A total of 30,475 patients were included (12,667 RRMS and 4,122 SPMS in Sweden, 10,681 RRMS and 3,005 SPMS in Denmark). A federated learning method using gradient descent for logistic regression across many iterations was developed in R. This allowed the use of a shared model for both registries without pooling data. The outcome variable was SPMS (TRUE/FALSE), and explanatory variables were age at index date, sex (female = TRUE), and country (Sweden = TRUE).

Results: Proportions of SPMS patients were 24.6% in Sweden and 22.0% in Denmark. Mean age (SD) for SPMS was 64.4 (10.6) years in Sweden and 62.3 (10.1) years in Denmark. For RRMS, the mean age (SD) was 47.1 (12.7) years in Sweden and 47.6 (12.1) years in Denmark. Female patients constituted 71.3% (Sweden) and 70.1% (Denmark) of the total population. The odds ratios with 95% confidence intervals for the logistic model were 1.120 [1.117 - 1.124] for age, 0.824 [0.769 - 0.883] for sex (females had lower odds), and 1.067 [1.002 - 1.136] for country (Sweden had higher odds).

Conclusion: These findings indicated a significantly higher likelihood of SPMS in Sweden compared to Denmark after adjusting for age and sex distributions. However, the observed difference between the countries was modest, and the age and sex descriptive data for the various subtypes were strikingly similar. Given these similarities, the higher odds ratio may be partly attributable to delays in recognising SPMS in clinical practice. The novel federated learning method utilised in this study demonstrates the potential for cross-national research collaborations without compromising data privacy.

Disclosure of interest: Lars Forsberg: nothing to disclose

Jan Hillert: JH has received honoraria for serving on advisory boards for Biogen, Bristol-Myers-Squibb, Janssen, Merck KGaA, Novartis, Sandoz and Sanofi-Genzyme and speaker’s fees from Biogen, Janssen, Novartis, Merck, Teva, Sandoz and Sanofi-Genzyme. He has served as P.I. for projects sponsored by, or received unrestricted research support from, Biogen, Bristol-Myers-Squibb, Janssen, Merck KGaA, Novartis, Roche, and Sanofi-Genzyme. His MS research is funded by the Swedish Research Council and the Swedish Brain foundation.

Elena Mouresan: nothing to disclose.

Anna Glaser: nothing to disclose.

Melinda Magyari: MM has served on scientific advisory board, as consultant for, received support for congress participation or speaker honoraria from Biogen, Sanofi, Roche, Novartis, Merck, Alexion, Bristol Myers Squibb .The Danish MS Registry received research support from Biogen, Genzyme, Roche, Merck, Novartis.

Luigi Pontieri: nothing to disclose.

P436/329

Age and extreme of outcomes in multiple sclerosis: aggressive and benign course

Alessia Bianchi^1,2, Richard Nicholas³, Paolo Muraro³, Antonio Scalfari³

¹Queen Square MS Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Science, University College London, London, United Kingdom, ²Department of Biomedicine, Neuroscience & Advanced Diagnostic, University of Palermo, Palermo, Italy, ³Centre for Neuroscience, Division of Brain Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom

Introduction: Among MS patients, progressive symptoms are only rarely seen at young age, while by growing older relapses become less common and the risk of progression increases.

Objectives/Aims: We investigated MS groups of outliers, unusually presenting with progression at young age, or remaining free of progressive course despite old age.

Methods: We analysed 1023 MS patients (RR n = 272, SP/PP n = 751) from the London Ontario Database, who were followed up for 28 years and never received DMTs. Based on the youngest 25^th percentiles of age at onset of progression and on the oldest 25^th percentiles of the age at last assessment, we identified 179 (PP = 34.64%; SP = 65.36%) “young progressors” (YPs), exhibiting a progressive course before age 33, and 61 “old relapsers” (ORs), who were still classified as RRMS after age 54. Multiple regression models were used to identify variables predicting the probability of becoming YPs or ORs.

Results: Compared to ORs, at onset YPs were significantly younger (23.1vs 34.4;p<0.001), more frequently presented with motor symptoms (14.53% vs 3.28%;p=0.018), had higher relapses within the first 2 years (2.2 vs 1.4;p<0.001), shorter first inter-attack interval (2.9 vs 4.5;p=0.019), and took shorter time to EDSS 3 (5.0 vs 18.1;p<0.001), EDSS 6 (9.8 vs 27.2;p<0.001) and EDSS 8 (17.3 vs 28.8;p<0.001). Younger age at onset (OR=0.76, p<0.001), shorter time to EDSS 3 (OR = 0.72, p<0.001), and longer first inter-attack interval (OR=1.19, p<0.001) were the best predictors of the risk of becoming YPs (specificity = 70%, sensibility = 70%, accuracy 68%). In contrast, older age at onset (OR=1.08, p<0.001), longer time to EDSS 3 (OR=1.18, p<0.001) and shorter first inter-attack interval (OR=0.91, p=0.016) were associated with higher probability of becoming ORs (specificity = 67%, sensibility = 41%, accuracy 65%). For each additional year between onset and EDSS 3, the probability of becoming YPs or ORs, decreased by 10% and increased by 10%, respectively.

Conclusion: The rate of early disability accumulation predicts the probability of experiencing aggressive or benign course. Further studies should investigate factors predisposing to fast degeneration in YPs or protecting ORs from developing a progressive course.

Disclosure of interest: AB has received a research grant from the Italian Society of Neurology; she has been awarded a MAGNIMS-ECTRIMS fellowship in 2023. RN attended paid advisory boards for Novartis and Roche, vice chair of NICE HTA committee, received funding from the UK MS Society. PM discloses travel support and speaker honoraria from unrestricted educational activities organized by Novartis, Bayer HealthCare, Bayer Pharma, Biogen Idec, Merck-Serono and Sanofi Aventis. He discloses consulting to Magenta Therapeutics, Jasper Therapeutics and Rubius Therapeutics. AS received support for attending conferences and advisory board meeting from Sanofi, Biogen, Merck and Roche.

P437/1733

An International Consensus with Delphi Methodology on Smoldering Disease in MS: Definition, Clinical Manifestations and Underlying Biology

Antonio Scalfari¹, Franesca Bagnato², Jiwon Oh³, Laura Airas⁴, Stefan Bittner⁵, Massimiliano Calabrese⁶, Jose Manuel Garcia Dominguez⁷, Cristina Granziera⁸, Benjamin M. Greenberg⁹, Kerstin Hellwig¹⁰, Zsolt Laszlo Illes¹¹, Jan Lycke¹², Veronica Popescu¹³, Anthony Traboulsee¹⁴, Gavin Giovannoni¹⁵

¹Imperial College, London, United Kingdom, ²Vanderbilt University Medical Center, Department of Neurology, Nashville, United States, ³St Michael's Hospital, Toronto, Canada, ⁴University of Turku, Turku, Finland, ⁵Johannes Gutenberg- University, Mainz, Germany, ⁶Clinica Neurologica I, Verona, Italy, ⁷Gregorio Marañón General University Hospital, Madrid, Spain, ⁸University of Basel, Basel, Switzerland, ⁹University of Texas Southwestern, Dallas, United States, ¹⁰St. Josef Hospital, Bochum, Germany, ¹¹Odense University Hospital, Odense, Denmark, ¹²University of Gothenburg, Gothenburg, Sweden, ¹³Noorderhart Hospital, Pelt, Belgium, ¹⁴University of British Columbia, Vancouver, Canada, ¹⁵Blizard Institute, Queen Mary's University of London, London, United Kingdom

Introduction: Most people with multiple sclerosis experience subtle neurological deterioration despite being free of clinical or radiological evidence of focal inflammatory activity. Evidence indicates that smoldering pathological processes affecting the whole central nervous system are active from the earliest phases and primarily drive disease worsening.

Objectives/Aims: Develop consensus-driven statements on the biology, clinical and radiological manifestations of Smoldering Disease.

Methods: A panel of 15 MS experts from eight countries across Europe, US, and Canada convened to establish, by using Delphi methodology, agreement on a 5-point scale on multiple domains of Smoldering MS. Consensus was defined a priori as >75% of participants agreeing or strongly agreeing.

Results: Consensus has been reached on all statements, including the definition of Smoldering/worsening disease, pathological drivers, clinical and paraclinical manifestations, future trial design and drug regulations. It was agreed that Smoldering Disease encompasses chronic pathobiological processes, which start early and drive the subtle physical and cognitive worsening even among patients free of acute focal inflammatory clinical and subclinical activity. This highlights the limitations of the current management model, which is over-reliant on relapses and new MRI activity as the only markers of disease activity. To address current challenges of monitoring Smoldering-Associated-Worsening (SAW), we propose routine implementation of patient-reported outcomes, wearable devices and measures beyond EDSS, additional tests such as SDMT, 9HPT and T25FW as well as neurological stress tests to capture subtle clinical changes, ultimately allowing to offer patients a more effective therapeutic management. Chronic active lesions, microglia activation, focal and global cortical pathology, resulting in brain and spinal cord atrophy, are the most likely drivers of the multifaceted smoldering deterioration.

Conclusion: Our recommendations will hopefully motivate further research activity to deepen the understanding of Smoldering Disease and help optimize clinical management of MS, fostering drug discovery through the identification of novel targets.

Disclosure of interest: The concepts and contents of this abstract emerged from several meetings facilitated by Sanofi. The experts involved are paid for attending the meetings. Experts are not compensated for any writing efforts. Medical writing support was provided by Lionel Thevathasan from LT Associates Ltd who was funded by Sanofi.

P438/1439

Barriers to clinical follow-up visits in Multiple Sclerosis: A nationwide register-based study

Agata Beczek¹, Eskild Landt², Lars Kristian Storr¹, Malene Beck^3,4,5, Morten Dahl^2,6

¹Zealand University Hospital, Neurology, Roskilde, Denmark, ²Zealand University Hospital, Clinical Biochemistry, Køge, Denmark, ³Zealand University Hospital, Pediatrics, Roskilde, Denmark, ⁴University of Southern Denmark, Faculty of Health, Institute of Regional Science, Odense, Denmark, ⁵Roskilde University, Faculty of People and Technology, Institute of Nursing Science, Roskilde, Denmark, ⁶University of Copenhagen, Clinical Medicine, Copenhagen, Denmark

Introduction: Treatment of people with Multiple Sclerosis (PwMS) is provided by specialized Multiple Sclerosis (MS) clinics in Denmark and is free of charge. Treatment focuses on recovery from attacks, preventing relapses, slowing the progression of the disease, and managing symptoms. However, not all PwMS attend free clinical follow-up visits at MS clinics.

Objectives/Aims: To identify barriers among people diagnosed with MS that could influence their ability to attend clinical follow-up visits at the MS clinics.

Methods: We performed a nationwide register-based cohort study to examine possible barriers to clinical follow-up visits at Danish MS clinics using data from the Danish Multiple Sclerosis Registry from 2000-2020.

Results: We identified 10,411 adults with MS in the registry, out of which 3,736 (36%) had less than one visit annually and were deemed as having low-attendance to follow-ups visits. Patients with low attendance to follow-up visits vs control subjects were on average older at disease onset (40 years vs 36 years, p<0.0001), had more often primary-progressive MS (25% vs 3%, p<0.0001) and Expanded Disability Scale scores ⩾4.5 (31% vs 17%, p<0.0001). People with low attendance to follow-up visits vs controls had more often Functional System Scale scores of 3 or higher for sphincter functions, 4 or higher for pyramidal functions, and 3 or higher for cerebellar functions (all P<0.0001).

Conclusion: PwMS with less than one annual follow-up visit at Danish MS clinics are more affected by the disease and are having a higher level of disabilities. Our findings suggest that strategies to improve adherence to MS clinics in Denmark should be targeted people with severe MS, especially those affected by primary-progressive disease course.

Disclosure of interest: Agata Beczek: Nothing to disclose

Eskild Landt: Nothing to disclose

Lars Kristian Storr: Nothing to disclose

Malene Beck: Nothing to disclose

Morten Dahl: Nothing to disclose

P439/2040

Progression independent of relapse activity and relapse-associated worsening predict future disability on multiple clinical domains

Carmen Tur¹, Pere Carbonell¹, Alvaro Cobo Calvo¹, Susana Otero-Romero^1,2, Claudia Guio-Sanchez¹, Georgina Arrambide¹, Luciana Midaglia¹, Joaquin Castillo-Justribo¹, Angela Vidal-Jordana¹, Breogan Rodriguez¹, Jordina Beltran¹, Neus Mongay-Ochoa¹, Andreu Vilaseca¹, Helena Ariño¹, Ana Zabalza¹, Luca Bollo¹, Agustín Pappolla¹, Maria Jesus Arevalo¹, Ingrid Galán¹, Carlos Nos¹, Manuel Comabella¹, Jordi Rio¹, Deborah Pareto³, Jaume Sastre-Garriga¹, Alex Rovira Cañellas³, Mar Tintoré¹, Xavier Montalban¹

¹Multiple Sclerosis Centre of Catalonia-Vall Hebron University Hospital, Barcelona, Spain, ²Preventive Medicinine Department-Vall Hebron University Hospital, Barcelona, Spain, ³Dept. of Radiology-VallHebron Unviersity Hospital, Magnetic Resosnance Unit, Barcelona, Spain

Introduction: Progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW) are associated with unfavourable long-term outcomes as measured by the expanded disability status scale (EDSS), strongly determined by the ability to walk. However, the potential long-term impact of PIRA or RAW on other clinical domains is unknown.

Objectives/Aims: To assess whether presenting PIRA or RAW predicts future disability accrual as measured by multi-dimensional patient-reported/administered outcome measures (PROMs).

Methods: Patients from the Barcelona first-attack cohort with a diagnosis of 2017 McDonald MS who had been assessed on PROMs at least once within the MS PATHS framework were included. PROM evaluations (2016-2022) comprised the Multiple Sclerosis Performance Test (MSPT), including manual dexterity, walking speed, and processing speed tests (MDT, WST, and PST); patient-determined disease steps (PDDS); and quality of life scores. Patients were also assessed on the EDSS and relapses from their first MS attack. PIRA and RAW were defined, respectively, as a 6-month confirmed (EDSS-based) disability accumulation within and outside a free-relapse period. Linear regression models adjusted for disease duration at the first PROM visit were built.

Results: Out of 1375 patients with a first demyelinating attack, 419 fulfilled our criteria (123 male [29%]; mean [SD] age at first attack: 31 [8] yrs). PROM visits started at a median [IQR] disease duration of 12 [7; 17] yrs. During the pre-PROM period, 117 (28%) and 179 (43%) patients had ⩾1 PIRA or ⩾1 RAW event, respectively, occurring at a median (IQR) disease duration of 7 (4; 12) or 2 (0.6; 7) yrs. Presenting PIRA or RAW in the pre-PROM period was associated with higher lower-limb motor disability, measured by the PDDS (both p<0.01) or WST (p<0.01; p=0.02), and higher cognitive decline, measured by the PST (p=0.03; p=0.04) at the first PROM visit. RAW was also associated with higher upper-limb motor disability (p<0.01). Finally, whereas both PIRA and RAW were associated with perception of upper and lower-limb dysfunction (p<0.01) or stigma (p<0.05), only RAW was associated with abnormal levels of anxiety, fatigue, and sleep disturbance, cognitive dysfunction, and reduced social satisfaction (p<0.01).

Conclusion: Both PIRA and RAW are associated with future lower-limb motor and cognitive disability measured by PROMs. However, RAW, unlike PIRA, is associated with upper-limb motor disability and may have a stronger negative impact on the quality of life.

Disclosure of interest: Disclosures:

The study was NOT supported by any commercial entity or government agency.

C. Tur is currently being funded by a Junior Leader La Caixa Fellowship (fellowship code is LCF/BQ/PI20/11760008), awarded by “la Caixa” Foundation (ID 100010434). She has also received the 2021 Merck’s Award for the Investigation in MS, awarded by Fundación Merck Salud (Spain) and a grant awarded by the Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia e Innovación de España (PI21/01860). In 2015, she received an ECTRIMS Post-doctoral Research Fellowship and has received funding from the UK MS Society. She is a member of the Editorial Board of Neurology and Multiple Sclerosis Journal. She has also received honoraria from Roche and Novartis and is a steering committee member of the O’HAND trial and of the Consensus group on Follow-on DMTs.

P. Carbonell-Mirabent’s yearly salary is supported by a grant from Biogen to Fundació

privada Cemcat for statistical analysis.

A. Cobo-Calvo has received a grant from Instituto de Salud Carlos III, Spain; JR19/00007.

S. Otero-Romero has received speaking and consulting honoraria from Genzyme, Biogen-Idec, Novartis, Roche, Excemed and MSD; as well as research support from Novartis

C. Guío-Sánchez is an ECTRIMS clinical fellowship awardee 2022-2023 and has received travel expenses for scientific meetings from Sanofi-Genzyme, Biogen-Inc and Merck.

G. Arrambide has received compensation for consulting services, participation in advisory boards or speaking honoraria from Merck, Roche, and Horizon Therapeutics; and travel support for scientific meetings from Novartis, Roche, and ECTRIMS. G. Arrambide is editor for Europe of the Multiple Sclerosis Journal – Experimental, Translational and Clinical; a member of the executive committee of the International Women in Multiple Sclerosis (iWiMS) network, and a member of the European Biomarkers in MS (BioMS-eu) consortium steering committee. She is a recipient of grants PI19/01590 and PI22/01570, awarded by the Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia e Innovación de España.

L. Midaglia reports no disclosures.

J. Castilló reports no disclosures.

A. Vidal-Jordana has received support has received support for contracts Juan Rodés (JR16/00024) and from Fondo de Investigación en Salud (PI17/02162 and PI22/01589) from Instituto de Salud Carlos III, Spain, and has engaged in consulting and/or participated as speaker in events organized by Roche, Novartis, Merck, and Sanofi.

B. Rodríguez-Acevedo has received speaking honoraria from Merck and honoraria for consulting services from Novartis.

L. Bollo’s research is supported by a one-year stipend endowed by the NMSS/AAN John Dystel Prize for Multiple Sclerosis Research awarded to Prof. Xavier Montalban in 2022.

P440/2064

Assessing progression with multidimensional patient-reported and self-administered outcome measures

Carmen Tur¹, Fancesca Bovis², Alessio Signori², Alvaro Cobo Calvo¹, Susana Otero-Romero^1,3, Claudia Guio-Sanchez¹, Georgina Arrambide¹, Luciana Midaglia¹, Joaquin Castillo-Justribo¹, Angela Vidal-Jordana¹, Breogán Rodríguez¹, Jordina Beltran¹, Neus Mongay-Ochoa¹, Andreu Vilaseca¹, Helena Ariño¹, Ana Zabalza¹, Luca Bollo¹, Agustín Pappolla¹, Maria Jesus Arevalo¹, Ingrid Galán¹, Carlos Nos¹, Manuel Comabella¹, Jordi Rio¹, Deborah Pareto⁴, Jaume Sastre-Garriga¹, Maria Pia Sormani², Alex Rovira Cañellas⁴, Xavier Montalban¹, Mar Tintoré¹

¹Multiple Sclerosis Centre of Catalonia-Vall Hebron University Hospital, Barcelona, Spain, ²Department of Health Sciences, University of Genova, Genova, Italy, ³Preventive Medicine-Vall Hebron University Hospital, Barcelona, Spain, ⁴Dept. of Radiology-Vall Hebron University Hospital, Magnetic Resonance Unit, Barcelona, Spain

Introduction: Progression independent of relapse activity (PIRA) is the main mechanism of disability accrual in MS. However, PIRA has only been defined by the expanded disability status scale (EDSS), which is not always available in routine practice.

Objectives/Aims: To assess the ability of patient-reported/administered outcome measures (PROMs) to predict concurrent and future disability on different clinical domains, focussing on EDSS-based PIRA.

Methods We included patients from the Barcelona first-attack cohort who had a diagnosis of 2017 McDonald MS and had been assessed on PROMs at least once, in the context of the MS PATHS framework. During the PROM evaluation period, patients were scored on the Multiple Sclerosis Performance Test (MSPT), including manual dexterity, walking speed, and processing speed tests (MDT, WST, and PST); patient-determined disease steps (PDDS); and quality of life scores. Patients were also assessed on the EDSS and relapses from their first demyelinating attack. PIRA and relapse-associated worsening (RAW) were defined as a 6m-confirmed disability accumulation (CDA) event within and outside a relapse-free period, respectively. We assessed the association between PROM worsening and concurrent or future outcomes.

Methods: Results: Out of a total of 1375 patients, we included 419 fulfilling our inclusion criteria (123 male [29%]; mean [SD] age and disease duration at first PROM evaluation: 42 [8] and 11 [6] yrs, respectively). During the PROM period (median duration: 3 yrs), 13% had ⩾1 PIRA event (+/- RAW), 8% had only RAW events, and 79% did not have any EDSS-based CDA; 41%, 32%, and 17% patients showed ⩾30% MDT, WST, and PST progression, respectively; and 12% had ⩾1-step PDDS increase. A ⩾30% decline in MDT or WST was associated with a higher concurrent EDSS (p<0.01 for both) and subjective upper-limb function worsening (p<0.01 and p=0.03). A ⩾30% decline in PST was associated with higher depression scores (p=0.04). Also, ⩾1-step PDDS increase was associated with greater concurrent EDSS increases (p<0.01) and a 3-fold higher risk of concurrent PIRA (p=0.01). Finally, a ⩾30% deterioration in WST or PST was associated with a steeper EDSS increase (p=0.04) or a 4-fold higher risk of RAW (p<0.01) in the post-PROM period, respectively.

Conclusion: While some PROMs may capture that disability accrual measured by the EDSS, including PIRA, others reflect deterioration on clinical domains beyond the EDSS and may predict future disability, suggesting their potential to evaluate progression in clinical practice.

Disclosure of interest: C. Tur is currently being funded by a Junior Leader La Caixa Fellowship (fellowship code is LCF/BQ/PI20/11760008), awarded by “la Caixa” Foundation (ID 100010434). She has also received the 2021 Merck’s Award for the Investigation in MS, awarded by Fundación Merck Salud (Spain) and a grant awarded by the Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia e Innovación de España (PI21/01860). In 2015, she received an ECTRIMS Post-doctoral Research Fellowship and has received funding from the UK MS Society. She is a member of the Editorial Board of Neurology and Multiple Sclerosis Journal. She has also received honoraria from Roche and Novartis and is a steering committee member of the O’HAND trial and of the Consensus group on Follow-on DMTs.

P. Carbonell-Mirabent’s yearly salary is supported by a grant from Biogen to Fundació

privada Cemcat for statistical analysis.

F. Bovis received the 2022 Biostatistic/Informatics Junior Faculty Award (grant code BI-2107-38160) awarded by the National MS Society.

A. Signori reports no disclosures.

A. Cobo-Calvo has received a grant from Instituto de Salud Carlos III, Spain; JR19/00007.

S. Otero-Romero has received speaking and consulting honoraria from Genzyme, Biogen-Idec, Novartis, Roche, Excemed and MSD; as well as research support from Novartis.

C. Guío-Sánchez is an ECTRIMS clinical fellowship awardee 2022-2023 and has received travel expenses for scientific meetings from Sanofi-Genzyme, Biogen-Inc and Merck.

G. Arrambide has received compensation for consulting services, participation in advisory boards or speaking honoraria from Merck, Roche, and Horizon Therapeutics; and travel support for scientific meetings from Novartis, Roche, and ECTRIMS. G. Arrambide is editor for Europe of the Multiple Sclerosis Journal – Experimental, Translational and Clinical; a member of the executive committee of the International Women in Multiple Sclerosis (iWiMS) network, and a member of the European Biomarkers in MS (BioMS-eu) consortium steering committee. She is a recipient of grants PI19/01590 and PI22/01570, awarded by the Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia e Innovación de España.

L. Midaglia reports no disclosures.

J. Castilló reports no disclosures.

Á. Vidal-Jordana has received support has received support for contracts Juan Rodés (JR16/00024) and from Fondo de Investigación en Salud (PI17/02162 and PI22/01589) from Instituto de Salud Carlos III, Spain, and has engaged in consulting and/or participated as speaker in events organized by Roche, Novartis, Merck, and Sanofi.

B. Rodríguez-Acevedo has received speaking honoraria from Merck and honoraria for consulting services from Novartis.

L. Bollo’s research is supported by a one-year stipend endowed by the NMSS/AAN John Dystel Prize for Multiple Sclerosis Research awarded to Prof. Xavier Montalban in 2022.

A. Pappolla has received funding travel from Roche and speaking honoraria from Novartis. He performed an ECTRIMS Clinical Training Fellowship program during 2021, and is currently performing an MSIF-ARSEP Fellowship program.

MJ. Arévalo reports no disclosures

I. Galán reports no disclosures.

J. Beltran reports no disclosures.

N. Mongay-Ochoa has a predoctoral grant Rio Hortega, from the Instituto de Salud Carlos III (CM21/00018). She also has received speaking honoraria and travel expenses from Merck and Roche.

A. Vilaseca has received a Rio Hortega grant (CM22/00247) by Institute of Health Carlos III (ISCIII).

H. Ariño has received a grant from Instituto de Salud Carlos III, Spain; JR22/00072.

A. Zabalza has a predoctoral grant Rio Hortega, from the Instituto de Salud Carlos III, Spain (CM22/00237), received travel expenses for scientific meetings from Biogen-Idec, Merck Serono and Novartis; speaking honoraria from Eisai; and a study grant from Novartis.

C. Nos has received funding for travel from Biogen Idec and F. Hoffmann-La Roche, Ltd. and speaker honoraria from Novartis.

M. Comabella has received compensation for consulting services and speaking honoraria from Bayer Schering Pharma, Merk Serono, Biogen-Idec, Teva Pharmaceuticals, Sanofi-

Aventis, and Novartis.

J. Río has received speaking honoraria and personal compensation for participating on Advisory Boards from Biogen-Idec, Genzyme, Janssen, Merck, Mylan, Novartis, Roche, Teva, and Sanofi-Aventis.

D. Pareto has received a research contract with Biogen Idec, and a grant from Instituto Salud

Carlos III (PI18/00823).

J. Sastre-Garriga serves as co-Editor for Europe for the Multiple Sclerosis Journal and as Editor-in-Chief of Revista de Neurología, receives research support from Fondo de Investigaciones Sanitarias (19/950 and 22/750) and in the last twelve months has served as a consultant/speaker for BMS, Roche, Sanofi, Janssen, and Merck.

MP. Sormani received consulting fees from Biogen, Merck, Novartis, Roche, Sanofi, Immunic, Alexion.

A. Rovira serves on scientific advisory boards for Novartis, Sanofi-Genzyme, Synthetic MR, Roche, Biogen, and OLEA Medical; has received speaker honoraria from Bayer, SanofiGenzyme, Merck-Serono, Teva Pharmaceutical Industries Ltd, Novartis, Roche, and Biogen; and is CMO and co-founder of TensorMedical.

X. Montalban has received speaking honoraria and travel expenses for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Abbvie, Actelion, Alexion, Biogen, Bristol-Myers Squibb/Celgene, EMD Serono, Genzyme, Hoffmann-La Roche, Immunic, Janssen Pharmaceuticals, Medday, Merck, Mylan, Nervgen, Novartis, Sandoz, Sanofi Genzyme, Teva Pharmaceutical, TG Therapeutics, Excemed, MSIF and NMSS.

M. Tintore has received compensation for consulting services, speaking honoraria and research support from Almirall, Bayer Schering Pharma, Biogen-Idec, Genzyme, Janssen, Merck-Serono, Novartis, Roche, Sanofi-Aventis, Viela Bio and Teva Pharmaceuticals. Data Safety Monitoring Board for Parexel and UCB Biopharma.

P441/501

Comparing pre- and post-diagnosis presentations of multiple sclerosis and other inflammatory diseases in primary care: an agnostic study of French and British health records

Octave Guinebretiere¹, Thomas Nedelec¹, Laurene Gantzer², Beranger Lekens², Stanley Durrleman¹, Céline Louapre³

¹ICM Institute for Brain and Spinal Cord, Paris, France, ²Cegedim R&D, Boulogne-Billancourt, France, ³Assistance Publique-Hôpitaux de Paris, Department of Neurology, Paris, France

Introduction: Several studies have identified a prodrome in multiple sclerosis (MS) which may lead to early prevention and the targeting of new interventions, especially in individuals known to be at high risk of developing symptomatic MS. However, the specificity of the prodrome relative to other auto-immune diseases is unknown.

Objectives/Aims: This study aimed to evaluate the associations between diseases and symptoms diagnosed in primary care and the risk of incident multiple sclerosis (MS) relative to other autoimmune inflammatory diseases. A secondary objective was to investigate whether the prodrome differs by sex, age at diagnosis and year of diagnosis.

Methods: A nested case-control study was conducted from Jan 1, 1996 to March 28, 2022 in the UK and from Jan 4, 1998 to March 28, 2022 in France, using electronic health records from the Health Improvement Network database. We agnostically assessed the associations between 113 diseases and symptoms in the five years before and after diagnosis with subsequent diagnosis of MS. Individuals with a diagnosis of MS were compared to individuals without MS, and individuals with two other auto-immune diseases, Crohn’s disease and lupus.

Results: The study population consisted of patients with MS (n= 20,174), patients without MS (n=54,790), Crohn’s disease (n=30,477) or lupus (n=7,337). Twelve ICD-10 codes were significantly positively associated with the risk of MS compared to controls without MS. After considering ICD-10 codes suggestive of neurological symptoms as the first diagnosis of MS, five ICD-10 codes remained significantly associated with MS: depression (UK OR 1.22 [95%CI 1.11-1.34]), sexual dysfunction (1.47 [1.11-1.95]), constipation (1.5 [1.27-1.78]), cystitis (1.21 [1.05-1.39]), and urinary tract infections (1.38 [1.18-1.61]). Having at least two of these five health conditions resulted in an exacerbated risk of occurrence of MS for men (pooled OR 2.46 [2.05-2.95]) compared to women (OR 1.31 [1.20-1.43]). However, none of these conditions was selectively associated with MS in comparisons with both lupus and Crohn’s disease. All five ICD-10 codes identified were still associated with MS during the five years after diagnosis.

Conclusion: We identified 5 health conditions associated with subsequent MS diagnosis, which may be considered not only prodromal but also early-stage symptoms. However, these health conditions overlap with prodrome of two other autoimmune diseases, hence lacking specificity to MS.

Disclosure of interest: Celine Louapre : has received consulting or travel fees from Biogen, Novartis, Roche, Sanofi, Teva and Merck Serono, none related to the present work.

Laurene Gantzer and Beranger Lekens are full time employees of Cegedim.

Octave Guinebretiere : Nothing to disclose.

Thomas Nedelec : Nothing to disclose.

Stanley Durrleman : Nothing to disclose.

P442/1887

Exposure to oral contraceptives is not associated with subsequent MS: evidence from a large, diverse primary care cohort

Qiqi Zhang¹, Alastair Noyce¹, Charles Marshall¹, Ruth Dobson¹

¹Wolfson Institute of Population Health, Queen Mary University London, Preventive Neurology Unit, London, United Kingdom

Introduction: Conflicting data exists around oral contraceptive exposure and subsequent MS. Secondary care-based case-control studies associate oral contraceptive use with higher risk of MS, however primary-care record studies associated “ever” use with lower subsequent MS risk. Evidence that prescription practices may change during the MS prodrome support a behavioural influence on these observations.

Objectives/Aims: To investigate exposure to oestrogen-containing (COCP) and progesterone-only (POP) oral contraceptives in the years prior to MS diagnosis.

Methods: A nested case control study was performed using East London electronic primary care data. Cases had a diagnosis of MS with associated date; 4 age-matched controls were assigned per case. Each control was assigned a dummy date of MS diagnosis corresponding to diagnosis date of their matched case. Analyses were restricted to females. Logistic regression was used to evaluate associations between contraceptive exposure and subsequent MS, without and with adjusting for age, ethnicity, and Index of Multiple Deprivation (IMD). Three time periods (0-2, 2-5, and >5 years before diagnosis) were analysed in addition to the entire pre-diagnostic period.

Results: 4470 females were included: 894 cases and 3576 controls. Median age at MS diagnosis was 35.0 years; 61.9% MS cases were White. No association was seen between ever use of oral contraceptive and subsequent MS (unadjusted odds ratio, uOR 1.12, 95%CI 0.94–1.34; adjusted OR, aOR 1.13, 95%CI 0.94–1.35).No effect was seen when restricting to COCP (ever uOR 1.11, 95%CI 0.91–1.35; aOR 1.09, 95%CI 0.89–1.34) or POP (ever uOR 1.14, 95%CI 0.91–1.41; aOR 1.14, 95%CI 0.9–1.42). No relationship was seen between any contraceptive, COCP or POP use at either 0-2, 2-5, or >5 years prior to MS. No clear sequential change in odds of overall contraceptive or COCP use during the time epochs studied was seen.

Conclusion: In the largest population-based study of oral contraceptive use prior to MS to date, we find no evidence to support a disease modifying or delaying effect of either oestrogen containing or progesterone only oral contraceptives prior to diagnosis.

Disclosure of interest: QZ: nothing to disclose

AN: nothing to disclose

CM: nothing to disclose

RD has received payments to her institution, including grants from Biogen, Merck, Celgene, National MS Society, MS Society UK, Horne Family Trust, and the BMA Foundation; honoraria and/or advisory board payments to institution from Biogen, Janssen, Merck, Novartis, Roche, Sanofi, Sandoz, and Teva; and received support for attending meetings or travel from Biogen, Janssen, Merck, Novartis, Roche, and Sanofi

P443/2074

The impact of changing diagnostic criteria on disability in a 25-year Brazilian cohort of multiple sclerosis

Felipe Menezes¹, ALEXANDRE LOPES¹, Jessica Alencar¹, Nilton Souza¹, Denis Bichuetti¹, Enedina Oliveira¹

¹Universidade Federal de São Paulo, Neurology Department, Sao Paulo, Brazil

Introduction: Multiple sclerosis (MS) diagnostic criteria (DC) showed increased sensitivity with each update. It allows early diagnosis and treatment, preventing accumulated disability.

Objectives/Aims: Evaluate if new DC provided earlier diagnosis through decades in Brazilian patients and assess the impact of changing DC on acquiring a severe disability.

Methods: Retrospective study of patients admitted between 1994 and 2019, aged 18 years (yrs) or older at disease onset, with any MS phenotype. We compared three groups according to the epoch of the first appointment (appt). Epoch 1 (E1) was between 1994 and 2001, when Poser criteria were the default for MS diagnosis, Epoch 2 (E2) from 2002 to 2010, equivalent to the use of McDonald 2001 (Mc01) and 2005 (Mc05) criteria, and Epoch 3 (E3), between 2011 and 2019, corresponding to the use of McDonald 2010 (Mc10) and 2017 (Mc17) criteria. We performed logistic regression (LR) to measure the impact of updating DC on achieving the EDSS 6. We grouped patients according to DC used: Poser, Mc01 and Mc05, and Mc10 and Mc17. For multivariate LR, we also used as independent variables: incomplete recovery of first symptoms (IRFS), the time between first and second relapse, and annualized relapse rate (ARR) of the first 2 and 5 yrs. We used R software®.

Results: We included 629 patients: 71% woman, 72% White, and 12.3 yrs of median disease duration. Time to diagnosis was 2.5 yrs for E3, 3.4, and 3.5 for E2 and E1, respectively (p=007). The E3 had a median age at first appt of 33.5 yrs, while E2 had 36.1 and E1 had 37.2 (p=0.005). The ARR before the first appt was 1.1 in, 0.8 in, and 0.5 in E3, E2, and E3, respectively (p=001), denoting a shorter time to diagnosis. Simple LR demonstrated that Mc01 and Mc05 patients had an OR 0.36 (95% confidence interval 0.29-0.76) to reach the EDSS 6.0, compared to Poser, while Mc10 and Mc17 patients had an OR 0.13 (0.07-0.24). Multivariate LR showed that IRFS was the most significant negative prognostic factor with an OR 9.98 (6.10-16.34)—however, the more recent the DC, the lower the risk of reaching EDSS 6.0. We found a probability of achieving EDSS 6.0 around 65% for Poser, 50% for Mc01 and Mc05, and 25% for Mc10 and Mc17.

Conclusion: Updating DC impacted early MS diagnosis among Brazilian patients, modifying the risk of reaching severe disability. We still need prospective studies to fully assess the impact of different factors on their natural history.

Disclosure of interest: Felipe Menezes: nothing to disclose.

Alexandre Lopes: nothing to disclose.

Jéssica Alencar: nothing to disclose.

Nilton Souza: nothing to disclose.

Enedina Oliveira has received speaker fee from Teva, Biogen Idec, Sanofi-Genzyme and Novartis, travel grant from Merck; consulting honoraria from Merck, Sanofi-Genzyme.

Denis Bichuetti has received speaking/consulting honoraria from Bayer Health Care, Biogen Idec, Merck, Sanofi-Genzyme, TEVA and Roche and had travel expenses to scientific meetings sponsored by Bayer Health Care, Merck Serono, TEVA and Roche.

P444/269

Neuropathic pain-related pharmacotherapy and the multiple sclerosis prodrome: A population based matched cohort study

Himali Bergeron-Vitez^1,2, Fardowsa Yusuf^3,4, Feng Zhu⁴, Yinshan Zhao⁴, Charity Evans⁵, John Fisk⁶, Ruth Ann Marrie⁷, John Kramer^1,2,4, Helen Tremlett⁴

¹University of British Columbia, International Collaboration on Repair Discoveries (ICORD), Vancouver, Canada, ²University of British Columbia, Faculty of Medicine, Department of Anesthesiology, Pharmacology and Therapeutics., Vancouver, Canada, ³University of British Columbia, School of Population and Public Health, Vancouver, Canada, ⁴University of British Columbia, Djavad Mowafaghian Centre for Brain Health and Faculty of Medicine (Neurology), Vancouver, Canada, ⁵University of Saskatchewan, College of Pharmacy & Nutrition, Saskatoon, Canada, ⁶Dalhousie University, Nov Scotia Health and the Departments of Psychiatry, Psychology & Neuroscience, and Medicine, Halifax, Canada, ⁷University of Manitoba, Health Sciences Centre, Max Rady College of Medicine, Rady Faculty of Health Sciences, Departments of Internal Medicine and Community Health Sciences, Health Sciences Centre, Winnipeg, Canada

Introduction: There is growing evidence of a prodromal phase in multiple sclerosis (MS) which may involve increased health care visits for pain-related issues in the years preceding MS onset. After diagnosis, over 50% of MS patients experience neuropathic pain, with gabapentinoids and/or other anticonvulsants among the first-line treatments for neuropathic pain. However, little is known about the use of such treatments during the prodromal phase (pre-MS onset).

Objectives/Aims: To estimate the use of neuropathic pain-related medications in the five years before MS onset.

Methods: This was a population-based matched cohort study which utilized linked health administrative data from British Columbia, Canada from 1996 to 2013. Individuals with ⩾3 MS-specific physician and/or hospital claims coded by International Classification of Diseases (ICD)-9/10 (340/G35), and/or with ⩾1 MS disease-modifying drug prescriptions, were defined as MS cases. The cases’ first demyelinating-disease related claim was defined as the index date. Up to 5 controls from the general population were matched to cases by sex, age, calendar-year, and geographic location at the index date. In the five years before the index date, cases and controls were compared for whether they had ⩾1 prescription for any anticonvulsants, and ⩾1 prescriptions for gabapentanoids not combined with other anticonvulsants (use of both drugs may suggest treatment for epilepsy). Odds ratios (aOR) and 95% confidence intervals (CIs) adjusted for sex and age at the index date were estimated using logistic regression.

Results: The cohort comprised 4,862 MS cases and 22,669 controls, and most were female (72%). In the 5 years before the index date, 992 (20%) cases and 1,600 (7.1%) controls filled at least one prescription for any anticonvulsant, while 371 (7.6%) cases and 473 (2.1%) controls filled at least one prescription for gabapentinoids without other anticonvulsants. The odds of a filled prescription were higher for cases than controls for any anticonvulsants (aOR = 3.40, 95% CI: 3.12, 3.71), and for gabapentinoids without other anticonvulsants (aOR = 4.05, 95% CI: 3.52, 4.66).

Conclusion: Pharmacotherapy medications use as first-line treatments for neuropathic pain was more common in the five years before a first demyelinating event (‘MS onset’) for those with MS versus the matched general population. Results suggest that neuropathic pain may be part of the MS prodrome, which may provide opportunities for earlier recognition and intervention.

Disclosure of interest: Acknowledgments:

This study was supported, in part, by the National Multiple Sclerosis Society and MS Canada (RG5063A4/1; RFA-2103-37392; EGID: P002; PI:Tremlett).

Access to data provided by the Data Steward(s) is subject to approval but can be requested for research projects through the Data Steward(s) or their designated service providers. All inferences, opinions, and conclusions drawn in this publication are those of the author(s), and do not reflect the opinions or policies of the Data Steward(s).

Disclosures:

Helen Tremlett has received research support in the last 3 years from the: Canada Research Chair Program, National MS Society, Canadian Institutes of Health Research, Canada Foundation for Innovation, MS Canada, and the EDMUS Foundation (‘Fondation EDMUS contre la sclérose en plaques’).

Fardowsa Yusuf is funded by a Fredrick Banting and Charles Best Canada Graduate Scholarship from the Canadian Institutes of Health Research (CIHR).

Ruth Ann Marrie receives research funding from: Canadian Institutes of Health Research, Research Manitoba, Multiple Sclerosis Society of Canada, Multiple Sclerosis Scientific Foundation, Crohn’s and Colitis Canada, National Multiple Sclerosis Society, Consortium of MS Centers, the Arthritis Society, US Department of Defense, is supported by the Waugh Family Chair in Multiple Sclerosis, and is a co-investigator on a study funded in part by Biogen Idec and Roche (no funds to her or her institution)

John D. Fisk received research grant support from the Canadian Institutes of Health Research, the National Multiple Sclerosis Society, the Multiple Sclerosis Society of Canada, Crohn’s and Colitis Canada and Research Nova Scotia, and consultation and distribution royalties from MAPI Research Trust.

Himali Bergeron-Vitez, Feng Zhu, Charity Evans and John L.K. Kramer have no disclosures to declare.

P445/1011

The effect of multiple sclerosis on cancer risk: A Mendelian randomization study

Asli Buyukkurt^1,2, Ali Manouchehrinia³, Paul Giacomini^1,2, Adil Harroud^1,2,4

¹The Neuro (Montreal Neurological Institute-Hospital), Montreal, Canada, ²McGill University, Department of Neurology and Neurosurgery, Montreal, Canada, ³Karolinska University Hospital, Department of Clinical Neurosciences, Stockholm, Sweden, ⁴McGill University, Department of Human Genetics, Montreal, Canada

Introduction: Determining the baseline cancer risk in people with multiple sclerosis (MS) is of increasing interest partly due to elevated rates of secondary malignancies reported with immune-targeting disease modifying therapies. However, observational studies investigating cancer risk in people with MS have thus far produced conflicting findings with varying quality of evidence.

Objectives/Aims: To examine the evidence for a direct effect of genetic liability to MS on the risk of 12 common cancers using Mendelian randomization (MR).

Methods: We assembled genome-wide genetic associations with 12 common cancers, including melanoma, basal and squamous cell carcinomas, lymphoma, and breast, colorectal, lung, bladder, ovarian, endometrial, cervical, and prostate cancers. The sample sizes ranged from 85,716 to 490,803 individuals. To identify putative causal effects of MS on each cancer, we applied a range of MR methods using independent MS-associated variants from 47,429 MS cases and 68,374 controls. Analyses were performed with and without variants in the human leukocyte antigen (HLA) region given its increased potential for bias from pleiotropy due to extensive and long-range linkage disequilibrium.

Results: After correcting for multiple testing, we found no robust evidence of an effect of genetic liability to MS on the risk of any of the 12 cancers. There was a weak nominal association between MS liability and risk of cervical cancer only when including HLA variants (OR = 1.03 per doubling odds of MS, 95% CI = 1.01 to 1.06, P_unadjusted = 0.004). This association was driven entirely by pleiotropy in the HLA region, consistent with the roles of HLA and human papillomavirus infection in cervical cancer. We found another nominal association with risk of lymphoma (OR = 1.05, 95% CI = 1.01 to 1.09, P_unadjusted = 0.03), although this was not maintained after adjusting for multiple testing (P_FDR = 0.20) and sensitivity analyses revealed significant heterogeneity (I² = 0.54).

Conclusion: This study suggests that genetic liability to MS does not have a strong impact on the risk of common cancers. The results also reveal similarities in HLA risk between MS and cervical cancer and suggest potential shared genetic risk between MS and lymphoma that warrants further investigation. Future research should explore indirect and potentially modifiable contributors to cancer risk in MS, such as screening practices, lifestyle behaviours, and the use of disease modifying therapies.

Disclosure of interest: Ali Manouchehrinia has received funding from Margaretha af Ugglas Foundation. Adil Harroud has received consulting fees from Biogen, unrelated to the present work. Asli Buyukkurt and Paul S. Giacomini: Nothing to disclose.

P446/2092

The impact of SARS-CoV-2 pandemics on mortality for multiple sclerosis in Italy

Daiana Bezzini¹, Lucia Kundisova², Monica Ulivelli³

¹University of Siena, Life Sciences, Siena, Italy, ²ASL Toscana Centro, Pistoia, Italy, ³University of Siena, Medicine, Surgery and Neuroscience, Siena

Introduction: The SARS-CoV-2 pandemics occurred in 2020 had an unfavorable impact on overall mortality in Italy, both directly and indirectly. Most of subjects developing a severe form of COVID-19 had other comorbidities and this combination could bring to an increase of mortality.

Objectives/Aims: Our aim was to investigate the impact of COVID-19 in Italy on mortality for Multiple Sclerosis

Methods: Based on mortality data provided by the Italian National Institute of Statistics, an annual age-Standardized Mortality Rates (AMRs) for PD were computed for each year of the study period (1980-2020). The mortality trend was evaluated also through the joinpoint regression model, estimating the Annual Percent Change.

Results: From 1980 to 2020, 15,391 deaths for MS were recorded, 6,080 in males and 9,311 in females with a mean AMR of 0.58 per 100,000 (95% CI: 0.56-0.50) and 0.76 (95% CI: 0.75-0.78), respectively. From a first preliminary analysis, the linear regression analysis for whole Italy showed an initial decrease, more marked in males (females: up to 1991, APC -0.88%; males: up to 1996, APC -3.03%, p<0.05), followed by an increase in both sexes (females APC 3.18%, p<0.05; males APC 2.21%). No evidence of increasing mortality due to the pandemics was observed also analysing the trend in the different geographical areas

Conclusion: An increase of mortality for MS was observed from around 1991-96, but in the first year of SARS-CoV-2 pandemics we did not observe a peak of deaths. In fact, comparing 2019 and 2020 we recorded no statistically significant differences of AMRs in both sexes (females: from 1.0 to 1.13 per 100,000; males from 0.74 to 0.77).

Disclosure of interest: Daiana Bezzini, Lucia Kundisova, Monica Ulivelli: nothing to disclose

P447/438

Migraine in the multiple sclerosis prodrome. A prospective nationwide cohort study

Karine Eid^1,2, Øivind Torkildsen^1,3, Jan Harald Aarseth^3,4, Marianna Cortese¹, Trygve Holmøy^5,6, Kjell-Morten Myhr^1,3, Trond Riise^3,7, Cecilie Torkildsen⁸, Stig Wergeland^2,3, Nils Erik Gilhus^1,2, Marte-Helene Bjørk^1,2

¹University of Bergen, Department of Clinical Medicine, Bergen, Norway, ²Haukeland University Hospital, Department of Neurology, Bergen, Norway, ³Neuro-SysMed, Haukeland University Hospital, Department of Neurology, Bergen, Norway, ⁴The Norwegian Multiple Sclerosis Registry and Biobank, Haukeland University Hospital, Bergen, Norway, ⁵Akershus University Hospital, Department of Neurology, Lørenskog, Norway, ⁶Institute of Clinical Medicine, University of Oslo, Oslo, Norway, ⁷University of Bergen, Department of Global Health and Primary Care, Bergen, Norway, ⁸Stavanger University Hospital, Department of Obstetrics and Gynecology, Stavanger, Norway

Introduction: People with multiple sclerosis (MS) have an increased risk of experiencing migraines. It is unknown whether migraine co-occurs with MS due to common etiology, risk factors, or MS disease activity. Some evidence also suggest that migraine could be a part of the preclinical MS prodrome, especially in the years close to MS symptom onset.

Objectives/Aims: To study the risk of migraine in women with preclinical MS.

Methods: We studied pregnant women participating in the Norwegian Mother, Father and Child cohort study 1999–2008. We identified 246 women with preclinical MS through linkage with national health registries in 2018. Of these, 116 women had MS symptom onset 1–5 years after participating, 92 women after 6–10 years, and 38 women after 11–17 years. The women reported in a self-completed questionnaire in pregnancy week 18 if they had ever suffered from migraine or “other headache” prior to or during pregnancy. We excluded women with established MS diagnosis (n= 114) and women who already had their first clinical symptom of MS, but not yet an MS diagnosis (n= 81). The reference group comprised all other women participating in MoBa (n= 85,030). We used logistic regression to estimate adjusted odds ratios (aORs) with 95% confidence intervals (95% CIs).

Results: Migraine before or during pregnancy was more common among women with preclinical MS compared to the reference group, 18% vs 11%, OR 1.61 (1.2–2.3), after adjusting for age, smoking, socioeconomic status and overweight. The association persisted after additional adjustment for current and previous depression. The risk of other types of headaches was similar for women with preclinical MS compared to the reference group, 29% vs 27%, aOR 1.07 (0.8–1.4). Migraine was reported by 21 of 116 (18%) women with ⩽ 5 years until MS symptom onset (aOR 1.72 [1.1–2.8]) and 19 of 92 (21%) women with 6–10 years until MS symptom onset (aOR 1.89 [1.1–2.8]. 3 of 38 (8%) women with > 10 years until MS symptom onset reported migraine, aOR 0.69 (0.2–2.2).

Conclusion: Women with preclinical MS have increased risk of migraine, but not other headaches. This supports that migraine could be a symptom of the MS prodrome, up to a decade before the onset of classical MS symptoms. Special attention in people with migraine may lead to earlier recognition of MS.

Disclosure of interest: K.Eid has received research funding and speakers honaria from Novartis.

Ø.Torkildsen has received speaker honoraria from Teva, Novartis, Merck, Biogen, Sanofi, Bristol Myers Squibb

J.Aarseth reports no disclosures.

M.Cortese has received speaker honoria from Roche.

T.Holmøy has received speaker honoraria from Roche, Novartis, Merck, Biogen, Sanofi, Bristol Myers Squibb

KM.Myhr has received unrestricted research grants to his institution; scientific advisory board and speaker honoraria from Biogen, Merck, Novartis, Roche and Sanofi, and has participated in clinical trials organised by Biogen, Merck, Novartis, Roche and Sanofi.

T.Riise reports no disclosures.

CF. Torkildsen reports no disclosures.

S. Wergeland has received speaker honoraria from Novartis, Biogen, Sanofi

NE.Gilhus has received speaker’s or consultative honoraria from UCB, Argenx, Janssen, Roche, Merck, Alexion, Immunovant, Huma, Ra Pharma.

MH. Bjørk has received fees paid to her institution by valproate market authorization holders for EMA-mandated contract research; personal fees from Eisai, Novartis Norway, Jazz Pharmaceuticals, Angelini Pharma, Teva, Lilly, and Lundbeck; and grants from the Research Council of Norway and NordForsk

P448/844

Impact of COVID-19 and resiliency of the system in delivering healthcare to people with multiple sclerosis: A population-based study

Marcello Moccia^1,2, Giuseppina Affinito³, Ugo Trama⁴, Laura Palumbo³, Maria Grazia Gumo⁵, Roberta Giordana⁵, Massimo Di Gennaro⁵, Maria Triassi³, Roberta Lanzillo^2,6, Vincenzo Brescia Morra^2,6, Raffaele Palladino^3,7

¹Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy, ²Multiple Sclerosis Unit, Policlinico Federico II University Hospital, Naples, Italy, ³Department of Public Health, University of Naples Federico II, Naples, Italy, ⁴Regione Campania Health Department, Naples, Italy, ⁵Regional Healthcare Society (So.Re.Sa), Naples, Italy, ⁶Department of Neuroscience, Reproductive Sciences and Odontostomatology, Federico II University of Naples, Naples, Italy, ⁷Department of Primary Care and Public Health, Imperial College London, London, United Kingdom

Introduction: COVID-19 pandemic has profoundly affected the management of multiple sclerosis (MS), which did not necessarily resume at pre-pandemic levels.

Objectives/Aims: To evaluate the impact of COVID-19 pandemic and the resiliency of the healthcare system in delivering services to people with MS.

Methods: This is a population-based study, using retrospective analysis of routinely-collected healthcare data from 2015 to 2021. We included 6,097 MS patients from the validated cohort of the Campania Region (Italy). We identified 4 periods: pre-COVID-19 (January 2015-February 2020), lockdown (March 2020-May 2020), pre-vaccination (June 2020-December 2020), and vaccination (January 2021-December 2021). Differences in continuous outcomes between periods were explored using linear mixed models (annualized hospitalization rate (AHR) and adherence measured as medication possession ratio (MPR)). Differences in new disease modifying treatment (DMT) prescription rates (first DMT prescription, any DMT switch, switch from platform to highly effective DMT, and combination of first DMT prescription and any DMT switch) were assessed employing an interrupted time series design using a Poisson distribution.

Results: When compared with pre-COVID-19 period, AHR decreased during the lockdown (Coeff=-0.64; 95%CI = -0.69, -0.59; p<0.01), and remained significantly lower during pre-vaccination and vaccination periods. When compared with the pre-COVID-19 period, adherence (MPR) decreased during pre-vaccination (Coeff = -0.04; 95%CI = -0.05, -0.03; p<0.01) and vaccination periods (Coeff = -0.07; 95%CI =-0.08, -0.07; p<0.01). After the lockdown, there was an increase in any DMT switch (IRR 2.05 95%CI 1.38, 3.05; p<0.01), in switch from platform to highly effective DMTs (IRR 4.45; 95%CI 2.48, 8.26; p<0.01) and in first DMT prescriptions (IRR 2.48; 95%CI 1.64, 3.74; p<0.01).

Conclusion: The COVID-19 pandemic has changed the management of MS, but the return in the use of DMTs to pre-COVID-19 levels suggests good health system resilience. However, adherence has remained lower than the past, as from suboptimal care. Long-term assessment of COVID-19 impact on MS healthcare is needed.

Disclosure of interest: MM has received honoraria from Biogen, Merck, Novartis, Roche, and Sanofi-Genzyme. RL has received honoraria from Biogen, Merck, Novartis, Roche, and Sanofi-Genzyme. VBM has received research grants from Roche, and the Italian MS Foundation; honoraria from Almirall, Biogen, Ipsen, Merck, Novartis, Roche, Sanofi-Genzyme.

P449/2058

Changing age of multiple sclerosis onset from 1920 to 2022: a population-based study in Western Norway

Andrea Habbestad^1,2, Johannes Sverre Willumsen^3,4, Jan Harald Aarseth^1,5, Nina Grytten^1,2, Rune Midgard³, Stig Wergeland^1,2,5, Kjell-Morten Myhr^1,2, Øivind Torkildsen^1,2

¹Neuro-SysMed, Bergen, Norway, ²University of Bergen, Clinical medicine, Bergen, Norway, ³Molde Hospital, Molde, Norway, ⁴Norwegian University of Science and Technology, Trondheim, Norway, ⁵Norwegian Multiple Sclerosis Registry and Biobank, Bergen, Norway

Introduction: Increasing age at multiple sclerosis-onset has recently been reported in different populations with a disproportionally high rate of late-onset multiple sclerosis (MS). Furthermore, there has also been reported an increasing incidence of MS among women, most pronounced with late onset. Whether these observed changes represent a global trend is unknown.

Objectives/Aims: To study change in age at onset of relapsing-remitting multiple sclerosis (RRMS) during the past century.

Methods: This is a population-based cohort study of persons diagnosed with RRMS in two Norwegian counties, Hordaland and Møre og Romsdal, from 1920 to 2022. Participants were identified through hospital records, the Norwegian Multiple Sclerosis Registry and Biobank and previous epidemiological studies in the same counties. Participants were categorized according to onset period before statistical analysis on temporal trends in age at onset, time from onset to diagnosis and distribution of onset over time.

Results: We identified 3364 persons with confirmed RRMS. The mean age at onset significantly increased (p<0.001) throughout the study period, despite a decrease in time from symptom onset to diagnosis (p<0.001). The proportion of persons with MS onset after 40 years of age increased from 2.6% before 1970 to 11.9% after 2010. We also found a trend towards a bimodal distribution of age at onset that peaked at around 30 years and 40-45 years of age in the latest period.

Conclusion: Age at onset of MS significantly increased throughout the study period. We found an increase in the absolute number of persons with age at onset ⩾40 years, whereas the number of patients with age of onset <40 years did not change during the observation period. The trend was most evident in women. This bimodal distribution could indicate different susceptibility periods of MS or changes in exposure to risk factors during the observation period.

P450/144

The multiple sclerosis prodrome: Rates of physician visits were elevated in the 15 years before a first demyelinating event and differed by age and sex; an international matched cohort study

Helen Tremlett¹, Feng Zhu¹, Asaf Ayesha², Ali Manouchehrinia³, Fardowsa Yusuf¹, Ping Li², Kyla McKay³, Yinshan Zhao¹, Colleen Maxwell⁴, Ruth Ann Marrie⁵

¹The University of British Columbia, Vancouver, Canada, ²ICES, Toronto, Canada, ³Karolinska Institutet, Stockholm, Sweden, ⁴University of Waterloo, Toronto, Canada, ⁵University of Manitoba, Winnipeg, Canada

Introduction: Elevated heath care use, including higher rates of physician visits, have been seen 5-10 years before MS onset. However, prior studies have focused on one region, rarely examine sex or age differences and few examine an earlier period pre-MS onset

Objectives/Aims: To examine rates of physician visits 15 years (also by age and sex) before a first demyelinating event (MS onset) in Ontario, Canada and Sweden (combined population [2019]=24.9 million)

Methods: Using population-based linked administrative and registry data from Canada and Sweden, we identified MS cases via a validated algorithm, requiring ⩾3 hospital or physician MS diagnostic codes (International Classification of Diseases 9/10 340/G35). The earliest MS/demyelinating disease code defined MS onset (the index date), and ⩾5 years of residency with no such codes pre-index date ensured that cases were incident. Cases were matched by sex, birth year, region (postal code or county) at the index date, and residency time in the region, with up to 5 controls from the general population who had no MS/demyelinating disease codes. We compared physician visit rates in each of the 15 years pre-MS onset between cases and controls using negative binomial regression with generalized estimating equations. Effect modification by sex and age (<18, 18-<30, 30-<50, ⩾50 years) was assessed via interaction terms. Adjusted rate ratios (RRs) and 95% confidence intervals from Canada and Sweden were combined via random-effects meta-analyses.

Results: We included 46,727 MS and 194,493 matched controls; 69% were female, averaging 43 years at the index date (SD=10). Physician visits in the 15 years pre-MS onset were higher for MS cases than controls. The relative increase in annual rates of visits among MS cases rose steadily from 15 years pre-MS onset (RR:1.18, 1.08-1.29), peaking one year prior (RR:3.02, 2.64-3.45). Relative rates of physician visits were higher for males and younger individuals. In the year pre-MS onset, the RR for males (MS vs controls) was 3.02 (2.64-3.45) and females was 2.35 (1.70-3.25) and RRs declined from 3.52 to 2.24 (MS vs controls) for the youngest (<18 years) to oldest (⩾50 years).

Conclusion: In this international study, rates of physician visits were higher for MS cases than matched controls up to 15 years before MS onset. Sex and age affected findings; a higher relative burden (visit rates) was seen for males and amongst younger persons with MS. Findings suggest an extended and likely heterogeneous prodromal phase worthy of phenotyping.

Disclosure of interest: Feng Zhu: nothing to disclose

Ayesha Asaf: nothing to disclose

Ali Manouchehrinia: nothing to disclose

Ping Li: nothing to disclose

Yinshan Zhao: nothing to disclose

Fardowsa Yusuf is funded by a Fredrick Banting and Charles Best Canada Graduate Scholarship, Canadian Institutes of Health Research.

Kyla A McKay is funded by the Swedish Research Council for Health, Working Life and Welfare and has received speaker honoraria from Biogen (2022) and Sanofi-Aventis (2023).

Colleen Maxwell receives research funding from a University of Waterloo Research Chair, CIHR, Multiple Sclerosis Society of Canada, National Multiple Sclerosis Society, CMSC and the Public Health Agency of Canada.

Helen Tremlett has received research support in the last 3 years from the: Canada Research Chair Program, National MS Society, Canadian Institutes of Health Research, Canada Foundation for Innovation, MS Society of Canada, MS Scientific Research Foundation and the EDMUS Foundation (‘Fondation EDMUS contre la sclérose en plaques’).

Ruth Ann Marrie receives research funding from: CIHR, Research Manitoba, Multiple Sclerosis Society of Canada, Multiple Sclerosis Scientific Foundation, Crohn’s and Colitis Canada, National Multiple Sclerosis Society, CMSC, The Arthritis Society, US Department of Defense and UK MS Society, and is a co-investigator on studies funded in part by Biogen Idec and Roche (no funds to her or her institution).

P451/285

Chronic infections and malignancy screening in Mexican patients with multiple sclerosis before initiating disease modifying treatments

Lizeth Zertuche-Ortuno¹, LINDA RIVERA SARABIA¹, Juan Garcia Ramirez¹, Victor Hernandez Castillo¹, Irene Treviño Frenk¹

¹National Institute of Medical Sciences and Nutrition, Mexico City, Mexico

Introduction: Initiating disease-modifying therapy (DMT) with highly effective drugs for multiple sclerosis (MS) is becoming more common, given the evidence supporting long-term benefits in slowing disease progression. While these therapies have an adequate safety profile, they have a significant immunosuppressive effect, which confers a theoretical increased risk of infections and malignancy. For these reasons, screening studies have been recommended prior to the initiation of DMT, with the aim of ruling out neoplasms and chronic infections that might contraindicate DMT

Objectives/Aims: To illustrate the importance of screening prior to initiating DMT and show the most frequent findings in a third world country.

Methods: We analyzed patients admitted to the MS clinic from 2020-2023, who underwent screening prior to initiating DMT. All patients were sampled for QuantiFERON for tuberculosis, serology against varicella zoster (VZV IgG), human immunodeficiency virus, hepatitis B virus, hepatitis C virus and VDLR, as well as Pap smear and mammogram in women

Results: We analyzed 102 patients, 73 were women (71.5%), and the average age was 42.8 ±15, average EDSS score was 2.72 ±1.8. 65% of patients with RRMS, 41% with PMSS and 19% with PPMS. Pathological findings were detected in 20 (19%) patients: latent tuberculosis 12 (11.7%), cervical human papillomavirus (HPV) infection 3 (4.1%), penile HPV 1 (0.98%), benign thyroid nodule 2 (1.9%), papillary thyroid carcinoma 1 (0.98%) and intraductal breast papilloma 1 (0.98%). None of these patients developed complications after DMT initiation. The time between screening tests and the start of DMT was 21.3 ± 14 days in patients without pathological findings, while in patients with any pathological findings it took 96.2 ± 78 days.

Conclusion: The implementation of screening tests prior to DMT allows to rule out potential contraindications for immunosuppressive treatments. Additionally, this increases the detection and treatment of chronic diseases, that even though they may be asymptomatic, could require changes in the therapeutic behavior, as well as delaying the onset of DMT.

Disclosure of interest: Lizeth Zertuche: Nothing to disclose

Victor Hernández: Nothing to disclose

Linda Rivera Sarabia: Nothing to disclose

Juan García: Nothing to disclose

Irene Treviño Frenk: Nothing to disclose

P452/594

Age-, period- and cohort-specific trends in inpatient treatment of multiple sclerosis

Richard Schmidt¹, Florian Then Bergh¹

¹University Hospital Leipzig, Department of Neurology, Leipzig, Germany

Introduction: While disease modifying therapy (DMT) for multiple sclerosis (MS) is increasingly managed in outpatient clinics, expedited diagnostic evaluation, relapse treatment and advanced symptom management remain reasons for inpatient treatment. Accurate data on MS associated hospital admissions and influencing factors are necessary to reasonably allocate resources. When investigating the influence of time on disease course, the linear relationship of age (A), period (P), and cohort (C) must be considered (A=P-C), which is why trends must be considered comprehensively.

Objectives/Aims: To investigate trends in hospital admissions of MS linked to age, period, and cohort.

Methods: Hospital administration and population data from the German Federal Statistical Office were used to extract hospital admissions due to MS from 2000 to 2020. Differences in age-, period- and cohort-specific time trends of admission rates (per 100,000) were investigated (mean (M); standard deviation (SD); 95% confidence interval (CI)).

Results: In both sexes, the age group 45 – 49yrs showed highest admission rates (male M=77.93, SD=11.01; female M=157.06, SD=27.30) with significantly lower rates in younger and older ages. Similarly, persons born between 1961 and 1965 showed significantly higher admission rates (male M=76.93, SD=15.48; female M=151.92, SD=31.25) than those born earlier or later. No significant changes over the observed period were seen, although admission rates were lowest in 2020 (male M=36.64, SD=19.68; female M=71.65 SD=37.87). Differences among birth cohorts within the same age group were seen, for example admission rate of women 45-49 years old and born 1971-1975 was lower than that of women at the same age born 1961-1965 (113.33 [CI 108.79-118.00]; 185.60 [CI 180.91-190.37]).

Conclusion: MS-associated hospital admission rates vary between different ages, years, and birth cohorts, which all interact. Frequently discussed differences between age groups may be due to biological effects of ageing but generational and time-historical effects such as growing awareness, introduction of DMT or environmental/societal impact, e.g., the Covid-19 pandemic and responses to it, must be considered. This study highlights the importance of complementary assessment of age, period, and cohort. Future studies should investigate causes of such changes in inpatient treatments due to MS, to estimate future requirements and plan accordingly.

Disclosure of interest: Richard Schmidt: nothing to disclose; Florian Then Bergh: nothing to disclose.

P453/765

Clinical outcomes and treatment strategy of multiple sclerosis in China: Results from a real-world cross-sectional survey

Xiao Zhang¹, Shuang Cai¹, Jie Cai¹, Yuxiang Yang¹, Wenhao Wang¹, Eddie Jones², mia unsworth²

¹Novartis Pharma AG, beijing, China, ²Adelphi real world, Manchester, United Kingdom

Introduction: Multiple sclerosis (MS) is a leading cause of disability, affecting especially young adults. The data on clinical outcome, such as no evidence of disease activity (NEDA) and treatment strategies remains very limited in China.

Objectives/Aims: In this study, we aim to describe status of diagnosis, treatment, and clinical outcomes in patients with MS, as well as treatment strategies in neurologists in real-world clinical setting in China.

Methods: This study is a secondary data analysis of data collected by Adelphi MS Disease Specific Program (DSP), a cross-sectional survey conducted among neurologists (n=160) and their MS patients (n=956) in different district of China between June and August 2021.

Results: In preventive treatment, 30.1% patients received the disease modifying treatment (DMT). Among these patients, the percentage of patients with progressive MS is higher than that of patients with relapsing-remitting MS (RRMS) (secondary progressive MS [SPMS]: 36.9%, primary progressive MS [PPMS]: 41.5%; RRMS:28.0%). The mean duration from diagnosis to receiving DMT was 3.7±3.8 years, and this duration in SPMS was the longest (8.0±4.8 years). Among 540 patients with complete follow-up data, 27.4% patients achieved no evidence of disease activity (NEDA)-3 in the past 12 months. In addition, among 160 neurologists, when patients had 1 relapse, disability progression without relapse and active lesions in MRI without relapse, 42.2%, 39.1% and 62.1% neurologists continued the current treatment respectively.

Conclusion: In China, the percentages of MS patients achieving NEDA-3 were low. This might be due to the low percentage, the late initiation and conservative switching of DMT.

Disclosure of interest: Nothing to disclose

P454/811

Divorce in Iranian multiple sclerosis patients: with focus on the relationship between divorce and prevalence of smoking, alcohol consumption, and substance abuse

Nasim Rezaeimanesh¹, Abdorreza Naser Moghadasi¹, Samira Navardi¹, Naghmeh Abbasi Kasbi¹, Ali Rezaei¹, Shima Jahani¹, Nazgol Behgam¹, Kosar Kohandel¹, Mohammad Ali Sahraian¹

¹Multiple sclerosis research center, Neuroscience institute, Tehran University of medical sciences, Tehran, Iran

Introduction: Multiple sclerosis (MS) may presents various symptoms including psychiatric, cognitive, motor, sensory Etc. Which could affect patients’ personal and social life. The prevalence of divorce is determined in some countries and it seems to be higher than the general population. Based on our knowledge, no study until now mentioned the prevalence of divorce in Iranian patients with MS (PWMS).

Objectives/Aims: To determine the prevalence of divorce and abandonment among Iranian PWMS, their relationship with MS onset, as well as their association with cigarette and water-pipe smoking, alcohol consumption, and substance abuse.

Methods: The present cross-sectional study was conducted at Sina MS research center, Tehran, Iran, from March to April 2023. A researcher-made questionnaire consisting of questions on demographic and clinical data, divorce, smoking, alcohol consumption and substance abuse was designed. This questionnaire was made available to the MS patients in collaboration with the neurologists and the Iran MS society through social networks, and having a definite diagnosis of MS was the criteria for entering this study. Data was analyzed with SPSS version 24 and presented as frequency and percentage.

Results: Totally 433 MS patients were enrolled in the study. The mean± SD age of participants was 34.50±7.10 years old and 65.1% (n:282) were women. The marital status of participants was as follows: 39.1 % (n: 169) single, 49.1 % (n: 212) married, 8.8% (n: 38) divorced [male:10.0%; female:8.2%], 2.3% (n:10) abandonment [male:2.0%; female: 2.5%], and 0.7% (n: 3) widow. Thirty-nine (9.0%) of participants were divorced/abandoned after MS diagnosis, which in 12 (2.8%) cases, MS onset were the reason. Cigarette smoking (P: 0.01), alcohol consumption (P: 0.02), and substance abuse (P<0.01) were significantly different in marital status categories. So, cigarette smoking (80.0%) and alcohol consumption (70.0%) were more prevalent among abandoned patients, and the prevalence of substance abuse was higher in divorced patients (21.1%).

Conclusion: Our results reported the prevalence of divorce and abandonment in Iranian PWMS in total and after MS onset for the first time, and a higher prevalence of cigarette smoking, alcohol consumption and substance abuse in divorced or abandoned patients. Our results can be helpful in policy making and planning in order to improve the socioeconomic status, reduce the burden of disease, improve the quality of life and reduce the prevalence of divorce in MS patients.

Disclosure of interest: N.R, A.N.M, N.A, A.R, Sh.J, N.B, and K.K: The authors declare no conflict of interest.

M.A.S: I have received educational, research grants, lecture honorarium, travel supports to attend scientific meetings from Biogen-Idec, Merck-Serono, Cinnagen, Zistdaru, Zahravi and Genzyme.

S.N: I have received educational, research grants, lecture honorarium, travel supports to attend scientific meetings from Biogen-Idec, Merck-Serono, Cinnagen, Zistdaru, and Nanoalvand.

P455/986

Update from the from the Latin American COVID-19 registry in MS and NMOSD patients

Ricardo Nicolas Alonso^1,2, Berenice Silva^1,3, Domingo Orlando Garcea¹, EDGAR PATRICIO CORREA⁴, Giordani Rodrigues dos Passos⁵, DEYANIRA RAMIREZ⁶, Luis Garcia Valle⁷, Luis Cesar Rodriguez⁸, GERALDINE GABRIELA LUETIC⁹, VERONICA ANALIA TKACHUK¹⁰, Jimena Miguez¹¹, Victor Fernando Hamuy Diaz de Bedoya¹², Lorna Galleguillos¹³, Nicia Ramirez Sanches¹⁴, Marcos Gabino Burgos¹⁵, Judith Steinberg¹⁶, Maria Balbuena¹⁰, Priscilla Monterrey Alvarez¹⁷, Edgar German Carnero Contentti¹⁸, Pablo Adrián López¹⁸, Maria Celica Ysrraelit¹⁹, Rosalva Leon²⁰, Aaron Benzadon-Cohen²¹, Fernando Gracia^22,23, Omaira Molina²⁴, Magdalena Casas¹, Norma Deri²⁵, Agustin Pappolla²⁶, Liliana Patrucco²⁷, Edgardo Cristiano²⁷, Dario Tavolini²⁸, Débora Nadur²⁹, Ana Toral Granda³⁰, Roberto Weiser³¹, Fatima Pagani Cassara^32,33, VLADIMIRO JOAQUIN SINAY³², Claudia Carcamo³⁴, Luciana Lazaro¹, MARIA LAURA MENICHINI³⁵, Raul Ronald Piedrabuena³⁶, Geraldine Orozco Escobar³⁷, Adriana Carra^16,32, Biany Santos Pujols³⁸, Carlos Vrech³⁹, Adriana Tarulla⁴⁰, Rene Carvajal⁴¹, Carolina Mainella⁴², Jefferson Becker⁴³, Javier Hryb⁴⁴, Liesbet Peeters⁴⁵, Clare Walton⁴⁶, Marina Alonso³, Juan Ignacio Rojas²⁷

¹Centro Universitario de Esclerosis Múltiple, Neurología. Hospital Ramos Mejía., Buenos Aires City, Argentina, ²Hospital Universitario Sanatorio Guemes, Neurology, Buenos Aires City, Argentina, ³Hospital Italiano, Neurology, Buenos Aires City, Argentina, ⁴Hospital Carlos Andrade Maín, Quito, Ecuador, ⁵4- Hospital São Lucas - Pontifícia Universidade Católica do Rio Grande do Sul, Rio Grande do Sul, Brazil, ⁶Hospital Docente Padre Billini, Santo Domingo, Dominican Republic, ⁷Hospital Militar Escuela Managua-Nicaragua, Managua, Nicaragua, ⁸Instituto Hondureño De Seguridad Social, Honduras, Honduras, ⁹Instituto de Neurociencias de Rosario, Rosario, Argentina, ¹⁰Hospital de Clinicas Jose de San Martin, Buenos Aires City, Argentina, ¹¹Hospital Italiano, Buenos Aires City, Argentina, ¹²Hospital IMT, Asuncion, Paraguay, ¹³Clinica Alemana, Santiago de Chile, Chile, ¹⁴Hospital Dr. Mario C. Rivas de San Pedro Sula, Honduras, Honduras, Honduras, ¹⁵Hospital San Bernardo, Salta, Argentina, ¹⁶Hospital Británico, Buenos Aires City, Argentina, ¹⁷Hospital San Rafael, San Jose, Costa Rica, ¹⁸Hospital Aleman, Buenos Aires City, Argentina, ¹⁹FLENI, Buenos Aires City, Argentina, ²⁰Private practice, Venezuela, Venezuela, ²¹Complejo Hospitalario CSS, Panama, Panama, ²²Hospital Santo Tomas, Panama, Panama, ²³Universidad Interamericana de Panamá, Panama, Panama, ²⁴Policlinica Maracaibo, Maracaibo, Venezuela, ²⁵Diabaid, Buenos Aires, Argentina, ²⁶CEMCAT, Barcelona, Spain, ²⁷CEMBA, Buenos Aires, Argentina, ²⁸INECO Rosario, Rosario, Argentina, ²⁹Hospital Naval, Buenos Aires, Argentina, ³⁰Hospital José Carrasco Arteaga, Cuenca, Ecuador, ³¹Hospital Horacio Oduber, Aruba, Aruba, Aruba, ³²Instituto de Neurociencias Fundacion Favaloro, Buenos aires, Argentina, ³³Hospital Austral, Pilar, Argentina, ³⁴Pontificia Universidad Católica, Santiago de Chile, Chile, ³⁵Sanatorio Británico de Rosario, Rosario, Argentina, ³⁶Clinica Reina Fabiola; Instituto Lennox, Cordoba, Argentina, ³⁷Hosp.Patrocinio P.Ruiz, San Cristobal, Venezuela, ³⁸Hospital Regional Universitario José Ma Cabral y Báez, Santiago De Los Caballeros, Dominican Republic, ³⁹Sanatorio Allende, Cordoba, Argentina, ⁴⁰Hospital de Agudos P. Piñero, Buenos Aires, Argentina, ⁴¹Hospital Universitario Nacional de Colombia, Bogotá, Colombia, ⁴²Hospital Español de Rosario, Rosario, Argentina, ⁴³43- Hospital São Lucas - Pontifícia Universidade Católica do Rio Grande do Sul, Rio Grande do Sul, Brazil, ⁴⁴Hospital Durand, Buenos Aires, Argentina, ⁴⁵Biomedical Research Institute & Data Science Institute, Hasselt University, Belgium, Belgium, ⁴⁶MS International Federation, London, United Kingdom

Introduction: Despite many studies about the epidemiology of COVID-19 in multiple sclerosis (MS), only a few come from Latin America (LATAM).

Objectives/Aims: The objective of this analysis was to provide an update on the clinical characteristics and outcomes of patients included in RELACOEM, a LATAM registry of MS and NMOSD patients infected with COVID-19.

Methods: RELACOEM is a longitudinal, strictly observational registry of MS and NMOSD patients who contracted COVID-19 in LATAM. The cohort was stratified into MS and NMOSD. Descriptive analyses of demographic and clinical variables were conducted. In MS patients, a binary logistic regression analysis models were performed to identify variables associated with hospitalizations/ICU as composite outcome (dependent variable).

Results: A total of 467 (96.1%) of the patients in the registry had MS and 19 had (3.9%) NMOSD. Of these, 89 patients were hospitalized due to COVID-19 infection. Among the MS patients, older age (OR 1.10, 95% CI 1.04 – 1.16) and progressive MS phenotype (OR 1.12, 95%CI 1.01-1.34) were associated with hospitalization/ICU. In the NMOSD patients, the hospitalized/ICU admitted patients were older (54.3 ± 3.1 vs. 39 ± 5.7 years, p < 0.001, had a higher EDSS (5.5 ± 1 vs 2.7 ±1, p 0.0012) and had a longer disease duration (18.5±4 vs. 14.4±5 years, p 0.001) than those not admitted. Among MS patients, the adjusted odds ratio (OR) for hospitalization in patients receiving anti-CD20 was 2.23 (95% CI 1.02 - 4.86, p = 0.04) compared to MS patients treated with non anti-CD20.

Conclusion: Older age and progressive MS phenotype were associated with hospitalization and ICU admission, while older age, longer disease duration and higher EDSS were associated in NMOSD. Anti-CD20 therapies were associated with a more severe course of COVID-19 infection among MS patients.

Disclosure of interest: The research was funded by BIOGEN.

P456/1646

COVID-19 vaccinations and infections in a large real-world clinical practice cohort of more than 2000 patients: what we learned after the pandemic

Dirk Schriefer¹, Hernan Inojosa¹, Yassin Atta¹, Undine Proschmann¹, Anja Dillenseger¹, Tjalf Ziemssen¹, Katja Akgün¹

¹Center of Clinical Neuroscience, Department of Neurology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden

Introduction: The COVID-19 pandemic has introduced unique challenges to the care of people with multiple sclerosis (pwMS). Disease severity, disease-modifying therapies (DMTs) and demographic characteristics may affect susceptibility to infections and vaccination patterns may be also associated to disease-related circumstances. Although several studies have examined these issues either in small and/or controlled settings or in relation to temporal subsections of the pandemic, real-world data reflecting clinical practice patterns during the pandemic are comparatively limited.

Objectives/Aims: To investigate patterns of COVID-19 infections and vaccinations throughout the different phases of the pandemic in a large real-world clinical practice cohort of more than 2000 pwMS in Germany.

Methods: We collected data from medical visits since beginning of the pandemic up to May 31st, 2022 at the Multiple Sclerosis Centre in Dresden, Germany. Data were analyzed descriptively for relevant subgroups of COVID-19-associated, MS-specific, comorbidity-related, and socio-demographic characteristics. Differences between subgroups were examined with χ2 tests, Mann-Whitney U tests or regression analyses, as appropriate. All eligible patients with either confirmed MS or CIS were included in the current analysis. DMTs were grouped based on their mechanism of action.

Results: Of 2115 patients, 77,4% had at least two vaccinations and 35,5% had at least one COVID-19 infection. A total of 816 infections occurred during the observation period. More infections were reported in patients with younger age (<40 years, p < 0.001), female gender (p = 0.004), lower expanded disability status score (EDSS <3, p < 0.001), and a relapsing MS course (p < 0.001).

More severe infections were associated with the male sex (p = 0.029), with no significant differences regarding age, EDSS, comorbidities, or DMTs. The presence of at least two vaccinations was associated with older age (> 60 years, p = 0.001), higher EDSS (EDSS >6.0, p = 0.043), and the presence of comorbidities (p = 0.041). Infections occurred more frequently in patients with B-cell depletion than in patients without DMTs (p < 0.001), with no significant differences between other DMT categories. Patients under B-cell depletion had more vaccinations than patients without immune therapy or with platform injectable DMTs.

Conclusion: Our study provides valuable insights into the impact of COVID-19 on pwMS, which could serve as the basis for individualized and tailored prevention strategies in the future.

Disclosure of interest: DS and YA: nothing to disclose. HI received speaker fee from Roche and financial support for research activities from Biogen, Teva and Alexion. UP received speaker fee from Merck, Biogen and Bayer and personal compensation from Biogen and Roche for consulting service. AD received personal compensation and travel grants from Biogen, Celgene/Bristol-Myers Squibb, Roche, Janssen-Cilag and Sanofi for speaker activity. TZ reports scientific advisory board and/or consulting for Biogen, Roche, Novartis, Celgene, and Merck; compensation for serving on speakers bureaus for Roche, Novartis, Merck, Sanofi, Celgene, and Biogen; research support from Biogen, Novartis, Merck, and Sanofi. KA reports scientific advisory board and/or consulting for Roche, Sanofi, Alexion, Teva, Biogen, and Celgene.

P457/1902

Risk of diagnostic delay in multiple sclerosis associated with sickness absence during the prodromal phase of the disease

Alejandra Machado¹, Kristina Alexanderson¹, Jan Hillert², Emilie Friberg¹

¹Karolinska Institutet, Division of Insurance Medicine, Department of Clinical Neuroscience, Stockholm, Sweden, ²Karolinska Institutet, Division of Neuro, Department of Clinical Neuroscience, Stockholm, Sweden

Introduction: Higher use of healthcare systems among patients with Multiple Sclerosis (MS) has been observed during the prodromal phase of MS. Due to the heterogeneity and wide range of MS symptoms, seek of specialist healthcare may not occur until MS symptoms are more evident or more common MS symptoms appear. Hence, a delay between onset and diagnosis may occur.

Objectives/Aims: To investigate the association between sickness absence (SA) diagnosis during the prodromal phase of MS and delay in MS diagnosis.

Methods: A longitudinal cohort study of all non-pediatric MS patients living in Sweden with onset years between 2006–2020 was conducted. The prodromal phase was set to one year prior to MS onset date, and diagnostic delay was calculated as the time (days) between onset and diagnosis dates. Specific SA diagnoses were classified according to the International Classification of Disease, 10^th-revision (ICD-10) as: Other neurological (non-MS), Mental, Cardiovascular, Cancer, Injury, Eye, Respiratory, Skin, Genitourinary, Other (all remaining ICD-10 codes) SA diagnosis. A final cohort of 7036 MS patients was included. Time to MS diagnosis was explored between MS patients with or without an indication of SA during the prodromal phase, controlling for sex, age at onset, and year of onset. Results are presented in hazard ratios (HR) and confidence intervals (CI).

Results: Indication of any SA (all-cause) during prodromal phase presented higher likelihood of diagnostic delay (HR=1.149, 95% CI=1.076-1227) when compared to those MS patients that did not have any SA indication a year prior to onset date. Moreover, indication of other neurological SA diagnosis (HR=1.341, 95% CI=1.076-1.227) and other SA diagnosis (HR=1.173, 95% CI=1.037-1.328) had higher likelihood of diagnostic delay compared to those without the same SA diagnosis.

Conclusion: A delay between MS onset and diagnosis may be related to the presentation of specific prodromal symptoms which can be captured with sickness absence measures. These findings, although explorative, may have further implications for clinical purposes.

Disclosure of interest: AM is funded partly by unrestricted research grant from Biogen. KA has received unrestricted researcher-initiated grants from Biogen. JH received honoraria for serving on advisory boards for Biogen, Bristol-Myers-Squibb, Janssen, Merck KGaA, Novartis, Sandoz and Sanofi-Genzyme and speaker’s fees from Biogen, Janssen, Novartis, Merck, Teva, Sandoz and Sanofi-Genzyme. He has served as P.I. for projects sponsored by, or received unrestricted research support from Biogen, Bristol-Myers-Squibb, Janssen, Merck KGaA, Novartis, Roche, and Sanofi-Genzyme. His MS research is funded by the Swedish Research Council and the Swedish Brain foundation. EF is funded partly by unrestricted research grant from Biogen and has received unrestricted research grants from Celgene/Bristol-Myers Squibb.

P458/2162

Multiple sclerosis relapse severity and recovery in the current disease-modifying therapy era

Ray Wynford-Thomas¹, Carolyn McNabb², Marija Cauchi³, Jonathan Hawken³, Mo Hu⁴, Joseph Simmonds³, Rachel Thomas³, Sioned Williams³, Valerie Anderson¹, Samantha Loveless¹, Mark Willis³, Trevor Pickersgill³, Neil Robertson¹, Emma Tallantyre¹

¹Cardiff University, Department of Neurology, Division of Psychological Medicine and Clinical Neuroscience, Cardiff, United Kingdom, ²Cardiff University, Cardiff University Brain Research Imaging Centre, Cardiff, United Kingdom, ³University Hospital of Wales, Department of Neurology, Cardiff, United Kingdom, ⁴Morriston Hospital, Department of Neurology, Swansea, United Kingdom

Introduction: There is a need for contemporary data on the clinical impact of relapses and predictors of relapse-recovery to better evaluate the utility of interventions that aim to reduce relapse rates in multiple sclerosis (MS).

Objectives/Aims: To determine the contribution of relapses to sustained disability accumulation in MS and to explore predictors of relapse severity and recovery.

Methods: People with MS (pwMS) presenting with new relapse symptoms were assessed at baseline and then at 3 time points over 26 weeks to assess recovery in terms of symptoms and disability. Pre-relapse Expanded Disability Status Scale (EDSS) was employed to express the proportion of people who experienced full versus incomplete recovery from relapse. Logistic regression was applied to determine predictors of relapse severity and recovery.

Results: 104 pwMS were assessed within a mean of 18 (SD 21.7) days of onset of new MS relapse symptoms, of whom 45 (43%) were receiving disease-modifying therapy (DMT). Mean change from pre-relapse EDSS to baseline visit was -1.0 (SD 1.4) EDSS point. 69% of relapses were disabling, with no difference between DMT treated and untreated patients. Return to pre-relapse EDSS was observed in 27% of patients at baseline visit, 51% at 6 weeks, 67% at 12 weeks, and 76% at 26 weeks. The majority of EDSS improvement occurred from baseline visit to 6 weeks. Increased disease duration, but not age, sex or DMT status, was significantly associated with a higher likelihood of full recovery (p=0.0179). Optic nerve relapses were significantly more likely to be non-disabling (p=0.03).

Conclusion: The majority of relapse recovery occurs within 6 weeks of presentation, but 24% do not recover to baseline by 26 weeks, and recovery is more likely in patients with longer disease duration. Concurrent use of DMTs did not significantly affect relapse severity or recovery.

Disclosure of interest: Ray Wynford-Thomas: Clinical research fellow grant co-funded by Novartis.

Carolyn McNabb: Nothing to disclose.

Marija Cauchi: Nothing to disclose.

Jonathan Hawken: Nothing to disclose.

Mo Hu: Nothing to disclose.

Joseph Simmonds: Nothing to disclose.

Rachel Thomas: Nothing to disclose.

Sioned Williams: Nothing to disclose.

Valerie Anderson: Nothing to disclose.

Sam Loveless: Nothing to disclose.

Mark Willis: Nothing to disclose.

Trevor Pickersgill: Nothing to disclose.

Neil Robertson: Honoraria from Roche, Sanofi Genzyme and Novartis, and research grants from Novartis, Sanofi Genzyme and Biogen.

Emma Tallantyre: Honoraria for consulting work from Novartis, Merck, Biogen and Roche, and funding to attend or speak at educational meetings from Biogen, Janssen, Merck, Roche, Takeda and Novartis.

P459/990

Disease course and disease-modifying treatment in men and women with early MS from the German NationMS cohort

Barbara Gisevius¹, Marianne Tokic², Philip Poser¹, Anna Lena Fisse¹, Thomas Grüter¹, Achim Berthele³, Katrin Giglhuber³, Martina Flaskamp³, Vinzenz Fleischer⁴, Stefan Bittner⁴, Sergiu Groppa⁴, Felix Lüssi⁴, Antonios Bayas⁵, Sven Meuth⁶, C. Heesen⁷, Corinna Trebst⁸, Brigitte Wildemann⁹, Florian Then Bergh¹⁰, Gisela Antony¹¹, Tania Kümpfel¹², Friedemann Paul^13,14, Sandra Nischwitz¹⁵, Hayrettin Tumani¹⁶, Uwe K. Zettl¹⁷, Bernhard Hemmer³, Heinz Wiendl¹⁸, Frauke Zipp⁴, Nina Timmesfeld², Ralf Gold¹, Jeremias Motte¹, Anke Salmen^1,19

Study Group: on behalf of the NationMS investigators and the German Competence Network Multiple Sclerosis

¹Ruhr-University Bochum, Department of Neurology, St. Josef-Hospital, Bochum, Germany, ²Ruhr-University Bochum, Department of Medical Informatics, Biometry and Epidemiology, Bochum, Germany, ³Technical University Munich, Department of Neurology, Klinikum rechts der Isar, Munich, Germany, ⁴University Medical Center of the Johannes Gutenberg University, Department of Neurology, Mainz, Germany, ⁵University Hospital of Augsburg, Department of Neurology, Augsburg, Germany, ⁶Heinrich-Heine University, Department of Neurology, Medical Faculty, Düsseldorf, Germany, ⁷University Hospital Hamburg-Eppendorf, Department of Neurology, Hamburg, Germany, ⁸Hannover Medical School, Department of Neurology, Hannover, Germany, ⁹University Hospital Heidelberg, Molecular Neuroimmunology Group, Department of Neurology, Heidelberg, Germany, ¹⁰University of Leipzig, Department of Neurology, Leipzig, Germany, ¹¹Philipps University Marburg, Central Information Office German Competence Network of multiple sclerosis, Marburg, Germany, ¹²Ludwig-Maximilian-University, Institute of Clinical Neuroimmunology, University Hospital, Munich, Germany, ¹³Charité Universitätsmedizin Berlin, Department of Neurology, Berlin, Germany, ¹⁴Charité Universitätsmedizin Berlin, NeuroCure Clinical Research Center, Berlin, Germany, ¹⁵Max Planck Institute of Psychiatry, Outpatient Clinic, Munich, Germany, ¹⁶University of Ulm, Department of Neurology, Ulm, Germany, ¹⁷University of Rostock, Department of Neurology, Neuroimmunological Section, Rostock, Germany, ¹⁸University Hospital Münster, Department of Neurology with Institute of Translational Neurology, Münster, Germany, ¹⁹Bern University Hospital and University of Bern, Department of Neurology, Inselspital, Bern, Switzerland

Introduction: Sex differences have been described in the susceptibility and course of multiple sclerosis (MS). In the German NationMS cohort study, more than 1200 patients with early MS were followed up to 8 years.

Objectives/Aims: To identify possible sex-specific differences in MS disease course and disease-modifying treatment (DMT) within the NationMS cohort of early MS patients diagnosed with RRMS and CIS.

Methods: Data of 1268 initially DMT-naïve patients diagnosed with relapsing-remitting MS (RRMS) or clinically isolated syndrome (CIS), recruited between 2010 and 2017, were analyzed for first symptoms, relapse treatment, Expanded Disability Status Scale (EDSS) evolution and DMT. We compared women and men using Chi-square test, Cox-proportional-hazards-regression, and logistic regression.

Results: The female-to-male ratio of the cohort was 2.4:1 (women: n=890, median age (min, max) 32.0 (18.0, 75.0) years; men: n=378, 33.0 (18.0, 66.0)). We found no significant differences in the distribution of mono- versus polysymptomatic onset, acute treatment of the first relapse, or total DMT exposure. 5.0% of men (n=19) and 5.1% of women (n=45) were initially treated with a high-efficacy DMT (alemtuzumab, fingolimod, natalizumab, rituximab). Time to EDSS ⩾3.0 was comparable between men and women (hazard ratio (HR), 95% confidence interval (95%-CI): 1.36, 0.97-1.90; reference: women; adjusted for age, DMT). Logistic regression showed that younger age (odds ratio (OR), 95%-CI: 0.95, 0.92-0.98; p<0.001) and higher initial EDSS (1.79, 1.40-2.27; p<0.001), but not sex as factors for first treatment with a high-efficacy DMT.

Conclusion: In our large German early MS sample, we did not detect sex differences in initial presentation, disease course and treatment over an observational period of up to 8 years. The decision for initial treatment with a high-efficacy DMT was influenced by younger patient age and higher initial EDSS, but not by sex. However, the proportion of patients exposed to high-efficacy DMTs was low, given the length of recruitment and the availability of different DMTs.

Disclosure of interest: Bayas, A: received personal compensation from Merck Serono, Biogen, Novartis, TEVA, Roche, Sanofi/Genzyme, Celgene/BMS, Sandoz/Hexal and Janssen; he received grants for congress travel and participation from Biogen, TEVA, Novartis, Sanofi/Genzyme, Merck Serono, Celgene and Janssen. None related to this report.

Berthele, A: consulting and/or speaker fees from Alexion, Biogen, Celgene, Horizon, Novartis, Roche and Sandoz/Hexal. His institution has received compensation for clinical trials from Alexion, Biogen, Merck, Novartis, Roche, and Sanofi Genzyme.

Bittner, S: received honoraria from Biogen Idec, Bristol Meyer Squibbs, Merck Serono, Novartis, Sanofi-Genzyme, Roche and Teva. His research is funded by the Deutsche Forschungsgemeinschaft (DFG) and Hertie Foundation.

Fleischer, V: received research support from Novartis, not related to this work.

Giglhuber, K: received travel reimbursement by UCB.

Gisevius, B: received research support from Novartis, not related to this work.

Gold, R: received speaker’s and board honoraria from Baxter, Bayer Schering, Biogen Idec, CSL Behring, Genzyme, Merck Serono, Novartis, Stendhal, Talecris, and Teva. His department received grant support from Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, and Teva.

Heesen, C: received speaker honoraria and research grants from Merck, Novartis, Roche, Sanofi.

Hemmer, B: has served on scientific advisory boards for Novartis; he has served as DMSC member for AllergyCare, Sandoz, Polpharma, Biocon and TG therapeutics; his institution received research grants from Roche for multiple sclerosis research. He has received honoraria for counseling (Gerson Lehrmann Group). He holds part of two patents; one for the detection of antibodies against KIR4.1 in a subpopulation of patients with multiple sclerosis and one for genetic determinants of neutralizing antibodies to interferon. All conflicts are not relevant to the topic of the study.

Kümpfel, T: has received speaker honoraria and/or personal fees for advisory boards from Roche Pharma, Alexion/Astra Zeneca, Horizon, Merck, Chugai and Biogen. The Institution she works for has received grant support for her research from Bayer-Schering AG, Novartis and Chugai Pharma in the past. None resulted in a conflict of interest

Meuth, S: received honoraria for lecturing and travel expenses for attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi-Aventis, Chugai Pharma, QuintilesIMS and Teva. His research is funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Else Kröner Fresenius Foundation, German Academic Exchange Service, Hertie Foundation, Interdisciplinary Center for Clinical Studies (IZKF) Muenster, German Foundation Neurology and by Almirall, Amicus Therapeutics Germany, Biogen, Diamed, Fresenius Medical Care, Genzyme, Merck Serono, Novartis, ONO Pharma, Roche and Teva.

Motte, J: received speaker honoraria for activities with Alnylam, and Biogen, and research support by Biogen and the Medical Faculty of the University Bochum and Hertie foundation.

Nischwitz, S: received speaker honoraria/consultancy fees from Roche, Bristol Myers Squibb, Merck Serono, Novartis.

Paul, F: research support to Neurosciences Clinical Research Center, German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Einstein Foundation, Guthy Jackson Charitable Foundation, EU FP7 Framework Program, Biogen, Genzyme, Merck Serono, Novartis, Bayer, Roche, Parexel and Almirall, received honoraria for lectures, presentations, speakers from Guthy Jackson Foundation, Bayer, Biogen, Merck Serono, Sanofi Genzyme, Novartis, Viela Bio, Roche, UCB, Mitsubishi Tanabe and Celgene, in addition received compensation for serving on a scientific advisory board of Celgene, Roche, UCB and Merck, is an Academic Editor PLos One and Associate Editor von Neurology® Neuroimmunology & Neuroinflammation, all unrelated to the presented work.

Salmen, A: received speaker honoraria for activities with Bristol Myers Squibb, CSL Behring, Novartis, and Roche, and research support by the Baasch Medicus Foundation, the Medical Faculty of the University of Bern and the Swiss MS Society, all not related to this work.

Then Bergh, F: has received, through his institution, research support and travel grants from the DFG (German Research Fund), BMBF (Federal Ministry of Education and Science), Actelion, Bayer, Biogen, Merck, Novartis, Roche, Sanofi, TEVA ; speaker honoraria or/and compensation for advisory board from Actelion, Alexion, Biogen, Horizon, Merck, Novartis, Roche ; none were related to this work

Trebst, C: received honoraria for consultation and expert testimony from Alexion Pharma Germany, Chugai Pharma Germany and Roche Pharma. None of this interfered with the current report.

Tumani, H: received research institutional support and/or consulting/speaker honoraria from Alexion, Bayer, Biogen, Bristol-Myers Squibb, Celgene, Diamed, Fresenius, Fujirebio, GlaxoSmithKline, Horizon, Janssen-Cilag, Merck, Novartis, Roche, Sanofi Genzyme, TEVA. His research is also funded by Ministry of Education and Research (BMBF), Ministry of Science, Research and Arts Baden Württemberg (MWK-BW), German Society of Multiple Sclerosis (DMSG), DMS-Stiftung, AMSEL-Stiftung, Bayern-DMSG and Chemische Fabrik Karl Bucher GmbH.

Wiendl, H: received honoraria for acting as a member of Scientific Advisory Boards for Janssen, Merck and Novartis as well as speaker honoraria and travel support from Alexion, Amicus Therapeuticus, Biogen, Biologix, Bristol Myers Squibb, Cognomed, F. Hoffmann-La Roche Ltd, Gemeinnützige Hertie-Stiftung, Medison, Merck, Novartis, Roche Pharma AG, Genzyme, Teva and WebMD Global. HW is acting as a paid consultant for Biogen, Bristol Myers Squibb, EMD Serono, Idorsia, Immunic, Novartis, Roche, Sanofi, the Swiss Multiple Sclerosis Society and UCB. His research is funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgesellschaft (DFG), Deutsche Myasthenie Gesellschaft e.V., Alexion, Amicus Therapeutics, Argenx, Biogen, CSL Behring, F. Hoffmann - La Roche, Genzyme, Merck KgaA, Novartis Pharma, Roche Pharma and UCB Biopharma.

Wildemann, B: received grants from the German Ministry of Education and Research, Deutsche Forschungsgemeinschaft, Dietmar Hopp Foundation and Klaus Tschira Foundation, grants and personal fees from Merck, and personal fees from Alexion, Bayer, Biogen, Teva; none related to this work.

Zettl, UK: received speaking fees, travel support, and financial support for research activities from Alexion, Almirall, Bayer, Biogen, Bristo-Myers-Squibb, Celgene, Janssen, Merck Serono, Novartis, Octapharma, Roche, Sanofi Genzyme, Teva as well as EU, BMBF, BMWi and DFG. None resulted in a conflict of interest.

Zipp, F: recently received research grants and/or consultation funds from Biogen, Ministry of Education and Research (BMBF), Bristol-Meyers-Squibb, Celgene, German Research Foundation (DFG), Janssen, Max-Planck-Society (MPG), Merck Serono, Novartis, Progressive MS Alliance (PMSA), Roche, Sanofi Genzyme, and Sandoz.

All other authors report no conflicts of interest relevant to this work.

P460/885

The Impact of Menopause on the Clinical Trajectory of Multiple Sclerosis

Francesca Bridge^1,2, Paul Sanfilippo¹, Olga Skibina², Ai-Lan Nguyen^3,4, Tomas Kalincik^3,4, Katherine Buzzard^3,5, Bruce Taylor⁶, Jennifer MacIntyre⁷, Lesley-Ann Hall⁸, Lisa Taylor⁹, Mark Slee¹⁰, Richard Macdonell¹¹, Vicki Maltby^12,13, Jeannette Lechner-Scott^12,13, PAMELA MCCOMBE¹⁴, Helmut Butzkueven^1,2, Anneke van der Walt^1,2, Vilija Jokubaitis^1,2

¹Monash University, Department of Neurosciences, Melbourne, Australia, ²Alfred Health, Department of Neurology, Melbourne, Australia, ³Royal Melbourne Hospital, Neuroimmunology Centre, Melbourne, Australia, ⁴University of Melbourne, CORe, Department of Medicine, Melbourne, Australia, ⁵Monash University, Eastern Health Clinical School, Melbourne, Australia, ⁶University of Tasmania, Menzies Institute for Medical Research, Hobart, Australia, ⁷Royal Hobart Hospital, Department of Neurology, Hobart, Australia, ⁸Flinders Medical Centre, Department of Neurology, Adelaide, Australia, ⁹Royal Melbourne Hospital, MS Centre, Department of Neurology, Melbourne, Australia, ¹⁰Flinders University of South Australia, College of Medicine and Public Health, Adelaide, Australia, ¹¹Austin Health, Department of Neurology, Melbourne, Australia, ¹²John Hunter Hospital, Department of Neurology, Newcastle, Australia, ¹³University of Newcastle, School of Medicine and Public Health, Newcastle, Australia, ¹⁴Royal Brisbane and Women's Hospital, Department of Neurology, Brisbane, Australia

Introduction: There is emerging evidence that the post-menopausal period may represent a time of more rapid disease progression for women with multiple sclerosis (MS). Following menopause, concentrations of protective sex hormones are at their lowest which may have a deleterious effect on neurodegeneration in MS. The impact of menopause on MS disease accumulation remains unclear.

Objectives/Aims: To investigate whether the onset of menopause changes the disability trajectory in women with MS.

Methods: We conducted a national-multisite retrospective longitudinal cohort study. Participants were recruited across eight tertiary MS centres throughout Australia from 2018-2019. Participants completed a reproductive survey and data was matched to clinical records in the MSBase Registry. Inclusion criteria were post-menopausal women with clinically isolated syndrome or relapse-onset MS with at least one Expanded Disability Status Scale (EDSS) recorded pre- and post-menopause. We used inflection point analysis using a linear spline mixed effects model with a change in EDSS slope at the time of menopause to examine the longitudinal changes in EDSS over a ten-year period pre-and post-menopause.

Results: Of the 1467 women enrolled, 479 were post-menopausal. 205 women fulfilled the inclusion criteria and were included in our primary analysis. The mean age of menopause was 49.5 years (SD 4.7). While there was a trend towards post-menopausal worsening, menopause was not found to represent a significant inflection point in EDSS changes: the pre-menopause slope of change 0.066 units/year (95% CI: 0.036 – 0.092) versus post-menopause slope of change 0.096units/year (95% CI: 0.065-0.127); slope change 0.033units (CI: -0.014 – 0.079; p = 0.17).

Conclusion: The onset of menopause was not associated with a significant worsening in disability for women with MS. Future studies are needed to examine the effect on menopause on other markers of clinical progression including the risk of transition to a progressive clinical course.

Disclosure of interest: Francesca Bridge has received travel support from Biogen.

Paul Sanfilippo nothing to disclose.

Olga Skibina nothing to disclose.

Ai-Lan Nguyen has received research grants from Novartis, Biogen, Merck Serono and MS Research Australia; speaker honoraria from Roche, Biogen, Teva, Merck Serono and Novartis. She has served on advisory boards for Merck Serono and Novartis.

Tomas Kalinčik served on scientific advisory boards for MS International Federation and World Health Organisation, BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Merck and Biogen, steering committee for Brain Atrophy Initiative by Sanofi Genzyme, received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Roche, Sanofi-Genzyme, Teva, BioCSL and Merck and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck.

Katherine Buzzard has received speaker’s honoraria and/or educational support from Roche, Merck, Alexion, Biogen, Sanofi Genzyme and Novartis. She has serviced on Scientific Advisory Boards for Biogen and Merck.

Bruce Taylor nothing to disclose.

Jennifer MacIntyre nothing to disclose.

Lesley-Ann Hall served on advisory boards for Novartis, Biogen and Merck Serono, and has received speaker honoraria / consulting fees / conference travel support from Novartis, Alexion AstraZeneca, Biogen, Merck Serono and Bristol Myer Squibb.

Lisa Taylor has received conference travel support from Biogen, Merck, Novartis and Roche; nurse advisory consultant support from Novartis and Merck.

Mark Slee nothing to disclose.

Richard Macdonell or his institution have received remuneration for his speaking engagements, advisory board memberships, research and travel from Biogen, Merck, Genzyme, Bayer, Roche, Teva, Novartis, CSL, BMS, MedDay and NHMRC.

Vicki Maltby nothing to disclose

Jeannette Lechner-Scott received travel compensation from Novartis, Biogen, Roche and Merck. Her institution received the honoraria for talks and advisory board commitment as well as research grants from Biogen, Merck, Roche, TEVA and Novartis.

Pamela McCombe nothing to disclose

Helmut Butzkueven received compensation for same activities from Oxford Health Policy Forum, Merck, Biogen, Novartis. His institution (Monash university) received compensation for consulting, talks, advisory / steering board activities from Biogen, Merck, Novartis, Genzyme, Alfred Health; research support from Novartis, Biogen, Roche, Merck, NHMRC, Pennycook Foundation, MSRA.

Anneke van der Walt served on advisory boards for Novartis, Biogen, Merck and Roche and NervGen. She received unrestricted research grants from Novartis, Biogen, Merck and Roche. She is currently a co-Principal investigator on a co-sponsored observational study with Roche, evaluating a Roche-developed smartphone app, Floodlight-MS. She has received speaker’s honoraria and travel support from Novartis, Roche, Biogen and Merck. She serves as the Chief operating Officer of the MSBase Foundation (not for profit). Her primary research support is from the National Health and Medical Research Council of Australia and MS Research Australia.

Vilija G. Jokubaitis received research support from the Australian National Health and Medical Research Council (NHMRC) to support this work. She received research funding support from MS Australia, Pennycook Foundation and F.Hoffman-La Roche outside of this work.

P461/662

Development of 2-year-old children after natalizumab exposure during pregnancy in women with Multiple Sclerosis

Natalia Friedmann¹, Andrea Ciplea¹, Sandra Thiel¹, Ralf Gold², Kerstin Hellwig¹

¹Catholic Hospital Bochum - St. Josef-Hospital, Neurology, Bochum, Germany, ¹Catholic Hospital Bochum - St. Josef-Hospital, Neurology, Bochum, Germany

Introduction: In women with highly active multiple sclerosis natalizumab (NTZ, Biogen)-treatment up to or during pregnancy can be necessary. Short term pregnancy outcomes are available, however, long-term data on child development are lacking but in high demand.

Objectives/Aims: Methods: Eligible cases from the German Multiple Sclerosis and Pregnancy Registry with NTZ pregnancy exposure up to 3 months before the last menstrual period (LMP) or during pregnancy (exposed group) or no disease modifying therapy pregnancy exposure (control group) were identified. Data are collected with a standardized questionnaire in telephone-interviews conducted during pregnancy and postpartum, data on infants are derived from children’s medical check-up booklet. Infant follow-up will continue until 5 years postpartum. Outcomes include body weight, length and head circumference at regular medical check-ups, developmental delays and chronic diseases, and will be compared between exposed and control group.

Results: We included 150 exposed cases, of which the majority (n=103/68.7%) received NTZ also during the 2^nd or 3^rd trimester of pregnancy, in n=47 the last infusion occurred during the 1^st trimester or up to 3 months before the LMP. Women received a median of 4 (range 1-8) infusions during pregnancy. The control group presently consists of 84 cases (interferon-beta, glatiramer acetate or NTZ before pregnancy). 2-year child data are presented.

Body measurements were comparable between exposed and unexposed children during the observed period, although exposed boys showed a median of 150 gram lower weight (at birth and at about 1 week and 3/6/12 months of age) than boys in controls, which was not statistically significant. Percentages of developmental delays were within the expected range of the national population and no statistically significant differences were found between both groups (7/150, 4.7% vs. n=2/84, 2.4%, p=0.493 [excluding children with genetic defects known to be accompanied by developmental impairments]); in total, 6/150, 4.0% exposed children were diagnosed with a chronic disease compared to n=1/84, 1.2% in controls, p=0.495.

Inclusion of controls and overall follow-up is still ongoing; updated data will be presented at the congress.

Conclusion: 2-year child data suggest that infants exposed to NTZ during pregnancy developed normally in the first two years of life, as differences were not statistically different between the groups and values lay within the expected range of the general population.

Disclosure of interest: NF: has received speaker honoraria and travel grants from Biogen GmbH

AIC: has received speaker honoraria from Bayer Healthcare, Biogen GmbH and Teva and sponsorship for congress participation and travel grants from Teva

ST: has received speaker honoraria from Bayer Healthcare and Biogen GmbH as well as payment for manuscript writing from HEXAL AG

RG: has received speaker honoraria and research support from Bayer-Schering Healthcare, Biogen-Idec Germany, Merck-Serono, Teva Pharma, Novartis Pharma and Sanofi Aventis and has received honoraria as a journal editor from SAGE and Thieme Verlag

KH: has received speaker honoraria and research support from Bayer, Biogen, Merck, Novartis, Sanofi-Genzyme, Roche, and Teva, has received support for congress participation from Bayer, Biogen, Merck, Roche, Sanofi Genzyme and Teva, and has served on scientific advisory boards for Bayer, Biogen, Sanofi, Teva, Roche, Novartis, Merck

P462/188

Pregnancy and birth outcomes in MS women : comparison of the RESPONSE cohort to the general French population

Elisabeth Maillart¹, Bertrand Bourre², Romain Casey³, Kumaran Deiva⁴, Anne-Marie Guennoc⁵, Christine Lebrun-Frenay⁶, Emmanuelle Leray⁷, Romain Marignier³, Fabien ROLLOT³, Sandra Vukusic³

Study Group: on behalf of RESPONSE, OFSEP and SFSEP investigators.

¹Pitie-Salpetriere Hospital, APHP, Neurology, Paris, France, ²Universitary Hospital, Neurology, Rouen, France, ³Hospices Civils de Lyon, Neurology, Bron, France, ⁴Bicetre Hospital, APHP, Pediatric Neurology, Kemlin-Bicetre, France, ⁵Universitary Hospital, Neurology, Tours, France, ⁶Universitary Hospital, Neurology, Nice, France, ⁷Univ Rennes, EHESP, CNRS, Inserm, ARENES UMR 6051, RSMS U 1309, Rennes, France

Introduction: Multiple sclerosis (MS) typically affects young women in the childbearing years. In retrospective studies, there is no increased risk of adverse maternal issues, congenital malformations, or fetal deaths.

Objectives/Aims: To compare demographics and pregnancy management/outcomes in MS women included in a prospective national cohort with the French general population.

Methods: Since August 2019, French women with MS and ongoing pregnancy have been proposed to participate in the RESPONSE prospective cohort. Through web-based auto-questionnaires, patients provide information on MS, pregnancy management and outcomes, delivery, and the child's health at birth and up to 6 years of age. The present study compared demographics, pregnancy, and birth outcomes in the RESPONSE cohort to the 2022 report on perinatal epidemiology in France from 2010-2019.

Results: On April 7^th, 2023, 515 women were included, and provided information on 383 births. Mean maternal age at delivery was 32.6 years (SD=4.4), older than the general population (30.3 years in 2019). 4.8% of patients (18/378) gave birth preterm (i.e., < 37 amenorrhea weeks), a similar rate to the general population (6.3%). A cesarian section was performed in 25% (96/384), higher than in the general population in 2019 (20.2%). 84.9% of patients (327/384) had loco-regional analgesia for delivery (epidural 73.2%; spinal 11.7%).

Among 384 births, there were 12 twins (3.1%), a similar rate to the general population (3.3% in 2019). Children with low (11.9%, 46/388) or elevated birthweight (10.8%, 42/388) for gestational age were similar to the general French population, respectively 12 % and 10.7% in 2019. While leaving maternity ward, 40.5% (153/378) breastfed exclusively, less than the general population (52.2%).

No maternal death was observed. Two deaths were reported in the first week (severe neonatal anoxia, severe chromosomal abnormality), and one in-utero fetal death (no details available).

Conclusion: Pregnancy and birth outcomes for MS women are quite similar to the general French population. In this first analysis of the RESPONSE cohort, we observed an increased maternal age at delivery, increased use of the cesarian section, and less exclusive maternal breastfeeding. As expected, we did not observe any increase in pregnancy complications.

Disclosure of interest: Dr. Maillart has received consulting or travel fees from Alexion, Biogen, Janssen, Novartis, Sanofi, Teva and Merck Serono, and research grant from Biogen, none related to the present work.

Dr. Bourre has received consulting or travel fees from Abbvie, Alexion, Biogen, BMS,Janssen, Novartis, Sanofi, and Merck Serono, none related to the present work.

Dr Deiva received personal compensation for speaker activities from Novartis, Horizon, Alexion, Biogen, and Sanofi.

Dr. Guennoc has received consulting or travel fees from Biogen, Novartis, Sanofi, Teva and Merck Serono.

Dr. Leray has received consulting and lecture fees or travel grants from Biogen, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, and Roche.

Dr. Marignier has received personal consulting fees from Alexion, Biogen, Horizon Therapeutics, Novartis, Roche and UCB.

Dr. Vukusic has received grants, non- personal consulting fees and travel fees from Biogen, BMS-Celgene, Janssen, Merck, Novartis, Roche and Sanofi.

Dr. Lebrun-Frenay, Dr Casey, F Rollot have no disclosure.

P463/513

Pregnancy reduces the risk of reaching irreversible EDSS 3 in women with multiple sclerosis, but there's a catch!

Chao Zhu¹, Paul Sanfilippo¹, Karolina Vodehnalová², Olga Skibina³, Ai-Lan Nguyen^4,5, Tomas Kalincik^4,5, Katherine Buzzard^5,6, Raed Alroughani⁷, Bruce Taylor⁸, Jennifer MacIntyre⁹, Lesley-Ann Hall¹⁰, Mark Slee¹¹, Richard Macdonell¹², Vicki Maltby¹³, Jeannette Lechner-Scott^13,14, PAMELA MCCOMBE¹⁵, Helmut Butzkueven^1,3, Anneke van der Walt^1,3, Vilija Jokubaitis^1,3

¹Monash University, Department of Neuroscience, Melbourne, Australia, ²Charles University and General Teaching Hospital, Prague, Czech Republic, ³Alfred Health, Department of Neurology, Melbourne, Australia, ⁴University of Melbourne, CORe, Department of Medicine, Parkville, Australia, ⁵Royal Melbourne Hosptial, Neuroimmunology Centre, Parkville, Australia, ⁶Eastern Health, Department of Neurosciences, Box Hill, Australia, ⁷Amiri Hospital, Kuwait City, Kuwait, ⁸University of Tasmania, Menzies Institute for Medical Research, Hobart, Australia, ⁹Royal Hobart Hospital, Department of Neurology, Hobart, Australia, ¹⁰Flinders Medical Centre, Department of Neurology, Adelaide, Australia, ¹¹Flinders University of South Australia, College of Medicine and Public Health, Adelaide, Australia, ¹²Austin Health, Department of Neurology, Heidelberg, Australia, ¹³John Hunter Hospital, Department of Neurology, Newcastle, Australia, ¹⁴University of Newcastle, School of Medicine and Public Health, Newcastle, Australia, ¹⁵Royal Brisbane and Women's Hospital, Department of Neurology, Brisbane, Australia

Introduction: Although pregnancy is not harmful to the disease course of MS, there is no consensus on its impact on long-term disability outcomes.

Objectives/Aims: To determine whether pregnancy can reduce the risk of reaching the disability milestone of irreversible EDSS 3. To determine whether MS outcomes depend on pregnancy timing.

Methods: Women with relapse-onset MS enrolled in the MSBase Registry were surveyed regarding their reproductive histories. To account for the longitudinal nature of our dataset, we applied Marginal structural models incorporating a stabilized inverse probability of treatment weighting (IPTW). Baseline was set at the first EDSS visit in MSBase. IPTW-weighted Cox regression, clustered by patient ID, was used to assess time to reach irreversible EDSS 3. Flexible parametric survival models were used to assess the relationship between pregnancy timing and MS outcomes.

Results: We included 2,619 women with relapse-onset MS (EDSS <3 at baseline), of whom 687 (26.2%) had at least 1 pregnancy after baseline. We found that in the pregnant state, the risk of reaching irreversible EDSS 3 was reduced by 58% (HR 0.42; 95% CI 0.20 – 0.90, p=0.02). Restricted mean survival analysis, however, demonstrated that the benefit of pregnancy on reducing the long-term risk of reaching irreversible EDSS 3 was limited to women aged under 30, with a disease duration of 2 years or less. Hazard ratios for reaching irreversible EDSS 3 for women with one pregnancy and a disease duration of 2 years were: aHR 0.78 - 20 years of age (95% CI 0.64, 0.99); aHR 0.83 – 25 years of age (95% CI 0.73, 0.97); aHR 0.89 – 30 years of age (95% CI 0.78, 1.01); aHR 0.94 – 35 years of age (95% CI 0.77, 1.14).

Conclusion: We provide evidence that during pregnancy, the risk of reaching irreversible EDSS 3 is substantially reduced. However, the optimal window to derive long-term pregnancy benefit is narrow, diminishing with increasing age and disease duration.

Disclosure of interest: Chao Zhu nothing to disclose.

Paul Sanfilippo nothing to disclose

Karolina Vodehnalova received compensation for traveling, conference fees and consulting fees from Merck, Teva, Sanofi Genzyme, Biogen Idec, Novartis, Roche.

Olga Skibina nothing to disclose

Ai-Lan Nguyen has received research grants from Novartis, Biogen, Merck Serono and MS Research Australia; speaker honoraria from Roche, Biogen, Teva, Merck Serono and Novartis. She has served on advisory boards for Merck Serono and Novartis.

Tomas Kalinčik served on scientific advisory boards for MS International Federation and World Health Organisation, BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Merck and Biogen, steering committee for Brain Atrophy Initiative by Sanofi Genzyme, received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Roche, Sanofi-Genzyme, Teva, BioCSL and Merck and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck.

Katherine Buzzard has received speaker’s honoraria and/or educational support from Roche, Merck, Alexion, Biogen, Sanofi Genzyme and Novartis. She has serviced on Scientific Advisory Boards for Biogen and Merck.

Raed Alroughani received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche and Sanofi-Genzyme.

Bruce Taylor nothing to disclose

Jennifer MacIntyre nothing to disclose

Lesley-Ann Hall served on advisory boards for Novartis, Biogen and Merck Serono, and has received speaker honoraria / consulting fees / conference travel support from Novartis, Alexion AstraZeneca, Biogen, Merck Serono and Bristol Myer Squibb.

Mark Slee nothing to disclose

Richard Macdonell or his institution have received remuneration for his speaking engagements, advisory board memberships, research and travel from Biogen, Merck, Genzyme, Bayer, Roche, Teva, Novartis, CSL, BMS, MedDay and NHMRC.

Vicki Maltby nothing to disclose

Jeannette Lechner-Scott received travel compensation from Novartis, Biogen, Roche and Merck. Her institution received the honoraria for talks and advisory board commitment as well as research grants from Biogen, Merck, Roche, TEVA and Novartis.

Pamela McCombe nothing to disclose

Helmut Butzkueven received compensation for same activities from Oxford Health Policy Forum, Merck, Biogen, Novartis. His institution (Monash university) received compensation for consulting, talks, advisory / steering board activities from Biogen, Merck, Novartis, Genzyme, Alfred Health; research support from Novartis, Biogen, Roche, Merck, NHMRC, Pennycook Foundation, MSRA.

Anneke van der Walt served on advisory boards for Novartis, Biogen, Merck and Roche and NervGen. She received unrestricted research grants from Novartis, Biogen, Merck and Roche. She is currently a co-Principal investigator on a co-sponsored observational study with Roche, evaluating a Roche-developed smartphone app, Floodlight-MS. She has received speaker’s honoraria and travel support from Novartis, Roche, Biogen and Merck. She serves as the Chief operating Officer of the MSBase Foundation (not for profit). Her primary research support is from the National Health and Medical Research Council of Australia and MS Research Australia.

Vilija G. Jokubaitis received research support from the Australian National Health and Medical Research Council (NHMRC) to support this work. She received research funding support from MS Australia, Pennycook Foundation and F.Hoffman-La Roche outside of this work.

P464/1173

RESPONSE, a French cohort of pregnant women with MS and related disorders and their children until the age of 6. Protocol and baseline characteristics

Sandra Vukusic¹, Bertrand Bourre², Romain Casey³, Kumaran Deiva⁴, Anne-Marie Guennoc⁵, Christine Lebrun-Frenay⁶, Emmanuelle Leray⁷, Elisabeth Maillart⁸, Romain Marignier¹, Fabien ROLLOT³

Study Group: RESPONSE, OFSEP and SFSEP investigators

¹Hospices Civils de Lyon, Neurology, neuro-inflammation, BRON, France, ²Centre Hospitalo-Universitaire de Rouen, Neurology, ROUEN, France, ³Observatoire Français de la Sclérose en Plaques, BRON, France, ⁴Assistance Publique des Hôpitaux de Pars, CH du Kremlin-Bicêtre, LE KREMLIN-BICETRE, France, ⁵Centre Hospitalo-Universitaire de Tours, CRC-SEP and neurology, TOURS, France, ⁶Centre Hospitalo-Universitaire de Nice Pasteur 2, CRC-SEP Côte d'azur, NICE, France, ⁷Ecole des Hautes Etudes en Santé Publique, RENNES, France, ⁸Assistance Publique des Hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière, PARIS, France

Introduction: Since the publication of the PRIMS study, counselling women with MS has radically changed, and many have fulfilled their desire for motherhood. However, many unanswered questions remain, in particular concerning emerging disease-modifying treatments (DMTs).

Objectives/Aims: To set up a French prospective pregnancy cohort for women with MS and related diseases, owing to a better understanding of interactions between MS and pregnancy-related issues (pregnancy itself, locoregional analgesia, breastfeeding, the impact of using or stopping DMTs on women/children. . .).

Methods: Prospective, observational, multicentric, and national epidemiological cohort nested into the OFSEP registry, including MS, CIS, RIS, NMOSD and MOGAD, with no age limit, and ongoing pregnancy. Women are followed during pregnancy and the year after delivery, and their children until of the age of 6. Neurological data are extracted from the OFSEP database, and additional information is displayed directly by women through web-based auto-questionnaires at pre-specified dates. For children, parents provide information available on the mandatory medical certificates completed by pediatricians at birth, 9 months, 2, and 6 years. They also respond to an auto-questionnaire on neuro-development at ages 1, 2, and 6, which will be compared to similar data available from the ELFE cohort (20.000 children from the general population born in 2011). We plan to include 1000 patients in 5 years.

Results: Inclusions started in August 2019. On April 7^th, 2022, 515 women were included and 384 children were born. There were 490 MS, 9 CIS, 5 RIS, 6 NMOSD, and 4 MOGAD. The mean age at inclusion was 32.6 +/-4.4 years. Inclusion occurred in the first, second, and third trimesters of pregnancy in 32.8, 41.4 and 25.8%, respectively. Forty pregnancies (8.2%) required reproductive assistance. 73 patients (15%) were treatment naïve. The most frequently used DMT prior to pregnancy was natalizumab (93, 22.9%), followed by glatiramer acetate (79, 19.4%), anti-CD20 (77, 18.9%), dimethyl-fumarate (64, 15.7%), interferon beta (54, 13.2%), teriflunomide (17, 4.2%), fingolimod (16, 3.9%), others (7, 1.6%).

Conclusion: RESPONSE is the first prospective cohort study that will be able to provide parallel information on mothers (including MS and pregnancy outcomes) and on their children until the age of 6, in comparison to the general population.

Disclosure of interest: Dr. Vukusic has received grants, non- personal consulting fees and travel fees from Biogen, BMS-Celgene, Janssen, Merck, Novartis, Roche and Sanofi.

Dr. Bourre has received consulting or travel fees from Abbvie, Alexion, Biogen, BMS, Janssen, Novartis, Sanofi and Merck Serono, none related to the present work.

Dr. Casey has nothing to disclose.

Dr. Deiva has received personal compensation for speaker activities from Novartis, Horizon, Alexion, Biogen, and Sanofi.

Dr. Guennoc has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Novartis, Merck, Sanofi-Genzyme, Teva.

Dr. Lebrun-Frenay has nothing to disclose.

Dr. Leray has received consulting and lecture fees or travel grants from Alexion, Biogen, Genzyme, Merck, Novartis, and Roche. Nothing related to the contents of the present work.

Dr. Maillart has received consulting or travel fees from Alexion, Biogen, Janssen, Novartis, Sanofi, Teva and Merck Serono, and research grant from Biogen, none related to the present work.

Dr. Marignier has received personal consulting fees from Alexion, Biogen, Horizon Therapeutics, Novartis, Roche and UCB.

Mr. Rollot has nothing to disclose.

P465/692

Do symptoms occurring prior to MS diagnosis vary according to background - A nested case control study

Pooja Tank¹, Benjamin Jacobs¹, Jonathan Bestwick¹, Ruth Dobson¹

¹Wolfson Institute of Preventive Medicine, London, United Kingdom

Introduction: Prodromal symptoms in Multiple Sclerosis (MS) have been previously described. However, little is known about how socio-demographic factors influence the earliest manifestations of MS.

Objectives/Aims: Investigate whether associations between prodromal MS symptoms and subsequent MS vary according to ethnicity, deprivation(IMD), and gender using electronic healthcare records.

Methods: A retrospective nested case-control study was conducted using UK Clinical Practice Research Datalink. Clinical and demographic data were evaluated in MS cases (aged ⩾18 years at index date) and age-matched controls with at least 5 years of data prior to index date (MS diagnosis or neurology referral between 1990-2022). Symptoms were grouped into categories including autonomic, pain, psychiatric, cognitive, and neurological symptoms. The relationship between symptoms and subsequent MS was assessed according to ethnicity (White, Black, Asian, Mixed/Other), IMD quintile and gender at 0-2 years, 2-5 years, and 5-10 years prior to index date. Multivariable logistic regression, adjusting for age and demographic factors were used. Likelihood ratio tests were used to evaluate heterogeneity in interactions.

Results: 15,395 MS cases and 89,741 controls were included. More cases than controls were female (70% vs 50%), white (86% vs 57%) and less deprived (45% vs 40% in upper 2 IMD quintiles) with mean age 44.6 years at index date. The relationship between autonomic, neurological, pain and psychiatric symptoms and subsequent MS were similar across ethnic and IMD groups. Neurological symptoms showed the strongest association with subsequent MS (OR: 8.00[7.66-8.35]). The association between neurological symptoms and subsequent MS was higher for males than females at 0-2 years (M: OR: 23.02[20.81-25.47] vs F: OR: 16.25[15.05–17.56]), 2-5 years (M: OR: 4.64[4.11-5.32] vs F: OR: 3.69[3.39-4.02]) and 5-10 years prior MS (M: OR: 4.26[3.66–4.96] vs F: OR: 3.11[2.81–3.45]). The relationship between prodromal symptoms and subsequent MS was stronger at 0-2 years for most ethnic, IMD groups and gender compared to 2-5 years and 5-10 years prior MS onset.

Conclusion: Prodromal symptoms may represent the earliest manifestations of MS. They appear to be consistent across demographic groups, highlighting the importance of targeting early interventions equitably across all groups. Neurological symptoms recorded in the 2 years prior to diagnosis likely represent the presenting symptoms of MS; the increased odds in males requires further investigation.

Disclosure of interest: PT: Nothing to disclose

BJ: Nothing to disclose

AB: Nothing to disclose

JB: Nothing to disclose

RD has received payments to her institution, including grants from Biogen, Merck, Celgene, National MS Society, MS Society UK, Horne Family Trust, and the BMA Foundation; honoraria and/or advisory board payments to institution from Biogen, Janssen, Merck, Novartis, Roche, Sanofi, Sandoz, and Teva; and received support for attending meetings or travel from Biogen, Janssen, Merck, Novartis, Roche, and Sanofi

P466/1333

A real life, multicenter, observational study to evaluate safety and efficacy of the switch from alemtuzumab to ocrelizumab in MS patient with evidence of disease activity after two alemtuzumab courses: the italian experience

Caterina Lapucci¹, Jessica Frau², Eleonora Cocco², Giancarlo Coghe², Maria Petracca³, Roberta Lanzillo⁴, Marco Vercellino⁵, Paola Cavalla⁵, Assunta Bianco⁶, Massimiliano Mirabella⁶, Giovanni Di Mauro⁷, Doriana Landi⁸, Girolama Alessandra Marfia⁸, Valentina Torri Clerici⁹, Eugenia Tomas Roldan^9,9, Maria Teresa Ferrò¹⁰, Paola Grossi¹⁰, Mauro Zaffaroni¹¹, MARCO RONZONI¹², Agostino Nozzolillo¹³, Lucia Moiola¹³, Federica Pinardi¹⁴, GIovanni Novi¹, Maria Cellerino¹⁵, Ucccelli Antonio¹⁶, Matilde Inglese^1,15

¹IRCCS Ospedale Policlinico San Martino, Genoa, Italy, ²Multiple Sclerosis Centre, ASL Caglliari, Cagliari, Italy, ³Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy, Rome, Italy, ⁴Multiple Sclerosis Clinical Care and Research Centre, Department of Neuroscience, Reproductive Science and Odontostomatology, Federico II University, Naples, Italy., Naples, Italy, ⁵Multiple Sclerosis Center, Neurologia I U, Department of Neuroscience and Mental Health, AOU Città della Salute e della Scienza di Torino, Via Cherasco 15, 10126, Torino, Italy, Torino, Italy, ⁶Multiple Sclerosis Center, Department of Department of Aging, Neurological, Orthopedic and Head and Neck Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168, Rome, Ital, Rome, Italy, ⁷Multiple Sclerosis Clinical and Research Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy., Rome, Italy, ⁸Multiple Sclerosis Clinical and Research Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy, Rome, Italy, ⁹Fondazione IRCCS Istituto Neurologico "C. Besta" U.O. Neuroimmunologia e Malattie Neuromuscolari, Italy, Milan, Italy, ¹⁰Neuroimmunology, Center for Multiple Sclerosis, Cerobrovascular Department, Neurological Unit, ASST Crema, Crema, Italy, ¹¹Centro Sclerosi Multipla, ASST della Valle Olona, Ospedale di Gallarate, Gallarate, Italia, Gallarate, Italy, ¹²UO neurologia ASST Rhodense, Garbagnate Milanese, Garbagnate Milanese, Italy, ¹³Neurology Unit, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy, Milan, ¹⁴UOSI Multiple Sclerosis Rehabilitation, IRCCS, Bologna, Italy, Bologna, Italy, ¹⁵DINOGMI, University of Genoa, Genoa, Italy, ¹⁶IRCCS Ospedale Policlinico San Martino, Genova, Italy; Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI) and Center of Excellence for Biomedical Research (CEBR), University of Genoa, Genoa, Italy, Genoa

Introduction: Therapeutic sequencing after high-efficacy induction treatments is a matter of debate in MS. No safety and efficacy data about the switch to ocrelizumab (OCR) in patients (pts) with evidence of disease activity/progression after two alemtuzumab (ALM) courses have been reported yet.

Objectives/Aims: To evaluate safety and efficacy of the switch from ALM to OCR in an Italian, multicentric cohort of MS patients with evidence of disease activity and/or progression after two ALM courses

Methods: Data collection from different Italian MS Centers

Results: 73 MS patients were enrolled from May 2019 to. . .[at OCR start: mean age 39.2 (SD9.2) years; female, 63%; Relapsing Remitting, (RR): 78.1%, Relapsing Progressive, (RP): 13.7%; 67 (91.7%) started OCR for relapses/MRI activity, 6 (8.3%) for disability progression; cumulative number of relapses:69; mean number of new T2 and Gd+ lesions:3 (3.2) and 1 (2); median EDSS:3.5 (range 0-8)]. The mean follow-up (FU) from OCR start was 2.3±1 years. Safety: (i) Infusion Associated Reactions (IARs) occurrence was lower than in ALM (p<0.005); (ii) infections (n=41, 56.2%): upper airways (n=20), urinary (n=18), HSV (n=1), VZV (n=1) reactivations, appendicectomy (n=1). No patients developed severe forms of COVID19 (n=48); (iii) cancer (n=2, 1 colic, 1 cervix). Considering pts with at least 2-years FU (n=55), immunophenotype and IgG levels were available for 20 and 25 pts respectively: no pts showed evidence of T CD4 +cells lymphopenia and for all pts a complete B CD19+ cells depletion (<5/mm3) was obtained. Hypo-IgG was observed in 8 (32%) pts [with respect to 2/32 (6.25%) pts at 1-y FU]; (iv) autoimmunity: n=1 developed thyroiditis 1 month after OCR start while, out of the 15 pts with TSH abnormality at OCR start, 13 pts (86.7%) showed TSH normalization within 1-year. Efficacy: at 2-y FU (n=55), relapse-free survival was 92.7%, MRI-activity-free survival was 89.1%, progression-free survival was 76.4% [47/55 pts (85.5%) considering only pts with RRMS at OCR start, with a Progression Independent of Relapse Activity (PIRA) evidence in 7/55 (12.7%) pts].

Conclusion: the results of our study show that the switch to OCR after 2 ALM courses is safe and effective, despite the severity of MS characterizing our patients’ cohort. Infectious rate was not higher than that reported in clinical trials involving OCR. In addition, the data show a positive effect on the development/ongoing thyroidal autoimmunity.

Disclosure of interest: Lapucci C., Frau J., Cocco E., Coghe G., Petracca M, Lanzillo R., Vercellino M., Cavalla P., Bianco A., Mirabella M., Di Mauro G., Landi D., Marfia G., Torri Clerici V., Tomas E., Ferrò M.T., Grossi P., Zaffaroni M., Ronzoni M., Nozzolillo A., Moiola L., Pinardi F., Novi G., Cellerino M., Uccelli A., Inglese M

declare no conflict of interest related to the study

P467/418

Prevalence and Anatomical Generators of Movement Disorders in Relapsing and Progressive Multiple Sclerosis

Hannah Kelly¹, Rongyi Sun¹, Mohamed Elkasaby^1,2, Alexander Wang^1,2, Hesham Abboud^1,2,3

¹Case Western Reserve University School of Medicine, Cleveland, United States, ²University Hospitals Cleveland Medical Center, Parkinson's and Movement Disorders Center, Cleveland, United States, ³University Hospitals Cleveland Medical Center, Multiple Sclerosis and Neuroimmunology Program, Cleveland, United States

Introduction: Recent studies suggest that movement disorders are more common in multiple sclerosis (MS) than previously thought. Because most original reports of movement disorders in MS were based on retrospective studies, the true prevalence is difficult to assess. We previously conducted a prospective study of movement disorders in early MS, but the prevalence and characteristics of movement disorders at different disease stages remain unknown.

Objectives/Aims: To determine the prevalence and anatomic underpinnings of movement disorders in a large cohort of MS patients and compare these factors at different disease stages.

Methods: Adult MS patients seen over 5 years (2017-2022) were evaluated for demyelination-related movement disorders via a movement disorder survey and examination by a neurologist trained in neuroimmunology and movement disorders. We classified movement disorders based on phenomenology and identified anatomic correlates according to lesion locations on MRI and relation to relapses.

Results: In total, 328 MS patients were screened, and 69% were found to have demyelination-related movement disorders. Regarding disease phenotype, 56% had relapsing-remitting MS (RRMS), 23% had secondary progressive MS (SPMS), and 21% had primary progressive MS (PPMS).

Spinal movement disorders were the most common and occurred in 79% of patients. Brainstem or cerebellar movement disorders occurred in 26%, and striatal or thalamic movement disorders were seen in 2% of patients. In total, we observed 22 cases (9%) in which movement disorders represented a new relapse, 20 of which heralded the first MS attack.

Patients with SPMS or PPMS were older than RRMS patients (37.9, 34.1, p=0.03) and were less likely to be female (63%, 75.6%, p=0.0). Patients with progressive MS were also more likely to have demyelination-related movement disorders (81.5%, 56%, p<.0) and to have both spinal (67.2%, 47.8%, p<.0) and brainstem or cerebellar movement disorders (27.7%, 14.4%, p=0.0). No significant differences were observed between progressive and relapsing MS for striatal or thalamic movement disorders (4.2%, 0.96%, p=0.1).

Conclusion: Demyelination-related movement disorders are commonly seen in all stages of MS, especially in those with progressive MS and with spinal cord and infratentorial lesions. In some patients, movement disorders may represent a new relapse including the first disease presentation. This emphasizes the need to recognize movement disorders as an important MS symptom to improve diagnosis and monitoring.

Disclosure of interest: Hannah Kelly: Nothing to disclose

Rongyi Sun: Nothing to disclose

Mohamed Elkasaby: Nothing to disclose

Alexander Wang: Nothing to disclose

Dr. Hesham Abboud is a consultant for Biogen, Genentech, Bristol-Myers-Squib, Alexion, and Horizon. He receives research support from Novartis, Sanofi-Genzyme, Bristol-Myers-Squib, Genentech, and the Guthy-Jackson charitable foundation.

P468/701

Erectile dysfunction in men with multiple sclerosis

Ivan Adamec¹, Tomislav Sambolić², Mihovil Santini², Antea Karić¹, Anamari Junaković¹, Barbara Barun¹, Tereza Gabelic¹, Magdalena Krbot Skoric¹, Mario Habek¹

¹University Hospital Center Zagreb, Department of Neurology, Referral Center for Autonomic Nervous System Disorders, Zagreb, Croatia, ²School of Medicine, University of Zagreb, Zagreb, Croatia

Introduction: Erectile problems are frequent in men with multiple sclerosis (mwMS). The causes of erectile dysfunction vary and sometimes MS isn't directly to blame, as it can be side effects of medication or an unrelated health condition.

Objectives/Aims: To evaluate the prevalence and predictors of erectile dysfunction (ED) in mwMS.

Methods: 216 consecutive mwMS (age 37.03±9.48 years, disease duration 6.76, IQR 3.29-11.70 years) during their regular follow-up visit at the Department of Neurology, University Hospital Center Zagreb, and 37 (34.92±8.65 years) healthy controls (HC) were enrolled. Expanded disability status scale (EDSS) was determined and superficial abdominal and cremasteric reflexes were examined. mwMS completed The sexual health inventory for men (IIEF-5), Modified Fatigue Impact Scale (MFIS) (cognitive, physical, and psychosocial subdomain), Beck depression inventory (BDI-2), COMPASS-31 and The 5-level EQ-5D questionnaire (your health today question, range from 0-100). HC completed the IIEF-5.

Results: From the available cohort, 8 (3.7%) mwMS and 1 (2.7%) HC were not sexually active (p=1.000). mwMS scored less on IIEF-5 compared to HC (23, IQR 18.25-25 vs 24, IQR 20.25-25, p=0.028). ED (defined as IIEF-5 score ⩽21) was present in 39.4% of mwMS and 27.8% of HC, p=0.198. A positive correlation for ED was observed with EQ-5D (r_s=0.327, p<0.001), and negative with depression (r_s=-0.311, p=0.001), fatigue (r_s=-0.426, p<0.001), and autonomic dysfunction (particularly bladder (r_s=-0.323, p=0.001) and gastrointestinal dysfunction (rs=-0.431, p<0.001)). In a multivariable linear regression analysis age (B=-0.156, 95% CI -0.233- -0.079), disease duration (B=0.150, 95% CI 0.039 – 0.261), EDSS (B=-1.423, 95% CI -1.918 - -0.928), and status of cremasteric reflex (B=1.536, 95% CI 0.065 - 3.007) were predictors for the IIEF-5 score.

Conclusion: Erectile dysfunction is frequent in mwMS and is influenced by age, level of disability, disease duration, and status of cremasteric reflex.

Disclosure of interest: None relevant

P469/1783

Factors explained the objective and subjective cognitive fatigue in people with multiple sclerosis

Hilal Karakas¹, Asiye Tuba Özdoğar², Özge Sağıcı¹, Serkan Ozakbas³

Study Group: Multiple Sclerosis Research Group

¹Dokuz Eylül University, Graduate School of Health Sciences, İzmir, Turkey, ²Van Yüzüncü Yıl University, Department of Physiotherapy, Faculty of Health Sciences, Van, Turkey, ³Dokuz Eylül University, Department of Neurology, İzmir, Turkey

Introduction: Cognitive fatigue is a clinical feature in people with multiple sclerosis (MS, pwMS). It has been suggested that cognitive fatigue may be evaluated by analyzing the course of performance during a single test offering a more objective way than self-report questionnaires in pwMS.

Objectives/Aims: To investigate factors affecting objective and subjective cognitive fatigue in pwMS.

Methods: This study has a cross-sectional design. The Symbol Digit Modalities Test (SDMT) was used to determine objective cognitive fatigue. For each test, the standard 90-second interval was further divided into three 30-second intervals. Scores from the last part (61-90 sec) were subtracted from scores from the first part (0-30 sec). The Modified Fatigue Impact Scale (MFIS) cognitive subscore was used to determine subjective cognitive fatigue. Increased scores on both assessments are associated with cognitive fatigue. European Quality of Life 5 Dimensions 3 Level (EQ-5D-3L), Hospital Anxiety and Depression Scale (HADS), Epworth Sleepiness Scale (ESS), California Verbal Learning Test-II (CVLT-II), The Brief Visuospatial Memory Test-Revised (BVMT-R) were used to assess the psychosocial parameters. The Expanded Disability Status Scale (EDSS), gender and age of the participants were recorded.

Results: Four hundred and fifty-four participants (67.6% were female) with an average age of 39.07±11.8 years were included in the study. The mean EDSS score was 1.53±1.96. According to linear regression analysis objective cognitive fatigue was determined to be positively associated with EDSS (β=0.17, t=2.624), age (β=0.37, t= 2.149) and ESS score (β=0.19, t=2.778). In addition, subjective cognitive fatigue was determined to be positively associated with HAD-anxiety score (β=0.205, t=3.386) and negatively associated with EQ-5D-3L-pain/discomfort (β=-0.163, t=-2.858) and EQ-5D-3L-anxiety/depression scores (β=-0.140, t=-2.295). These factors explained 10% of the variance in the objective and 30% variance in the subjective cognitive fatigue in pwMS.

Conclusion: Cognitive fatigue in MS is affected by clinical, demographic, and psychosocial characteristics of patients. Using SDMT as an outcome measure in this study, we performed a series of measurement design studies to evaluate cognitive fatigue trajectories in pwMS. The use of objective and subjective assessment methods together is important for a comprehensive assessment of cognitive fatigue.

Disclosure of interest: Hilal Karakas: nothing to disclose

Asiye Tuba Ozdogar: nothing to disclose

Ozge Sagici: nothing to disclose

Serkan Ozakbas: nothing to disclose

P470/433

Monitoring of upper extremity motor function: the 9-Hole Peg Test in Multiple Sclerosis revisited

Viola Pongratz¹, Held Friederike¹, Antonios Bayas², Sven Rohr³, Soto Rey Iñaki³, Monika Christ², Joachim Havla⁴, Jonathan A. Gernert⁴, Harald Meier⁵, Boeker Martin⁶, Achim Berthele¹, Bernhard Hemmer^1,7, Mark Mühlau¹

¹Technical University of Munich, Neurology, Munich, Germany, ²University of Augsburg, Medical Faculty, Neurology, Augsburg, Germany, ³University of Augsburg, Institute for Digital Medicine, Augsburg, Germany, ⁴Ludwig-Maximilians-Universität München, Insitute of Clinical Neuroimmunology, Munich, Germany, ⁵Ludwig-Maximilians-Universität München, Medical Technology and IT (MIT), Munich, Germany, ⁶Technical University of Munich, Institute of Artificial Intelligence and Informatics in Medicine, Munich, Germany, ⁷Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

Introduction: The 9-Hole Peg Test (9-HPT) is used to monitor upper extremity motor function in multiple sclerosis (MS). Usually, tests from both hands are averaged. However, recent studies have shown that left-right hand difference increases with disability and disease duration. In patients with progressive MS, substantially more worsening events were detected with separate analysis of both hands.

Objectives/Aims: To investigate longitudinal changes of 9-HPT separately for each hand.

Methods: A cohort of 509 MS patients (16 clinically isolated syndrome (CIS), 459 relapsing remitting MS, 26 secondary progressive MS, 8 primary progressive MS at the time point of last 9-HPT) has been analysed over a mean follow-up period of 9.2 years. Inclusion criteria was a diagnosis of MS or CIS and a minimum follow-up time of about 5 years (> 1800 days). Paired t-tests between first and last 9-HPT were performed separately for both hands. The change of the 9-HPT over the study period was compared between dominant and non-dominant hand by paired t-test (time first non-dominant minus time last non-dominant 9-HPT versus time first dominant MINUS time last dominant 9-HPT). Significant worsening (time increase of > 20%) was investigated separately for each hand and for the mean of both hands.

Results: Over a mean period of 9.2 years only the non-dominant hand deteriorated significantly (mean +/- standard deviation, first 9-HPT 20.09 ± 4.69 seconds, last 9-HPT 21.02 ± 8.86 seconds; + 0.9 seconds; paired T-test, two-sided, p 0.003), while no significant deterioration was found for the dominant hand (mean +/- standard deviation, first 9-HPT 19.10 ± 4.39 seconds, last 9-HPT 19.14 ± 5.47 seconds; + 0.05 seconds; paired T-test, two-sided, p = 0.4). The change in 9-HPT of the non-dominant hand was significantly larger than of the dominant hand (p 0.001, two-sided). When considering the mean of both hands, 40 patients deteriorated significantly. Separate analysis of both hands however revealed 76 worsening events (24 both hands, 33 non-dominant hand, 19 dominant hand).

Conclusion: The current practice to average 9-HPT from both hands needs to be reconsidered to monitor disease progression more accurately. A separate analysis of both hands seems appropriate. Validation of this finding in independent study cohorts is in process.

Disclosure of interest: Viola Pongratz received research support from Novartis (Oppenheim Förderpreis).

Friederike Held has nothing to disclose.

Antonios Bayas received personal compensation from Merck Serono, Biogen, Novartis, TEVA, Roche, Sanofi/Genzyme, Celgene/Bristol Myers Squibb, Janssen, and Sandoz/HEXAL. He received grants for congress travel and participation from Biogen, TEVA, Novartis, Sanofi/Genzyme, Merck Serono, Celgene and Janssen. None related to this study.

Sven Olaf Rohr has nothing to disclose.

Iñaki Soto Rey has nothing to disclose.

Monika Christ has nothing to disclose.

Joachim Havla reports grants from the Friedrich-Baur-Stiftung, Merck and Horizon, personal fees and non-financial support from Alexion, Horizon, Roche, Merck, Novartis, Biogen, BMS and Janssen, and non-financial support from the Guthy-Jackson Charitable Foundation and The Sumaira Foundation.

Jonathan Gernert has nothing to disclose.

Harald Meier has nothing to disclose.

Martin Boeker has nothing to disclose.

Achim Berthele has received consulting and/or speaker fees from Alexion, Biogen, Celgene, Horizon, Novartis, Roche and Sandoz/Hexal, and his institution has received compensation for clinical trials from Alexion, Biogen, Merck, Novartis, Roche, and Sanofi Genzyme; all outside the present work.

Bernhard Hemmer has served on scientific advisory boards for Novartis; he has served as DMSC member for AllergyCare, Sandoz, Polpharma, Biocon and TG therapeutics; his institution received research grants from Roche for multiple sclerosis research. He has received honoraria for counseling (Gerson Lehrmann Group). He holds part of two patents; one for the detection of antibodies against KIR4.1 in a subpopulation of patients with multiple sclerosis and one for genetic determinants of neutralizing antibodies to interferon. All conflicts are not relevant to the topic of the study.

Mark Mühlau reports no conflicts of interest, his funding sources are German Research Foundation, DFG Priority Programme 2177, Radiomics: Next Generation of Biomedical Imaging (project number 428223038), German Federal Ministry of Education and Research (BMBF), Medical Informatics Initiative (MII), Data Integration for Future Medicine (DIFUTURE) consortium (grants 01ZZ1603[A-D] and 01ZZ1804[A-I]), the National Institutes of Health (grant 1R01NS112161-01 [subinvestigator]), Bavarian State Ministry for Science and Art, Collaborative Bilateral Research Program Bavaria – Québec: AI in medicine (project number F.4-V0134.K5.1/86/45).

P471/1675

Characterization of Early Gait Alterations in Multiple Sclerosis using GAITRite Analysis in a large MS cohort

Hernan Inojosa¹, Heide Stoelzer-Hutsch¹, Dirk Schriefer¹, Katja Akgün¹, Katrin Trentzsch¹, Tjalf Ziemssen¹

¹Center of Clinical Neuroscience, Department of Neurology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

Introduction: Gait impairment is one of the most common symptoms of people with multiple sclerosis (pwMS) throughout the disease course. Early identification of gait deficits already in subclinical disease phases may facilitate effective preventive interventions. However objective real-world gait data are often based on either small sample sizes or mixed cohorts that include also more disabled pwMS.

Objectives/Aims: Consequently, our objective was to assess the gait performance of pwMS without clinical-relevant deficits in a large real-world cohort in relation to healthy controls. In particular, we aimed to examine the relation between preferred walking speed and possible alterations at early stages of the disease.

Methods: Gait was assessed using an instrumented walkway technology (GAITRite®, CIR Systems Inc., Clifton, NJ, U.S.A) at the Mobility Lab of the MS Centre Dresden, Germany. Both healthy controls (HC) and >1900 pwMS were instructed to walk at their preferred, comfortable walking speed. 220 pwMS without functionally relevant neurological disability with an Expanded Disability Status Score (EDSS) of up to 1.5 were included in this analysis. A 1:1 propensity score matching was performed to balance socio-demographic characteristics (age, sex, body max index) between both groups (pwMS, HC). Patients were stratified into quartiles according to disease duration and velocity performance.

Results: After propensity score matching, a total of 220 pwMS and 220 HCs remained for the analysis. 96.9% of pwMS had a relapsing remitting MS and median disease duration was 4 years (IQR 1-12). Median EDSS measured by Neurostatus was 1.5 (IQR 1.5-1.5). Interestingly, pwMS tended to show higher velocities and cadence than HCs. Considering disease duration, we observed a similar performance between HCs and pwMS with ⩽ 1 year disease duration. However, after stratification in four gait velocity categories, we observed that pwMS in the maximum speed group differed slightly from the HCs with higher cadence [124.4 (SD 6.9) vs 122.1 (SD 9.9) steps per minute] and shorter step [146.59 cm (SD 6.4) vs 74.1 cm (SD 5.0)] and stride [146.59 cm (SD 6.4) vs 148.6 cm (SD 10.1)] lengths. Temporal parameters (e.g. stance and swing time) were correspondingly lower.

Conclusion: In this cohort, we observed that pwMS without neurological disability had a tendency towards higher preferred walking speed. Differences of gait pattern could be better revealed at higher speed. Further analysis regarding fatigability could provide an insight of subtle gait alterations.

Disclosure of interest: HI received speaker fee from Roche and financial

support for research activities from Biogen, Teva and Alexion. KA reports scientific advisory board and/or consulting for Roche, Sanofi, Alexion, Teva,

Biogen, and Celgene. TZ reports scientific advisory board and/or consulting for

Biogen, Roche, Novartis, Celgene, and Merck; compensation for serving on speakers bureaus for

Roche, Novartis, Merck, Sanofi, Celgene, and Biogen; research support from Biogen, Novartis, Merck,

and Sanofi. HSH, DS and KT: nothing to disclose.

P472/1543

Differential Validity in the Written, Oral and Electronic SDMT in Multiple Sclerosis

Matthew Greenwald¹, Hector Cancel Asencio², Karan Kawatra², Jenifer Dwyer², Arshe Moss², Irene Cortese³, Daniel Reich¹, Maria Gaitan¹

¹National Institute of Neurological Disorders and Stroke, Translational Neuroradiology Section, Bethesda, United States, ²National Institute of Neurological Disorders and Stroke, Neuroimmunology Clinic, Bethesda, United States, ³National Institute of Neurological Disorders and Stroke, Experimental Immunotherapeutics Unit, Bethesda, United States

Introduction: The Symbol Digit Modalities Test (SDMT) is a widely used cognitive processing assessment tool for individuals with multiple sclerosis (MS), administered in written (wSDMT), oral (oSDMT), and electronic (eSDMT) formats. There is no substantial evidence indicating which modality of administration has the highest concurrent validity in measuring impaired cognition, and no subject-controlled comparison of all three tests has been conducted to date.

Objectives/Aims: To determine external reliability, demographic effects, and motor disability influence on the wSDMT, oSDMT, and eSDMT.

Methods: This prospective, within-subjects study analyzed scores on the wSDMT, oSDMT and eSDMT taken by individuals with established MS diagnosis enrolled in the NINDS MS natural history study between January and April 2023. All eSDMTs were administered using the iPad-based ‘CogEval’ app (Biogen). Relationships between variables were assessed using linear regression models (LRM), Fisher’s Z transformation, intraclass correlation coefficients (ICC), and Welsch’s t-test.

Results: 37 adults with MS (68% women, median age: 44 [range: 28–74], median EDSS: 1.5 [range: 0.0–8.0]) took the wSDMT, oSDMT, and eSDMT. Parallel-forms reliability calculated using pairwise correlations between test scores revealed high correlations in all three pairs (Pearson’s R > 0.80) and no significant differences between these correlations (p > 0.05). Intraclass reliability was also strong (Two-way Consistency ICC = 0.83, p < 0.01). Demographic analysis revealed no difference between men and women on any test version (Welsch Two Sample t-test: p > 0.05). Age had a significant negative correlation with scores on all tests, with the numerically strongest correlation present in eSDMT (Pearson’s R: wSDMT: -0.39, oSDMT: -0.36, eSDMT: -0.56). Years of education was not correlated with score on any tests in this small cohort. LRMs controlled for age and Paced Serial Addition Test (PASAT) scores showed a significant negative correlation between dominant-hand 9 Hole Peg Test (9HPT) time and wSDMT score (R²: 0.34, p < 0.05), but not between 9HPT and oSDMT or eSDMT (p > 0.05).

Conclusion: These results demonstrate high external reliability of the wSDMT, oSDMT, and eSDMT. Interestingly, the eSDMT is more prone to age-related effects, possibly reflecting a relationship between test performance and electronic familiarity. The wSDMT is uniquely sensitive to motor disability in the upper extremities, making it a potential multi-dimensional indicator of clinical progression.

Disclosure of interest: Matthew Greenwald: nothing to disclose

Hector Cancel Asencio: nothing to disclose

Karan Kawatra: nothing to disclose

Jenifer Dwyer: nothing to disclose

Arshe Moss: nothing to disclose

Irene Cortese: nothing to disclose

Daniel Reich: Additional research funding from Abata and Sanofi, unrelated to the this abstract.

Maria Gaitan: nothing to disclose

This study was supported by the intramural research program of NINDS.

P473/1829

Indicators of disease activity in people with MS treated with DMTs for mild/moderate MS: time to clinical and/or subclinical activity

Melanie Peters^1,2, David Ellenberger¹, Fneish Firas¹, Alexander Stahmann¹, Tim Friede³, Klaus Berger⁴, Peter Flachenecker⁵, Judith Haas⁶, Clemens Warnke⁷, Friedemann Paul⁸, Uwe K. Zettl⁹, Niklas Frahm¹

¹MS Forschungs- und Projektentwicklungs- gGmbH (MS Research and Project Development gGmbH [MSFP]), German MS Registry, Hannover, Germany, ²Gesellschaft für Versorgungsforschung mbH (Society for Health Care Research [GfV]), Hannover, Germany, ³University Medical Center Göttingen, Department of Medical Statistics, Göttingen, Germany, ⁴Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany, ⁵Neurological Rehabilitation Center Quellenhof, Bad Wildbad, Germany, ⁶Deutsche Multiple Sklerose Gesellschaft, Bundesverband e.V. (German Multiple Sclerosis Society [DMSG]), Hannover, Germany, ⁷Medical Faculty, University Hospital of Cologne, Department of Neurology, Cologne, Germany, ⁸Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany, ⁹University Medical Center of Rostock, Department of Neurology, Neuroimmunological Section, Rostock, Germany

Introduction: Disease activity (DA) in people with MS (PwMS) is defined by various clinical and imaging parameters and typically associated with an increased risk of future relapses and a faster disability progression.

Objectives/Aims: To determine the proportion of PwMS with DA during a period of 5 years after initiation of DMT for mild/moderate MS, considering different clinical criteria for the detection of DA.

Methods: Data as of 01-03-2023 from the German MS Registry were used for the analysis. Inclusion criteria were relapsing-remitting disease course, MS diagnosis ⩾2017, initial DMT for mild/moderate disease courses (dimethyl fumarate [DMF], diroximel fumarate [DRF], glatiramer acetate [GLAT], [peg-] interferon beta [IFN-β], teriflunomide [TER]) and ⩾1 follow-up during initial DMT. The frequency of DA within 5 years of DMT was examined according to following criteria: Relapse activity (⩾1 relapse), MRI activity (⩾1 gd+/new T2 lesion) and 3-month confirmed disability progression (CDP; ⩾1-point EDSS increase if EDSS⩽5.5, ⩾0.5-point EDSS increase if EDSS⩾6.0). The frequency of DA was estimated using Kaplan Meier estimators. For patients who did not show disease activity, delay was censored on the date of the last neurological consultation.

Results: 1159 PwMS were analysed (70.9% female; mean age at MS onset: 33.8 [±10.4] years; mean time to MS diagnosis: 1.14 [±3.2] years). At DMT initiation, the mean age of PwMS was 36.0 (±10.9) years and median EDSS score was 1.0 [1^st,3^rd quantiles: 0.0, 2.0]. The most frequently used initial DMT was GLAT (36.2%), followed by DMF/DRF (30.5%), IFN-β (20.3%) and TER (13.0%). In a mean observation period of 2.6 (±1.6) years from DMT start, 32.4% (n=376) of PwMS met ⩾1 criterion of DA during DMT. Within 2 years, MRI activity was detected in 17.2%, relapse activity in 17.9% and 3-month CDP in 11.1% of PwMS. Within 5 years, 38.9% were estimated to have had ⩾1 MRI event (⩾2: 11.6%), 31.4% 1 relapse (⩾2: 8.7%) and 23.9% 3-month CDP (6-month CDP: 19.0%).

Conclusion: At least one indicator of DA was detected in about one-third of PwMS treated with DMTs for mild/moderate disease courses within the observation period of 5 years. MRI activity and relapses are the most common indicators of DA. Careful monitoring is required to assess an adequate response to DMT as the basis for a potential switch decision to DMTs of individual higher efficacy.

Disclosure of interest: Niklas Frahm is an employee of the MSFP. Moreover, he is an employee of Rostock’s University Medical Center and received travel funds for research meetings from Novartis. None resulted in a conflict of interest.

David Ellenberger, Firas Fneish and Melanie Peters had no personal financial interests to disclose other than being employees of the German MS Registry.

Alexander Stahmann has no personal financial interests to disclose, other than being the leader of the German MS Registry, which receives (project) funding from a range of public and corporate sponsors, recently including G-BA, The German Retirement Insurance, The German MS Trust, German MS Society, Biogen, Bristol Myers Squibb, Merck, Novartis and Roche. None resulted in a conflict of interest.

Tim Friede has received personal fees for consultancies (including data monitoring committees) in the past three years from Bayer, BiosenseWebster, Boehringer Ingelheim, Cardialysis, CSL Behring, DaiichiSankyo, Enanta, Feldmann Patent Attorneys, Fresenius Kabi, Galapagos, IQVIA, Janssen, Mediconomics, Novartis, Penumbra, Roche, SGS, Vifor; all outside the submitted work.

Klaus Berger received a grant from the German Ministry of Education and Research (within the German Competence Net Multiple Sclerosis) plus additional funds from Biogen, all to the University of Muenster for an investigator initiated adverse events register for patients with multiple sclerosis. None resulted in a conflict of interest.

Peter Flachenecker has received speaker’s fees and honoraria for advisory boards from Almirall, Bayer, Biogen Idec, BMS-Celgene, Coloplast, Genzyme, GW Pharma, Hexal, Janssen-Cilag, Novartis, Merck, Roche, Sanofi, Stadapharm and Teva. None resulted in a conflict of interest.

Judith Haas serves as president of the German MS Society, federal association, which receives funding from a range of public and corporate sponsors, recently including BMG, G-BA, The German MS Trust, Biogen, BMS, Merck Serono, Novartis, Roche, Sanofi, and Viatris. None resulted in a conflict of interest. None resulted in a conflict of interest.

Clemens Warnke has received institutional support from Novartis, Alexion, Sanofi Genzyme, Biogen, Merck and Roche. None resulted in a conflict of interest.

Friedemann Paul has received speaking fees, travel support, honoraria from advisory boards and/or financial support for research activities from Bayer, Novartis, Biogen, Bristol Myers Squibb, Teva, Sanofi-Aventis/Genzyme, Merck Serono, Alexion, Chugai, MedImmune, Shire, German Research Council, Werth Stiftung of the City of Cologne, German Ministry of Education and Research, EU FP7 Framework Program, Arthur Arnstein Foundation Berlin, Guthy Jackson Charitable Foundation and National Multiple Sclerosis of the USA. He serves as academic editor for PLoS ONE and associate editor for Neurology, Neuroimmunology and Neuroinflammation. None resulted in a conflict of interest.

Uwe K. Zettl has received speaking fees, travel support and /or financial support for research activities from Alexion, Almirall, Bayer, Biogen, Bristol Myers Squibb, Janssen, Merck Serono, Novartis, Octapharma, Roche, Sanofi Genzyme, Teva as well as EU, BMBF, BMWi and DFG. None resulted in a conflict of interest.

P474/853

Family Functioning and Multiple Sclerosis: preliminary data of a Multicentric Italian Project

Giuseppina Miele¹, Luigi Lavorgna², SIMONA BONAVITA², Gianmarco Abbadessa³, Floriana Bile³, Girolama Alessandra Marfia⁴, Doriana Landi⁴, Francesca Proietti⁴, Matilde Inglese⁵, Alice Laroni⁵, ilaria poirè⁵, Elisabetta Signoriello², Giacomo LUS², Giuseppe Romano², Roberta Lanzillo⁶, Laura Rosa⁶, Francesca Lauro⁶, Stefania De Mercanti⁷, Virginia Perutelli⁷, Marialaura Di Tella⁸, Lidia Mislin⁷, Loris Castelli⁷, Marinella Clerico⁸

¹University of Campania Luigi Vanvitelli, Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy, via Panisini, Italy, ²University of Campania Luigi Vanvitelli, Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy, Naples, Italy, ³University of Campania Luigi Vanvitelli, Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy, Naples, Italy, ⁴Tor Vergata, University, Rome, Multiple Sclerosis Clinical and Research Unit, Department of Systems Medicine, Tor Vergata, University, Rome, Italy, Rome, Italy, ⁵University of Genoa, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy., Genoa, Italy, ⁶Federico II University of Naples, Multiple Sclerosis Clinical Care and Research Centre, Department of Neuroscience, Reproductive Sciences and Odontostomatology, Federico II University of Naples, Naples, Italy., Naples, Italy, ⁷University of Turin, Department of Psychology, University of Turin, Turin, Italy., Turin, Italy, ⁸University of Turin, Department of Clinical and Biological Sciences, School of Medicine, University of Turin, Azienda Ospedaliera Universitaria San Luigi Gonzaga, Turin, Italy., Turin, Italy

Introduction: Multiple Sclerosis (MS) may influence family functioning, with effects on both marital relationships and parental bonding.

Objectives/Aims: Our aim is to evaluate family functioning and related factors in patients with MS and their families.

Methods: A dedicated platform has been used for filling in the questionnaires for MS patients and their families. As controls, we selected families with no subjects referring chronic diseases. Socio-demographic and clinical information was preliminary collected. Administered questionnaires included: (1) the short form of the Family Assessment Measure Third Edition (FAM3); (2) the Hospital Anxiety and Depression Scale (HADS); (3) the Multidimensional Scale of Perceived Social Support (MSPSS); Dyadic Adjustment Scale (DAS) and the Inventory of Parent and Peer Attachment (IPPA)

Results: 129 MS patients, 93 family members (21 aged between 13 and 20 years old), and 210 control subjects (100 aged between 13 and 20 years old) completed the online questionnaires. MS family members are more anxious than control subjects (p= 0.0016) and MS partners have a higher degree of dyadic agreement (on finances, leisure time, home organization) than control subjects (p= 0.0167). Young people with ages between 13 and 20 years old who have at least one member with MS in their family, have higher quality attachments with significant others (both parents and peers), as assessed with the IPPA.

Conclusion: MS may affect the psychological state and family functioning by making MS family members more anxious, but also make more compliant partners and mature adolescents.

Disclosure of interest: Miele Giuseppina: grant support by Novartis, Merck-Serono, Roche, Biogen;

Lavorgna Luigi

Bonavita Simona: Advisory board and/0r speaker honoraria from: Novartis, Roche, Biogen, Merck-Serono, Viatris, Bristol, Sanofi, Alexion, Jannsen-Cilag

Reasearch fundiing by Roche;

Abbadessa Gianmarco: personal compensation Merk, Jansen;

Bile Floriana

Marfia Girolama Alessandra

Landi Doriana

Proietti Francesca

Inglese Matilde: is Co-Editor for Controversies for Multiple Sclerosis Journal. She has received research support from NIH, NMSS, the MS Society of Canada, the Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, H2020 EU Call. She has taken part in advisory boards/consultancy for Biogen Idec, Celgene/Bristol Myers Squibb, Janssen, Merck-Serono, Novartis, Roche, Sanofi Genzyme.

Laroni Alice

Poire Ilaria

Signoriello Elisabetta

Lus Giacomo

Lanzillo Roberta

Lauro Francesca

De Mercanti Stefania Federica

Perutelli Virginia

Di Tella Maria Laura

Streito Lidia Mislin

Lorys Castelli

Marinella Clerico

P475/1320

Frequency, severity and awareness of dysphagia in people with Multiple Sclerosis: the DYSPHAMS study

Paolo Ragonese¹, Miriam Martorana¹, Francesca Madonia¹, Francesca Catalano¹, Salvatore Iacono¹, Giuseppe Schirò¹, Gabriele Sorbello¹, Andrea Calì¹, Giuseppe Salemi¹

¹Department of Biomedicine, Neurosciences, and advanced Diagnostics. University of Palermo, Palermo

Introduction: Recent studies indicate that even in people with multiple sclerosis (MS) with low disability, silent disease progression occurs. At present, few accurate markers able to predict disease progression proven reproducible.

Objectives/Aims: To analyze this issue also from a clinical perspective, we investigated the frequency and severity of dysphagia in people with an apparently low to moderate disability (DisphaMS). Aim of the study is to investigate if dysphagia can be considered an early marker of disease progression.

Methods: We recruited a sample of 86 individuals affected by MS according to McDonald 2017 revised criteria, who agreed to participate to the study project. Exclusion criteria were: severe cognitive or language disturbances, ongoing treatments for swallowing disturbances or any head or neck concomitant disease. Patients underwent to a specific evaluation by a speech therapist specialist by specific anamnesis, and by the following scales: “DYMUS” questionnaire, “DOSS”, “DysphAScale”, swallowing water test, test with standardized consistency foods (liquid IDDSI 0, semi-solid IDDSI 4, solid IDDSI 7). We calculated the frequency and severity of swallowing disturbances among included people. Scales used in the study were also compared for agreement and consistency. Finally, we considered the patient awareness of swallowing disturbances according to disturbance severity and to the disability measured by the EDSS.

Results: 53 out of the 86 recruited individuals (65%) were women; mean age for the whole sample was 50 years. Sixty-seven (nearly 80%) had some degrees of swallowing disturbances while had 31% of them had a subclinical disturbance and 25% a borderline swallowing ability. Only 26% of people were aware of having dysphagia while the others were only partially aware (33%) or not aware at all (41%). Overall, the correspondence the DOSS and DYMUS scales comparisons showed low levels of concordance (i.e. 58% at risk for dysphagia according to DYMUS, whilst 98% of them were clearly affected according to DOSS scale).

Conclusion: Our study showed a high frequency of swallowing disturbances among people with MS. The Dysphascale indicated indeed a low level of awareness. The present study suggests that even dysphagia could be considered an early marker of silent progression, and need therefore to be early recognized to anticipate its diagnosis and care.

Disclosure of interest: All of the authors declare that they have nothing to disclose with regard to the present project

P476/2010

Multidimensional measurement of progression independent of relapse activity in early multiple sclerosis

Andre Braginets^1,2,3,4, Ting-Yi Lin^1,2,3, Susanna Asseyer^1,2,3,4, Klemens Ruprecht⁵, Friedemann Paul^1,2,3,4,5, Tanja Schmitz-Hübsch^1,2,3,4, Hanna G. Zimmermann^1,2,3,4,6

¹Experimental and Clinical Research Center, a cooperation between Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité - Universitätsmedizin Berlin, Berlin, Germany, ²Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany, ³Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany, ⁴Neuroscience Clinical Research Center (NCRC), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany, ⁵Department of Neurology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany, ⁶Einstein Center Digital Future, Berlin, Germany

Introduction: Progression independent of relapse activity (PIRA) is increasingly recognized as a significant contributor to disease progression in people with early multiple sclerosis (pweMS). While the Expanded Disability Status Scale (EDSS) is commonly used to assess disease progression, a multidimensional approach incorporating the 9-Hole Peg Test (9HPT) and Timed 25-foot Walk (T25FW) for upper and lower limb function, the Symbol Digit Modalities Test (SDMT) for cognitive function, and the Low-contrast Letter Acuity (LCLA) for visual function, may enhance the identification of PIRA.

Objectives/Aims: To describe the prevalence of PIRA in confirmed disability worsening (CDW) events in pweMS and compare EDSS, 9HPT, T25FW, SDMT and LCLA in identifying PIRA.

Methods: We retrospectively enrolled 65 pweMS (mean age: 34.9 ± 9.0 years, 56.2 % female, median (interquartile range (IQR)) time since onset: 0.5 (0.4 – 0.6) years) from a prospective cohort study who had ⩾ 3 visits over a follow-up of ⩾ 2 years (median (IQR) visit interval: 1.0 (0.9 – 1.1) years). Among them, 8 had a clinically isolated syndrome converting to relapsing remitting multiple sclerosis (RRMS) during follow-up, and 57 had RRMS since study inclusion. PIRA was defined as a confirmed change in EDSS (⩾ 1.5 point increase if reference EDSS = 0, ⩾ 1.0 point increase if EDSS 1-5, ⩾ 0.5 point increase if EDSS ⩾ 5.5), 9HPT (⩾ 20% increase), T25FW (⩾ 20% increase), SDMT (⩾ 4 points or ⩾ 10% decrease) or LCLA (⩾ 7 letters decrease).

Results: Among the 65 pweMS, 29 (44.6%) experienced a total of 32 CDW events over a median follow-up of 5.5 (IQR: 3.5 – 7.5) years. PIRA was present in 21 (72.4 %) of these 29 pweMS and accounted for 22 CDW events (68.8 %). Among the 22 PIRA events, 8 (36.3 %) were identified by EDSS increase, 4 (18.2 %) by T25FW increase and 10 (45.5 %) by SDMT decrease. No PIRA events were identified by 9HPT or LCLA. No participant experienced PIRA with more than one parameter simultaneously. Furthermore, pweMS with PIRA were older at baseline compared to those without PIRA (38.5 ± 9.6 vs. 33.2 ± 8.3 years, p = 0.025).

Conclusion: PIRA plays a significant role in disability worsening in pweMS. Complementing the EDSS with functional tests increases the identification of almost two-thirds of individuals with PIRA who would otherwise go unnoticed. Nearly half of the PIRA events were solely identified by SDMT, suggesting a relapse-independent cognitive decline that is not captured by EDSS.

Disclosure of interest: A. Braginets: nothing to disclose.

T.-Y. Lin received compensation from ADA Health, unrelated to the presented work.

S. Asseyer has received conference grant from Celgene and speaking honoraria from Bayer Healthcare, Roche, and Alexion.

K. Ruprecht received research support from Novartis, Merck Serono, German Ministry of Education and Research, European Union (821283-2), Stiftung Charité, Guthy-Jackson Charitable Foundation, and Arthur Arnstein Foundation; received travel grants from Guthy-Jackson Charitable Foundation; received speaker’s honoraria from Novartis; KR is a participant in the BIH Clinical Fellow Program funded by Stiftung Charité.

F. Paul served on the scientific advisory boards of Novartis and MedImmune; received travel funding and/or speaker honoraria from Bayer, Novartis, Biogen, Teva, Sanofi-Aventis/Genzyme, Merck Serono, Alexion, Chugai, MedImmune, and Shire; is an associate editor of Neurology: Neuroimmunology & Neuroinflammation; is an academic editor of PLoS ONE; consulted for Sanofi Genzyme, Biogen, MedImmune, Shire, and Alexion; received research support from Bayer, Novartis, Biogen, Teva, Sanofi-Aventis/Geynzme, Alexion, and Merck Serono; and received research support from the German Research Council, Werth Stiftung of the City of Cologne, German Ministry of Education and Research, Arthur Arnstein Stiftung Berlin, EU FP7 Framework Program, Arthur Arnstein Foundation Berlin, Guthy-Jackson Charitable Foundation, and NMSS.

T. Schmitz-Hübsch: nothing to disclose.

H.G. Zimmermann received research grants from Novartis and speaking honoraria from Novartis.

P477/2371

Multimodal evaluation of urinary dysfunction in people with multiple sclerosis

Sara Grlić¹, Katarina Tešija¹, Tereza Gabelic^1,2, Ivan Adamec^1,2, Barbara Barun^1,2, Jesper Hagemeier³, Magdalena Krbot Skoric^2,4, Mario Habek^1,2

¹School of Medicine, University of Zagreb, Deparment of Neurology, Zagreb, Croatia, ²University Hospital Center Zagreb, Department of Neurology, Referral Center for Autonomic Nervous System Disorders, Zagreb, Croatia, ³Manasota Consulting, Sarasota, United States, ⁴Faculty of Electrical Engineering, University of Zagreb, Zagreb, Croatia

Introduction: Lower urinary tract symptoms (LUTS) occur in more than 80% of people with multiple sclerosis (pwMS) during the course of the disease, significantly affecting the quality of life (QoL). The subjective impact of urinary dysfunction on everyday life is assessed with the International Consultation on Incontinence Questionnaire (ICIQ) modules

Objectives/Aims: The aim of this study was to correlate the results of the ICIQ questionnaire modules with Expanded Disability Status Scale (EDSS), Bowel/Bladder Function System (BFS), median and tibial somatosensory (SS) evoked potentials (EP), and presence of demyelinating lesions in brainstem or spinal cord MRI.

Methods: 42 consecutive pwMS (36 females, age 35.5 ± 9.3 years), were included and EDSS with BFS was calculated. SSEP of median and tibial nerve were performed with latency evaluation of waves N20 and P40 representing somatosensory cortex for arm and leg. The latest MRI of the brain and spinal cord were taken for analysis. All pwMS filled in the Croatian language validated three ICIQ questionnaires: ICIQ - overactive bladder (OAB), ICIQ-OAB QOL, and ICIQ - urinary incontinence (UI). All results were corrected for therapy.

Results: Positive correlation was found between objective neurological disability measured with EDSS and BFS with OAB symptoms measured with ICIQ-OAB (r=0.331, p=0.035 and r=0.692, p<.001) and ICIQ-OABqol (r=0.366, p=019 and r=0.771, p <.001 ), and symptoms of urinary incontinence measured with ICIQ-UI (r=0.481, p=0.001 and r=0.664, p <.001).

Prolonged latencies of the right P40 wave on the tibial SSEP positively correlated with OAB (ICIQ-OAB: r=0.374, p=0.016; ICIQ-OABqol: r=384, p=0.013) and prolonged latencies of both P40 waves with UI symptoms (r=0.582, p=<.001 and r=0.454, p=0.003). There was no significant correlation between ICIQ results and the presence of demyelinating lesions in the brainstem or spinal cord MRI.

Conclusion: Subjective significance of LUTS in everyday life measured by ICIQ-UI questionnaires positively correlated with clinical EDSS and BFS findings as well neurophysiological results of P40 latencies in tibial SSEP.

Disclosure of interest: Sara Grlić: Nothing to disclose

Katarina Tešija: Nothing to disclose

Tereza Gabelić: nothing to disclose

Ivan Adamec: Nothing to disclose

Barbara Barun: Nothing to disclose

Jesper Hagemeier: Nothing to disclose

Magdalena Krbot Skorić: Nothing to disclose

Mario Habek: nothing to disclose

P478/2368

Implications of progression independent of relapse activity (PIRA) for multiple sclerosis clinical trials: item banks could provide the precise patient-reported outcome measures needed

Jeremy Hobart¹, Tanya King¹, Ida Marais², Sonia Sappl², Licinio Craveiro³, jonathan Marsden¹, David Andrich²

¹University of Plymouth, Faculty of Health, Plymouth, United Kingdom, ²University of Western Australia, Perth, Australia, ³F-Hoffmann-La Roche Ltd, Basel, Switzerland

Introduction: It is now accepted that many people with early MS progress independent of relapses (PIRA). Therefore, clinical trials need to measure clinical variables precisely to detect meaningful change. It is also accepted that trials include patient reported outcome (PRO) measures to incorporate patients’ perspectives. Unfortunately, most PRO measures generate relatively imprecise estimates, with wide standard errors. They do not have the very large numbers of items, nor luxury of selecting items for individuals, precise PRO measurement requires.

Item banks offer a potential solution. These PRO measures consist of very large numbers of conceptually strong, calibrated items from which any subset can be used. At ECTRIMS21 we presented a proof-of-concept study for a 172-item bank measuring upper limb function (ULF).

Objectives/Aims: To report the next stage of the Bank’s examination.

Methods: Retrospective examination: we formed 6 item subsets, each with 37 items, targeted to different, overlapping levels of ULF. In existing data (n=1570), we computed, for everyone, ULF estimates from all 6 subsets and the degree to which they generated statistically equivalent estimates.

Prospective validation: 52 participants in an ongoing MS study (ISRCTN15993728) graded their ULF difficulty (none-to-severe). Gradings determined the item subset received. We tested the ability of the subsets to detect differences between groups defined by ULF grading. So far, 10 participants have completed >2 subsets. We tested the degree to which different subsets generated statistically equivalent estimates.

Results: Retrospective examination: Subsets generated statistically equivalent estimates. For example, person estimates derived from subsets 1 and 2 were statistically equivalent (-1.96 < t <1.96) for 99.4% (1748/1749) of people despite very narrow standard errors (as low as 0.18 logits).

Prospective examination: Mean person estimates for groups defined by their ULF grade showed a stepwise change consistent with expectation (6.27; 2.57;.1.95; 0.60), and with findings in the retrospective dataset (6.13; 3.31; 1.53; 0.52). When >2 subsets were completed, subsets generated equivalent estimates.

Conclusion: These promising results provide further evidence that item banks can work; independent item subsets generated statistically equivalent estimates. Importantly, targeted item subsets generate more precise estimates of ULF suitable for clinical trials and further elaborations of PIRA.

Disclosure of interest: Jeremy Hobart has received consulting fees, honoraria, support to attend meetings, research support or clinical service support from: Acorda, Bayer Schering, Biogen Idec, BMS, F. Hoffmann-La Roche, Janssen, Merck Serono, Novartis, Oxford PharmaGenesis, Sanofi-Genzyme, Teva.

Licinio Craveiro is an employee of F.Hoffmann-La Roche Ltd.

Jonathan Marsden, via Plymouth University, has received a project grant from F.Hoffmann-La Roche Ltd

Tanya King, Sonia Sappl, Ida Marais, David Andrich - no diclosures

P479/2325

Measuring fatigue in multiple sclerosis clinical trials: why patient reported outcome measure choice is not immaterial when measuring change

Jeremy Hobart¹, Tanya King¹, Sonia Sappl², Ida Marais², James Close¹, Pamela Vo³, David Andrich²

¹University of Plymouth, Faculty of Health, Plymouth, United Kingdom, ²University of Western Australia, Perth, Australia, ³Novartis Pharmaceuticals Corporation, Basel, Switzerland

Introduction: In multiple sclerosis (MS), fatigue is ubiquitous, burdensome, and frequently measured in clinical trials. MS studies have used 18 different fatigue patient-reported outcome (PRO) measures.

Objectives/Aims: We shortlisted 6 of these 18 PRO measures (list at end*) and compared their measurement performance to determine if choice among them is immaterial.

Methods: All 6 PRO measures were sent simultaneously to 740 people with MS. PRO measure response data were analyzed using Rasch measurement theory (RMT) methods. We examined: first, if each PRO measure was well-functioning enough according to RMT criteria; second, the degree to which PRO measures of the same fatigue component (overall, motor, cognitive) generated statistically equivalent estimates at group and individual person-levels.

Results: The response rate was 73% (538/740). All 6 fatigue PRO measures functioned well enough to imply their suitability for clinical trials. PRO measures of the same fatigue component: were very highly correlated (error-corrected r=0.85-0.98); had >96% common variance on RMT subtest analyses; generated statistically equivalent group mean scores (t<1.3). These findings imply all PRO measures of the same fatigue component measured the same variables (albeit not identical), and that PRO measure choice for measuring change in trials is immaterial.

However, PRO measures of the same fatigue component often generated profoundly different individual person-level estimates, with statistical non-equivalence up to 40% of the time. This indicates any changes detected, and conclusions reached, are unlikely to be equivalent at the individual level. Therefore, PRO measure choice is not immaterial. Further examinations highlighted that the greater the number of items, the greater the difference between individual and group-level interpretations from different PRO measures, due to greater measurement precision.

Conclusion: Results suggest PRO measure choice should consider both individual and group analyses. And, when selecting PRO measures, clinical trialists consider the item number as well as standard indicators (content validity, psychometric properties). Therefore, even when a group of fatigue PRO measures are high functioning and very highly correlated, the choice of measure for clinical trials is not immaterial.

* Modified Fatigue Impact Scale; NeuroQol Fatigue Scale; PROMIS Fatigue Scale; Neurological Fatigue Index MS; Fatigue Symptoms & Impact Questionnaire - Relapsing MS; Fatigue Scale for Motor & Cognitive Functions.

Disclosure of interest: Jeremy Hobart has received consulting fees, honoraria, support to attend meetings, research support or clinical service support from: Acorda, Bayer Schering, Biogen Idec, BMS, F. Hoffmann-La Roche, Janssen, Merck Serono, Novartis, Oxford PharmaGenesis, Sanofi-Genzyme, Teva.

Pamela Vo was an employee at Novartis during this work.

Tanya King, James Close, Sonia Sappl, Ida Marais, David Andrich - nothing to disclosure

P480/2027

Relationship Between Socioeconomic Status and Depression in Patients with Multiple Sclerosis

Bryn Rubin¹, Susan Olet², Jenny Feng³

¹The University of Queensland-Ochsner Clinical School, Medical School, New Orleans, United States, ²Ochsner Health, The Ochsner-Xavier Institute for Health Equity and Research, New Orleans, United States, ³Ochsner Health, Desi Roth Harrison Center for Multiple Sclerosis, New Orleans, United States

Introduction: Depression is a common psychiatric comorbidity in patients with multiple sclerosis (MS). Depressed MS patients have increased disease burden and radiographic disease activity. It has been suggested that MS patients with a low socioeconomic status (SES) may have increased risk for depression.

Objectives/Aims: To determine the prevalence of depression in MS patients and its association with socioeconomic status as well as other determinants of health.

Methods: A cross-sectional retrospective observation cohort was generated utilizing data from the electronic medical record system at Ochsner Health, a tertiary referral center in Southern United States. Adult MS patients evaluated between January 1^st, 2019 and July 31^st, 2022 were screened. Depression status at database entry was based on responses to the Center for Epidemiologic Studies Depression Scale (CES-D) (score⩾16) and/or Patient Health Questionnaire (PHQ-9) (score⩾4). Patients’ SES was characterized using the area deprivation index (ADI), and quantitatively categorized into 5 groups (0=top 20%, 4=bottom 20%). Multivariable linear regression models were performed to characterize SES relationship to depression scores, after adjusting for demographic and clinical covariates.

Results: Of the 1307 MS patients with available ADI scores, 90.9% of 393 patients with PHQ-9 scores, and 39.1% of 890 patients with CES-D scores were characterized as depressed, respectively. Distribution of ADI scores across quintiles were similar between groups. Adjusting for other covariates, with each increased ADI quintile (lower SES), there is 1.18 increased odds of depression as defined by PHQ-9 (p=0.2872), and 1.06 increased odds of depression as defined by CES-D (p=0.4936).

Conclusion: The prevalence of depression in MS patients at Ochsner Health was comparable to those of national/international registries and it varied by which questionnaire was used. ADI-defined lower SES was associated with worse depression, but the effect size was subtle. Other influential socioeconomic factors should also be considered when assessing for depression in MS patients.

Disclosure of interest: Bryn: nothing to disclose

Susan: nothing to disclose

Jenny: nothing to disclose

P481/1591

Disability-based clusters and their clinicodemographic determinants in patients with multiple sclerosis: preliminary results of an unsupervised clustering approach

Beyza Ciftci¹, Iman Beheshti¹, Lisa Lix¹, Amber Salter², Carson Leung¹, Ruth Ann Marrie¹

¹University of Manitoba, Bannatyne Campus, Winnipeg, Canada, ²UT Southwestern Medical Center, Dallas, United States

Introduction: The natural history of multiple sclerosis (MS) is characterized by marked heterogeneity with respect to severity and timing of disability. Information about the determinants of long-term disability in MS may facilitate personalized treatment approaches.

Objectives/Aims: 1. To identify disease clusters in MS based on longitudinal trajectories of Patient Determined Disease Steps (PDDS) scores using unsupervised machine learning. 2. To identify the determinants of membership in these clusters.

Methods: People with MS enrolled in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry with at least 6 PDDS scores from the first 5 years after diagnosis were included. Time series k-means clustering was performed. Cluster separability was determined based on the elbow score and silhouette coefficient. Patient characteristics, including sex, age of onset and diagnosis, time to diagnosis, level of education, ethnicity, fatigue and pain scores were compared between the identified clusters.

Results: A total of 2064 people were included in the study (82% female, median age of diagnosis 42 [interquartile range (IQR) 35-48]). Four distinct clusters (n_G1 = 436, n_G2 = 513, n_G3 = 432, n_G4 = 683) were identified (silhouette coefficient = 0.38 (min: -1, max: 1). Among these, group 1 had the lowest while group 4 had the highest disability score trajectory over 5 years from diagnosis (PDDS_median = 0 and 4, respectively). Clusters were further dichotomized based on early cane use into mild disability (Groups 1-3, never use cane, PDDS <4), and moderate-severe disability (Group 4, early cane use, PDDS >=4) based on their trajectories during the first 5 years from diagnosis (clustering period), and average PDDS scores per clusters over the 15-year period of available follow-up data. Participants with mild disability (G1-3) were more likely to be female, younger at diagnosis, and have a shorter time-to-diagnosis. Fatigue and pain scores were lower in the groups with mild disability.

Conclusion: Our findings are in keeping with the natural history of MS and suggest that four prognostically distinct clusters exist in MS early on from the diagnosis. Notably one cluster was identified to have moderate-severe disability with early cane use from onset, while remaining three clusters showed mild disability throughout. Future work will focus on identifying the determinants of membership in these clusters to inform personalized treatment decisions in MS.

Disclosure of interest: B. Ciftci receives research funding from University Research Grants Program of University of Manitoba.

I. Beheshti has no disclosures.

R.A. Marrie receives research funding from: CIHR, Multiple Sclerosis Society of Canada, Multiple Sclerosis Scientific Research Foundation, Crohn’s and Colitis Canada, National Multiple Sclerosis Society, CMSC, the Arthritis Society and the US Department of Defense, and is a co-investigator on studies receiving funding from Biogen Idec and Roche Canada

LM Lix receives research funding from CIHR, NSERC, and the NIH.

CK Leung receives research funding from NSERC.

Amber Salter receives research funding from Multiple Sclerosis Society of Canada, National Multiple Sclerosis Society, CMSC and the Department of Defense Congressionally Directed Medical Research Program and is a member of editorial board for Neurology. She serves as a consultant for Gryphon Bio, LLC. She is a member of the Data and Safety Monitoring Board for Premature Infants Receiving Milking or Delayed Cord Clamping (PREMOD2), Central Vein Sign: A Diagnostic Biomarker in Multiple Sclerosis (CAVS-MS), and Ocrelizumab for Preventing Clinical Multiple Sclerosis in Individuals With Radiologically Isolated Disease (CELLO). She holds the Kenney Marie Dixon-Pickens Distinguished Professorship in Multiple Sclerosis Research.

P482/1918

Covid-19 susceptibility and disease modifying therapies on working-aged individuals with multiple sclerosis: a survey study

Chantelle Murley¹, Emma Pettersson¹, Jan Hillert², Alejandra Machado¹, Emilie Friberg¹

¹Karolinska Institutet, Division of Insurance Medicine, Department of Clinical Neuroscience, Stockholm, Sweden, ²Karolinska Institutet, Division of Neuro, Department of Cinical Neuroscience, Stockholm, Sweden

Introduction: The risk of COVID-19 infection among people with multiple sclerosis (MS) on different disease modifying therapies (DMTs) is not well established despite pre-existing knowledge of varying infection risks by DMT for other viruses.

Objectives/Aims: To investigate the occurrence of COVID-19 and remaining symptoms among people with MS and the association of DMTs with these outcomes.

Methods: All individuals aged 20-51 listed in the Swedish Multiple Sclerosis Registry were invited to participate in an online survey in 2021. Responses to questions on COVID-19 infection and remaining symptoms were linked to individual-level register data. The risk of having COVID-19 by DMT and the risk of having remaining symptoms by DMT were estimated with logistic regression. Results are reported as odds ratios (ORs) with 95% confidence intervals (CIs).

Results: Of the 4393 participants with MS, 1030 (23.4%) self-reported having had COVID-19 (749 confirmed with a test and 281 suspected). The observed odds for COVID-19 did not differ by DMT. Higher education levels and less densely populated residential areas were associated with lower occurrence of COVID-19 (p-values <0.05). Secondary-progressive MS was also associated with a 32% lower COVID-19 occurrence compared with relapsing-remitting MS (OR: 0.68; CI: 0.47 - 0.96). Many participants reporting COVID-19 had fully recovered (68.5%), 4.2% were currently/recently sick, however, 27.0% had remaining symptoms after 2 months. The most frequently reported remaining symptoms involved one’s sense of smell or taste (37.0%), fatigue (20.0%), and breathing (12.0%). No statistically significant associations were observed between having remaining symptoms and one’s DMT.

Conclusion: Despite the initial concerns of differing infection risks by MS treatments, our findings suggest there were no significant differences among PwMS in having COVID-19 or remaining symptoms post infection by MS treatment. Nonetheless, participants may have adjusted their life situation during the pandemic to mitigate their risk.

Disclosure of interest: CM’s research has previously been partly funded by an unrestricted research grant from Biogen and Celgene/Bristol-Myers Squibb. She is now employed by Macanda, a market access consulting company, collaborating with several pharmaceutical companies. EP has no conflicts of interest to disclose. JH received honoraria for serving on advisory boards for Biogen, Bristol-Myers-Squibb, Janssen, Merck KGaA, Novartis, Sandoz and Sanofi-Genzyme and speaker’s fees from Biogen, Janssen, Novartis, Merck, Teva, Sandoz and Sanofi-Genzyme. He has served as P.I. for projects sponsored by, or received unrestricted research support from Biogen, Bristol-Myers-Squibb, Janssen, Merck KGaA, Novartis, Roche, and Sanofi-Genzyme. His MS research is funded by the Swedish Research Council and the Swedish Brain foundation. AM is funded partly by unrestricted research grant from Biogen. EF is funded partly by unrestricted research grant from Biogen and has received unrestricted research grants from Celgene/Bristol-Myers Squibb.

P483/2146

Clinical trial evidence of quality-of-life effects of disease modifying therapies for multiple sclerosis

Julian Hirt^1,2, Perrine Janiaud^1,2, Kinga Dembowska³, Tim Woelfle², Cathrine Axfors², Cristina Granziera², Jens Kuhle^1,2, Ludwig Kappos^1,2, Lars Hemkens^1,2

¹University Hospital Basel and University of Basel, Department of Clinical Research, Basel, Switzerland, ²University Hospital Basel and University of Basel, Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), Basel, Switzerland, ³Swiss TPH, University of Basel, Basel, Switzerland

Introduction: Quality of life (QoL) is critically important for persons with multiple sclerosis (PwMS).

Objectives/Aims: To systematically assess the available clinical trial evidence on effects of DMTs on QoL in PwMS.

Methods: Randomized trials comparing approved DMTs with any comparator on any QoL outcome in PwMS were systematically searched in PubMed and ClinicalTrials.gov. Trials published up to 10/2022 with results for at least one reported outcome referred to as “quality of life” were included. We considered comparative effects (i.e., between randomized groups) as QoL-results and converted reported quantitative effects to Cohen’s d. We summarized characteristics of trials and QoL-results.

Results: We identified 36 trials published between 1999 and 2022 with a median of 525 participants (interquartile range (IQR) 199-970; total 22,008 PwMS). Sixteen trials (44%) included PwMS with relapsing-remitting MS only and 9 (25%) did not restrict the type of MS. The evaluated DMTs were mostly interferon-beta (n=8; 22%), fingolimod (n=7; 19%), natalizumab and glatiramer acetate (n=4; 11%, each). Follow-up was 3 to 36 months (n=21 ⩾24 months; 58%). The 36 trials used 18 different QoL measures, with up to 11 QoL sub-scale measures per trial (median 2; IQR 1-3). A generic QoL measure was used in 27 trials (75%), mostly the Short Form 36 (SF-36; n=18; 50%) and the European Quality of Life 5 Dimension (EQ-5D; n=8; 25%). There was no MS-specific measure that was used in more than 11% of trials (the measure being Functional Assessment of Multiple Sclerosis; FAMS; n=4). QoL was never the single primary outcome, only 2 trials (6%) used it as a co-primary outcome. Only 18 trials (50%) pre-specified the outcome in a clinical trial registry. We identified quantitative QoL results for any group comparison or measure in 23 trials (64%), and narrative statements in 13 trials (36%). In 15 trials (42%), for at least one of the multiple evaluated comparisons or measures a statistically significant result was indicated. The effect sizes of DMTs on QoL were large (median d 1.02; IQR 0.3-1.74) in the 9 trials with significant quantitative QoL results.

Conclusion: The published clinical trial evidence on the effects of DMTs on QoL is relatively modest. There seems to be no generally accepted standard for assessing MS-specific QoL in PwMS, and rarely is this endpoint in the focus of DMT-evaluating trials. The critical importance of QoL for PwMS urgently needs to be better reflected in the design of future MS clinical trials.

Disclosure of interest: Julian Hirt declares no competing interests. RC2NB (Research Center for Clinical Neuroimmunology and Neuroscience Basel) is supported by Foundation Clinical Neuroimmunology and Neuroscience Basel.

Perrine Janiaud declares no competing interests. RC2NB (Research Center for Clinical Neuroimmunology and Neuroscience Basel) is supported by Foundation Clinical Neuroimmunology and Neuroscience Basel.

Kinga Dembowska declares no competing interests. RC2NB (Research Center for Clinical Neuroimmunology and Neuroscience Basel) is supported by Foundation Clinical Neuroimmunology and Neuroscience Basel.

Tim Woelfle declares no competing interests. RC2NB (Research Center for Clinical Neuroimmunology and Neuroscience Basel) is supported by Foundation Clinical Neuroimmunology and Neuroscience Basel.

Cathrine Axfors declares no competing interests. RC2NB (Research Center for Clinical Neuroimmunology and Neuroscience Basel) is supported by Foundation Clinical Neuroimmunology and Neuroscience Basel.

Cristina Granziera: The University Hospital Basel (USB), as the employer of Cristina Granziera has received the following fees which were used exclusively for research support: (i) advisory board and consultancy fees from Actelion, Novartis, Genzyme and F. Hoffmann-La Roche; (ii) speaker fees from Biogen and Genzyme-Sanofi; (iii) research support by F. Hoffmann-La Roche Ltd. Before my employment at USB, I have also received speaker honoraria and travel funding by Novartis.

Jens Kuhle received speaker fees, research support, travel support, and/or served on advisory boards by the Progressive MS Alliance, Swiss MS Society, Swiss National Research Foundation (320030_189140 / 1), University of Basel, Biogen, Celgene, Merck, Novartis, Octave Bioscience, Roche, Sanofi.

Ludwig Kappos has received no personal compensation. His institutions (University Hospital Basel/Stiftung Neuroimmunology and Neuroscience Basel) have received and used exclusively for research support payments for steering committee and advisory board participation, consultancy services, and participation in educational activities from: Actelion, Bayer, BMS, df-mp Molnia & Pohlmann, Celgene, Eli Lilly, EMD Serono, Genentech, Glaxo Smith Kline, Janssen, Japan Tobacco, Merck, MH Consulting, Minoryx, Novartis, F. Hoffmann-La Roche Ltd, Senda Biosciences Inc., Sanofi, Santhera, Shionogi BV, TG Therapeutics, and Wellmera, and license fees for Neurostatus-UHB products; grants from Novartis, Innosuisse, and Roche.

Lars G. Hemkens has no competing interests. RC2NB (Research Center for Clinical Neuroimmunology and Neuroscience Basel) is supported by Foundation Clinical Neuroimmunology and Neuroscience Basel

P484/66

Relapse activity after vaccination against COVID-19 in people with multiple sclerosis: 1-year follow-up results from a nationwide longitudinal observational study

Niklas Frahm^1,2, Fneish Firas¹, Melanie Peters^1,3, David Ellenberger¹, Judith Haas⁴, Micha Loebermann⁵, Dieter Pöhlau⁴, Anna-Lena Röper^1,4, Sarah Schilling¹, Alexander Stahmann¹, Herbert Temmes⁴, Friedemann Paul⁶, Uwe K. Zettl²

¹MS Forschungs- und Projektentwicklungs- gGmbH (MS Research and Project Development gGmbH [MSFP]), German MS-Registry, Hannover, Germany, ²University Medical Center of Rostock, Department of Neurology, Neuroimmunological Section, Rostock, Germany, ³Gesellschaft für Versorgungsforschung mbH (Society for Health Care Research [GfV]), German MS Registry, Hannover, Germany, ⁴Deutsche Multiple Sklerose Gesellschaft, Bundesverband e.V. (German MS Society Federal Association [DMSG]), Hannover, Germany, ⁵University Medical Center of Rostock, Department of Tropical Medicine, Infectious Diseases and Nephrology, Rostock, Germany, ⁶Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

Introduction: Several studies reported symptoms post vaccination (PV) against COVID-19. Even people with multiple sclerosis (PwMS) have concerns about disease activity PV occurring as relapses.

Objectives/Aims: To analyse the timely association between COVID-19 vaccination (VACC) and subsequent occurring relapses in PwMS.

Methods: This analysis is based on a longitudinal observational study of the safety and tolerability of COVID-19 vaccines in PwMS. Socio-demographic, clinical and VACC data were acquired via longitudinal online surveys. Inclusion criteria for the present analysis were ⩾18 years of age, relapsing MS diagnosis and ⩾1 COVID-19 VACC. The proportion of PwMS reporting ⩾1 relapse PV, time to relapses PV and annualized relapse rates (ARRs) were calculated. Periods analysed for the occurrence of relapse PV were from 1^st to next VACC (P1), from 2^nd to next VACC (P2) and from 1^st booster VACC to the end of observation (P3). If there was no further VACC after the 1^st or 2^nd VACC, P1 and P2 were considered until the end of the observation period for the respective PwMS.

Results: Out of 2432 PwMS, 13.9% (N=339) reported ⩾1 relapse PV. Relapses in P1/P2/P3 occurred in 90/146/145 PwMS (patients might simultaneously be part of different subgroups). The median time from any VACC to subsequent relapse was 8.0 (25%, 75% quantiles: 3.5, 18.3) weeks. After 1^st/2^nd/booster VACC, the median time to relapse was 4.1 (1.7, 5.6), 9.3 (3.8, 19.8) and 13.5 (6.6, 20.3) weeks, respectively. The ARR for the cohort was 0.154 (95% confidence interval [CI]: 0.139–0.169) with a median observation period since 1^st VACC of 1.2 (1.1, 1.3) years. Females showed a higher ARR 0.167 (0.150–0.185) than males 0.102 (0.077–0.133), with a risk ratio (RR) of 1.59 (95% CI: 1.19–2.13) for relapses PV. The ARRs of patients with relapses within the year prior to 1^st VACC (0.340 [0.286–0.402]) were higher compared to PwMS without relapses 1 year before 1^st VACC (0.116 [0.100–0.133]), with a RR of 2.89 (2.27–3.67). PwMS not treated with a DMT at baseline also showed a higher ARR (0.226 [0.171–0.292]) than PwMS treated with DMT (0.146 [0.131–0.162]), with a RR of 1.58 (1.15–2.17).

Conclusion: Disease activity immediately prior to initial VACC and DMT status appear to play determinant roles in disease activity PV. Moreover, time to relapse PV was the shortest after 1^st VACC, while most patients reported relapses after 2^nd VACC and 1^st booster.

Disclosure of interest: Niklas Frahm is an employee of the MSFP. Moreover, he is an employee of Rostock’s University Medical Center and received travel funds for research meetings from Novartis. None resulted in a conflict of interest.

David Ellenberger, Firas Fneish, Sarah Schilling and Melanie Peters had no personal financial interests to disclose other than being employees of the German MS Registry.

Judith Haas has no personal pecuniary interests to disclose, other than being the President of the German MS Society, federal association, which receives funding from a range of public and corporate sponsors, recently including BMG, G-BA, The German MS Trust, Biogen, (Bristol Myers Squibb, Merck Serono, Novartis, Roche, Sanofi, Viatris (former Mylan). None resulted in a conflict of interest.

Micha Löbermann received speaker honoraria from Sanofi, AbbVie and Pfizer, he served as investigator in vaccine studies sponsored by Janssen, GSK and Novartis. None resulted in a conflict of interest.

Friedemann Paul has received speaking fees, travel support, honoraria from advisory boards and/or financial support for research activities from Bayer, Novartis, Biogen, Bristol Myers Squibb, Teva, Sanofi-Aventis/Genzyme, Merck Serono, Alexion, Chugai, MedImmune, Shire, German Research Council, Werth Stiftung of the City of Cologne, German Ministry of Education and Research, EU FP7 Framework Program, Arthur Arnstein Foundation Berlin, Guthy Jackson Charitable Foundation and National Multiple Sclerosis of the USA. He serves as academic editor for PLoS ONE and associate editor for Neurology, Neuroimmunology and Neuroinflammation. None resulted in a conflict of interest.

Dieter Pöhlau received speaking fees, travel support and financial support for research projects from: Allmirall, Bayer, Biogen-Idec, Merck-Serono, Octapharma, Novartis, Roche, Sanofi-Aventis and Teva. None resulted in a conflict of interest.

Anna-Lena Röper is an employee of the MSFP and Germany MS society, which is funded by many public and corporate sponsors. She received travel funds from Novartis. None resulted in a conflict of interest.

Alexander Stahmann has no personal financial interests to disclose, other than being the leader of the German MS Registry, which receives (project) funding from a range of public and corporate sponsors, recently including G-BA, The German Retirement Insurance, The German MS Trust, German MS Society, Biogen, Bristol Myers Squibb, Merck, Novartis, Roche and Sanofi. None resulted in a conflict of interest.

Herbert Temmes has no personal pecuniary interests to disclose, other than being the Secretary General of the German MS Society, federal association, which receives funding from a range of public and corporate sponsors, recently including Bundesgesundheitsministerium (BMG), The German Innovation Fund (G-BA), The German MS Trust, Biogen, (Bristol Myers Squibb, Merck Serono, Novartis, Roche, Sanofi, Viatris (former Mylan). None resulted in a conflict of interest.

Uwe K. Zettl has received speaking fees, travel support and /or financial support for research activities from Alexion, Almirall, Bayer, Biogen, Bristol Myers Squibb, Janssen, Merck Serono, Novartis, Octapharma, Roche, Sanofi Genzyme, Teva as well as EU, BMBF, BMWi and DFG. None resulted in a conflict of interest.

P485/748

MS Falls InsightTrack (MS-FIT): Design and Stakeholder Perspectives on a Closed-loop Falls Monitoring and Prevention Application for MS Clinical Practice

Valerie Block¹, Kanishka Koshal², Jaeleene Wijangco², Nicolette Miller¹, Narender Sara¹, Kyra Henderson¹, Jennifer Reihm¹, Arpita Gopal¹, Sonam Dilwali-Mohan¹, Jeffrey Gelfand¹, Linda Glassel³, Chu-Yueh Guo¹, Lauren Oommen¹, Alyssa Nylander¹, James Rowson¹, Ethan Brown¹, Katherine Rankin¹, Stephan Sanders¹, Courtney Lyles^4,5,6, Ida Sim⁶, Riley Bove²

¹University of California San Francisco, San Francisco, United States, ²University of California San Francisco, Neurology, San Francisco, United States, ³National Multiple Sclerosis Society, Northern California, San Francisco, United States, ⁴University of California San Francisco, Center for Vulnerable Populations, San Francisco, United States, ⁵University of California San Francisco, Department of Epidemiology and Biostatistics, San Francisco, United States, ⁶University of California San Francisco, Department of Medicine, San Francisco, United States

Introduction: Falls are common in MS, causing injuries, fear of falling (FOF) and loss of independence. Although targeted interventions, i.e., physical therapy (PT) can help, patients under-report and clinicians under-treat this issue. Patient-Generated Data (PGD), combined with clinical data, can support prediction of falls and lead to timely intervention (e.g. referral to physical therapy, PT). Yet, to be actionable, such data must be efficiently delivered to clinicians, with care customized to the patient’s specific context.

Objectives/Aims: Describe the clinical and technological features of MS-FIT, a closed-loop app designed to support streamlined falls reporting, timely falls evaluation, and comprehensive and sustained prevention efforts.

Methods: Stakeholders were engaged in a “double diamond” process of human-centered design (HCD). Patient and clinician interviews adopted the Capability, Opportunity, and Motivation approach to Behavioral change (COM-B) and Michie’s Behavioral Change Wheel to align technological features with users’ needs. To support generalizability, patients and experts from other disciplines characterized by falls (geriatrics, orthopedics, Parkinson’s Disease) were also engaged. Final mocks were tested during routine clinical visits.

Results: A diverse sample of 30 patients and 14 clinicians provided at least one round of feedback. To support falls reporting, patients favored a simple biweekly survey built using REDCap to support “bring your own device” accessibility – with optional additional context (e.g. severity and location of each fall). To support evaluation and prevention of falls, clinicians favored a clinical dashboard featuring several key visualization widgets: (1) a longitudinal falls display coded by time of data, severity and context, (2) a comprehensive, multidisciplinary and evidence-based checklist of actions intended to evaluate and prevent falls and (3) MS resources local to a patient’s community. Further, in-basket messaging alerts clinicians of severe falls. The tool scored highly for usability, likability, usefulness and perceived effectiveness (Health IT Usability Model).

Conclusion: To our knowledge, this is the first falls app designed using HCD to prioritize behavioral change and while accessible at home for patients, to deliver actionable data to clinicians at the point of care. To test feasibility and effectiveness, an NIH-funded clinical trial is ongoing (NCT05837949).

Disclosure of interest: K.Koshal, J Wijangcom N Miller, N Sara, K Henderson, J Reihm, Dr. Gopal, Dr Dilwali-Mohan L Glassel, Dr. Oomen, Dr. Nylander, Dr Rowson, Dr Sanders, Dr Rankin And Dr Lyles have no relevant disclosures

Dr. Block is funded by the National MS Society Career Transition Award.

Dr Guo provides medical consulting for EMD Serono, Genentech, and Horizon Therapeutics.

Dr Gelfand receives research support to UCSF from Genentech, Hoffman-LaRoche, Vigil Neuroscience. Consulting for Arialys.

Dr. Brown reports research funding from the Michael J. Fox Foundation, the Gateway Foundation for Brain Research, the NIH, and Biogen Inc. Dr. Brown has received honoraria for his work as Neurology Section Editor of NEJM Knowledge+ and consulting fees from Rune Labs, Inc.

Dr Sim Is the Co-Founder of Open mHealth, General Assembly Member for The Commons Project, serves on the Medical Advisory Board for 98point6, is Co-Founder, Board of Directors, & Consultant for Vivli, is on the Scientific Advisory Board for Myovant, and hold stocks in Myia.

Dr. Bove is funded by the NMSS Harry Weaver Award, NIH, DOD, NSF, as well as Biogen, Novartis and Roche Genentech. She has received personal fees for consulting from Alexion, EMD Serono, Horizon, Jansen, Genzyme Sanofi, and TG Therapeutics.

P486/1651

Evaluating the patients' experience after switching from natalizumab intravenous to subcutaneous administration. Analysis of a case series

Jose Meca Lallana¹, Fuensanta Hellín-Gil¹, JORGE MILLAN-PASCUAL¹, Gabriel Valero López¹, Roger Guirro Caupena¹, Judith Jiménez-Veiga¹, Pedro Lucas Arnaldos Illán¹, Luis Ibáñez¹, Camila España Dos Santos¹, Francisca Iniesta Martinez¹

¹Multiple Sclerosis CSUR and Clinical Neuroimmunology Unit. Neurology Department. Virgen de la Arrixaca University Hospital (IMIB-Arrixaca)., Murcia, Spain

Introduction: Clinical experience in the real-world setting with the subcutaneous (SC) formulation of natalizumab (NTZ) is growing since its approval in 2021.

Objectives/Aims: To present our experience in a case series after switching to NTZ SC from NTZ intravenously (IV), assessing quality of life (QoL), fatigue, depression, treatment satisfaction and patient preference.

Methods: Unicentric cohort of 65 patients that switched to NTZ SC between March and October 2022 and had completed 6 months of NTZ SC. Scores of EQ-5D-3L, MFIS-21 (21-Modified Fatigue Impact Scale), BDI-II (Beck Depression Inventory-II), TSQM v1.4 (Treatment Satisfaction Questionnaire for Medication) were collected at the last NTZ IV infusion (M0) and after 6 months (M6). Higher EQ-5D-3L and TSQM v1.4 scores indicate better QoL and higher treatment satisfaction. Higher MFIS-21 and BDI-II scores indicate worse fatigue and depression outcomes.

Results: At M0, patients (76.9% female) had a mean age of 42.7 years, disease duration of 10.5 years, EDSS of 2.6, and mean time on NTZ IV of 64.1 months. All patients were free-from relapses during the last 6 months. At M6, no patients had experienced relapses and EDSS remained stable. We observed significant improvements when switching to NTZ SC in mean EQ-5D-3L index scores (64.3 vs 73.8, p<0.001), and TSQM domains effectiveness (64.4 vs 82.1, p<0.001), side-effects (78.7 vs 92.6, p<0.001), convenience (63.4 vs 79.7, p<0.001) and global satisfaction (76.9 vs 85.7, p<0.001). Decreased scores were observed in total MFIS-21 (42.7 vs 34.3, p<0.001), its domains physical (18.6 vs 15.9; p<0.001), psychosocial (4.5 vs 3.8, p=0.020), and cognitive (19.6 vs 15.5, p<0.001), and BDI-II (12.3 vs 10.7, p=0.003). 91.9% of the patients preferred SC administration. 18 patients reported 39 adverse events (AEs) of mild severity at the first month of switching (mainly site pain and erythema), decreasing to 4 AEs in 4 patients at M6.

Conclusion: NTZ SC is generally preferred by patients on NTZ treatment and patients switching to the new route of administration remained free from relapses and EDSS stable, while improved on key patients’ outcomes such as QoL, fatigue, depression.

Disclosure of interest: JEML has received honoraria as a consultant, as a chairman or lecturer in meetings and has participated in clinical trials and other research projects promoted by Alexion, Biogen, BMS, Janssen, Merck, Novartis, Roche, Sandoz, and Sanofi.

FHG has received honoraria as a lecturer in meetings and has participated in clinical trials and other research projects promoted by Alexion, Biogen, Merck, Novartis, Roche, and Sanofi.

JMP has received honoraria as a consultant, as a lecturer in meetings, and has participated in clinical trials and other research projects promoted by Biogen, BMS, Janssen, Merck, Novartis, Roche, and Sanofi.

GVL has received honoraria as a lecturer in meetings and has participated in clinical trials and other research projects promoted by Alexion, Biogen, Janssen, Merck, Novartis, Roche, and Sanofi.

FIM has participated in clinical trials and other research projects promoted by Alexion, Biogen, Merck, Novartis, Roche, and Sanofi.

RGC, JJV, PLAI, LIG and CEDS have nothing to disclose.

P487/1819

Recommendation regarding health-related quality of life measurement in people with multiple sclerosis

Asiye Tuba Özdoğar¹, Özge Sağıcı², Sinem Ozcelik³, SEDA DASTAN², Cavid Baba², Serkan Ozakbas³

Study Group: Multiple Sclerosis Research Group

¹Van Yüzüncü Yıl University, Department of Physiotherapy, Faculty of Health Sciences, Van, Turkey, ²Dokuz Eylül University, Graduate School of Health Sciences, İzmir, Turkey, ³Dokuz Eylül University, Department of Neurology, İzmir, Turkey

Introduction: The Multiple Sclerosis International Quality of Life (MusiQoL) and EuroQol-5D-3L (EQ-5D-3L) are widely used, standardized, health-related quality of life (HRQOL) measures. However, which is more related to physical and cognitive outcomes in multiple sclerosis (MS) is unknown.

Objectives/Aims: To determine the most related HRQOL with the commonly used outcome measures in MS.

Methods: 1698 people with MS (pwMS) were included. MusiQoL and EQ-5D-3L were applied to 676 (39.8%) and 1022 (60.2%) pwMS, respectively. Also, disease duration, Expanded Disability Status Score (EDSS), Timed 25 Foot Walk (T25FW), Nine-Hole Peg Test (N-HPT), Timed up Go (TUG), Multiple Sclerosis Walking Scale (MSWS-12), Activities-Specific Balance Confidence (ABC), Epworth Sleepiness Scale (ESS) and Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) battery, which included the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test-2 (CVLT2), and the Brief Visuospatial Memory Test-Revised (BVMT-R) scores were noted.

Results: Activity of daily living (ADL) subscore of MusiQoL was found to be strongly correlated with EDSS score (p<0.001, r=-0.689), MSWS-12 (p<0.001, r=-0.834), ABC (p<0.001, r=0.790). Also, there was a significant moderate correlation between the ADL subscore of MusiQoL and disease duration (p<0.001, r=-0.375), T25FW (p<0.001, r=-0.419), TUG (p<0.001, r=-0.418) and SDMT (p<0.001, r=0.385). Moreover, ADL subscores have a small relationship with N-HPT (p<0.001, r=-0.194), BVMT-R (p<0.001, r=0.300), and CVLT2 (p<0.001, r=0.226). According to EQ-5D-3L, the mobility subscore was strongly correlated with MSWS-12 (p<0.001, r=-0.662). Additionally, mobility subscores have a moderate relationship with EDSS (p<0.001, r=-0.446), ABC (p<0.001, r=0.578), and SDMT (p<0.001, r=0.310). On the other hand, there was a moderate correlation between the self-care subscore of EQ-5D-3L and T25FW (p<0.001, r=-0.312) and TUG (p<0.001, r=-0.312). There was a significant mild correlation between self-care subscore and BVMT-R (p<0.001, r=0.265) and CVLT2 (p<0.001, r=0.219).

Conclusion: In conclusion, the ADL subscore of MusiQoL is related to all physical and cognitive functions (except N-HPT). Mostly, studies report a total score of MusiQoL. According to our results, it may cause us to overlook the bigger perspective about the HRQOL results. We recommend using the ADL subscore of MusiQoL as an outcome measure to see the main results.

Disclosure of interest: Asiye Tuba Ozdogar: nothing to disclose

Ozge Sagici: nothing to disclose

Sinem Ozcelik: nothing to disclose

Seda Dastan: nothing to disclose

Cavid Baba: nothing to disclose

Serkan Ozakbas: nothing to disclose

P488/1965

Sleep quality and related clinical features in multiple sclerosis

Margherita Monti Bragadin¹, Michela Ponzio¹, Valeria Prada¹, Elisa Piccardo², Giulia Ramigni³, Chiara Furlan³, Giampaolo Brichetto¹

¹Italian MS Foundation, Genoa, Italy, ²Italian Multiple Sclerosis Society, Rehabilitation Service Liguria, Genoa, Italy, ³Italian Multiple Sclerosis Society, Veneto Rehabilitation Service, Padoa, Italy

Introduction: Sleep disturbances are common in people with Multiple Sclerosis (PwMS), and they may be due to demyelinating lesions in specific area of the central nervous system or be secondary to other disabling MS symptoms.

Objectives/Aims: This study aimed to examine the relationship between quality of sleep and clinical MS features

Methods: We evaluated 158 PwMS, mean age 55.5±9.7; EDSS: 5.0±1.7; disease duration: 21.5±10.0. All patients are followed by the Rehabilitation Services of the Italian Multiple Sclerosis Association. People older than 18 years and with a diagnosis of MS were included. The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality and to investigate sleep disorders. The PSQI result ranges from 0 to 21. A total score > 5 means a poor sleep quality. The assessment also included other patient reported outcomes: Functional Independence Measure (FIM); Modified-Fatigue Impact Scale (MFIS), Hospital Anxiety and Depression Scale (HADS), Overactive Bladder questionnaire (OAB-q) and Life Satisfaction Index (LSI).

Results: The mean total PSQI was 8.3±3.7; 129 PwMS (81.7%) reported a total PSQI score >5. In relation to subscale scores, moderate or severe difficulty was identified in habitual sleep efficiency (84.2%), sleep duration (44.9%), sleep latency (29.1%), and sleep disturbance (24.7%). Univariate logistic analyses found that higher age, SP disease form, higher OAB score, MFIS score, HADS subscale score, and lower LSI score were significantly correlated with poorer sleep quality. In the final logistic regression model, higher age (OR=1.08, p=0.006), SP course (OR=5.06, p=0.031), DMD user (OR=2.83, p=0.049), higher MFIS score (OR=1.03, p=0.047) and higher HADS anxiety subscale score (OR=1.36, p=0.001) were significantly correlated with poor sleep quality

Conclusion: high percentage of PwMS experiences sleep disorders, which are related to fatigue and reduced quality of life. PSQI is reliable, valid and quick to administer, it can be used for rapid screening of sleep quality in PwSM. Sleep quality, latency, duration, and efficiency are the most impaired components of PSQI. Sleep disorders in PwSM are a multifactorial and relatively complex problem. It emerges the importance of multidisciplinary interventions aimed at improving sleep quality in PwMS.

Disclosure of interest: Margherita Monti Bragadin has nothing to disclose; Michela Ponzio has nothing to disclose; Valeria Prada has nothing to disclose; Elisa Piccardo has nothing to disclose; Giulia Ramigni has nothing to disclose; Chiara Furlan has nothing to disclose; Giampaolo Brichetto has thing to disclose

P489/2158

Risk of Relapse and Sustained Disability Progression in People with MS during the COVID-19 Pandemic

Ethan Huson¹, Odelin Charron¹, Diana Andino¹, Amanda Montague², Alexis Crispino Kline², Joseph Wozny³, Trudy Millard Krause³, Ethan Meltzer¹, Avery Largent¹, Leorah Freeman¹

¹Dell Medical School, The University of Texas at Austin, Neurology, Austin, United States, ²Multiple Sclerosis Association of America, Cherry Hill, United States, ³School of Public Health, The University of Texas Health Science Center at Houston, Center for Healthcare Data, Houston, United States

Introduction: People with multiple sclerosis (pwMS) experience periods of temporary symptomatic worsening known as relapses. Relapses may contribute to sustained disability progression (SDP) in a manner known as relapse associated worsening (RAW). However, some patients experience SDP independent of relapse activity (PIRA).

Objectives/Aims: Investigate how pwMS acquired SDP over the course of the COVID-19 pandemic; identify factors associated with relapses, RAW and PIRA.

Methods: The CopeMS study led by The University of Texas at Austin and the MS Association of America investigates the COVID-19 pandemic’s impact on healthcare access and outcomes of pwMS. As part of the study, surveys were completed monthly by a national cohort of pwMS in the United States between December 2020 and December 2021. SDP was defined as an increase of at least one point of the Patient Determined Disease Steps (PDDS) score, sustained for at least 3 months. Relapses were self-reported. Generalized linear modeling (GLM) was used for multivariate analysis of factors associated with risk of relapse and SDP.

Results: 326 subjects were included in the analysis. Overall, higher Generalized Anxiety Disorder-7 (GAD7) scores at baseline were associated with higher risk of reporting a relapse during the study (p<0.001). Higher Patient Activation Measure (PAM13) scores were associated with greater likelihood that a patient would obtain treatment for their relapse (p=0.005). 13.5% (n=44) of subjects experienced SDP. Of those who experienced SDP, 75% (n=33) acquired disability in the absence of a reported relapse. The remaining 25% (n=11) of subjects experienced RAW. Among people who reported a relapse during the study period (N=108), the absence of disease modifying therapy (DMT) at baseline and progressive phenotype were significantly associated with higher risks of RAW (p= 0.023, p=0.019 respectively). Among those who did not report a relapse (N=218), older age was associated with a greater risk of PIRA (p<0.001).

Conclusion: During 2021, patients with higher anxiety experienced an increased risk of relapse. Among those reporting relapses, higher patient activation was associated with greater likelihood of obtaining treatment. Patients predominantly acquired disability through PIRA. Patients not utilizing a DMT and who identified as a progressive subtype were at higher risk for experiencing RAW while those experiencing PIRA did not experience these associations. Instead, PIRA was associated with aging.

Disclosure of interest: E.M. has received consulting fees from Horizon Therapeutics and TG Therapeutics, and grant support from Genentech through institution. O.C and J.W. report grant support from Genentech through institution. A.M. participates as a member of the MUSE Advisory Board with Johnson & Johnson; The International MS Committee Advisory Board with Novartis; Gilead Global Advisory Board: Patient Engagement Horizon Scanning, hosted by Gilead; EMD Serono Advisory Board: Effective Support and Information Sharing Post-COVID Era Advisory Board; MS in the 21st Century Global Advisory Board hosted by Merck; and MS Health Equities Advisory Board Co-Chair with Bristol Meyers Squibb; on behalf of MSAA has received grant support from Biogen, Genentech, Greenwich Bioscience, Novartis, Bristol Meyers Squibb, Johnson & Johnson, EMD Serono, Sanofi Genzyme, and Johnson & Johnson. A.C.K. participates as a Merit Reviewer and has received compensation from the Patient Center Outcomes Research Institute (PCORI); she has received speaker honorarium for presentations at the Multiple Sclerosis Update: Clinical, Economic, and Patient-Centric Strategies for Managed Care Professionals Asembia Specialty Pharmacy Summit; and has received grant support on behalf of MSAA from Biogen, Genentech, Greenwich Bioscience, Novartis, Bristol Meyers Squibb, Johnson & Johnson, EMD Serono, Sanofi Genzyme; and Johnson & Johnson. T.M.K. reports minimal shares in Abbvie and Abbot and grant support from Genentech through institution. L.F. has received fees for consultancy and/or advisory board participation from Genentech, Novartis, Bristol Myers Squibb, EMD Serono, Sanofi, Horizon Therapeutics and TG Therapeutics; has received honorarium for participation in educational programs from Medscape, Inc, the MS Association of America and Impact Education; has received program sponsorship from EMD Serono and grant support from NIH/NINDS, PCORI, Genentech, and EMD Serono through her institution; currently serves on the Healthcare Advisory Committee of the MS Association of America. D.A. received compensation for Advisory board participation for Genentech, EMD Serono and MSAA. A.L. and E.H. have nothing to disclose.

P490/1150

The socio-economic burden of AQP4-antibody seropositive NMOSD: a nationwide registry-based study

Viktoria Papp¹, Birgit Høyer², Malthe Faurschou Wandall-Holm³, Kristina Bacher Svendsen⁴, Jette Lautrup Frederiksen³, Finn Sellebjerg³, Zsolt Laszlo Illes⁵, Melinda Magyari³

¹Odense University Hospital, Neurology, Odense C, Denmark, ²Odense University Hospital, Open Patient data Explorative Network, Odense, Denmark, ³Copenhagen University Hospital, Danish Multiple Sclerosis Center and Danish Multiple Sclerosis Registry, Glostrup, Denmark, ⁴Aarhus University Hospital, Neurology, Aarhus, Denmark, ⁵Odense University Hospital, Odense, Denmark

Introduction: AQP4-antibody seropositive neuromyelitis optica spectrum disorder (AQP4-Ab+ NMOSD) is an antibody-mediated CNS disease associated with high risk of severe relapses leading to permanent disability.

Objectives/Aims: We examined the socioeconomic consequences of AQP4-Ab+ NMOSD: risk of losing income from salaries, disability pension, and “flex job” (special social welfare job when working capacity is significantly and permanently reduced due to illness) compared to the general population.

Methods: We conducted a longitudinal nationwide Danish registry study. Patients with AQP4-Ab+ NMOSD were identified in the Danish Multiple Sclerosis Registry and laboratories with disease onset between 1965 and 2020, and linked to national population-based registries: the Danish Income Statistics Registry, the Danish Rational Economic Agents Model, and the Population Statistics Register. Patients were matched based on sex-, education- and birth year to 510 controls from the general population. The study population was followed until December 31, 2020. To compare the characteristics of the case and control populations, chi² test was used. The risk of losing income, being granted disability pension, or “flex job” was plotted as cumulative incidence curves accounting for competing risks (emigration, state pension, death).

Results: Of 65 patients with AQP4-Ab+ NMOSD, 49 patients were of working age and were compared with the 510 matched controls. The mean age at disease onset was 46.5 years (SD: 14.0) for cases and 45.6 years (SD: 14.2) for controls. The majority was female (cases: 91.8%, controls: 92.2%). The proportion of persons on disability pension or “flex job” among cases was significantly higher than among controls (45% vs 15%, p<0.0001; 20% vs 5%, p<0.0001, respectively).

Conclusion: Patients with AQP4-Ab+ NMOSD experience a rapid decline in their socioeconomic status following disease onset and a substantial proportion of patients of working age loses work-capacity and receive disability pension resulting in an increased financial burden on their families and society.

Disclosure of interest: Viktoria Papp received travel grants from Merck and Sanofi and received research support from Roche.

Birgit B Høyer has no conflict of interest.

Malthe Faurschou Wandall-Holm has served on scientific advisory board for Sanofi and has received honoraria for lecturing for Novartis and Sanofi.

Kristina B. Svendsen has served as consultant for Takeda Pharma A/S and received travel grants from TEVA, Biogen, Merck, and Novartis.

Jette Frederiksen has received no funding to support the presented work. She has served on scientific advisory boards for and received funding for travel related to these activities as well as honoraria from Merck Serono, Sanofi-Aventis, Roche, Novartis and Chiesi.

Finn Sellebjerg has served on scientific advisory boards for, served as consultant for, received support for congress participation or received speaker honoraria from Alexion, Biogen, Bristol Myers Squibb, Merck, Novartis, Roche and Sanofi Genzyme. His laboratory has received research support from Biogen, Merck, Novartis, Roche and Sanofi Genzyme.

Zsolt Illes has received speakers’ honoraria and/or research grants from Biogen, Roche, Sanofi, Novartis, Merck, Alexion, Bristol Myers Squibb, Lundbeckfonden, and Jascha Fonden, has been member of advisory boards at Alexion, Biogen, Sanofi, Merck, Roche, Novartis, was member of the adjudication relapse committee in phase 3 trials, and has been principal investigator in studies sponsored by Biogen, Merck, Roche and Sanofi.

Melinda Magyari has served in scientific advisory board for Sanofi, Novartis, Merck, and has received honoraria for lecturing from Biogen, Merck, Novartis, Roche, Genzyme, Bristol Myers Squibb.

This study received funding from Alexion Pharmaceuticals and the Danish Multiple Sclerosis Society (A39992). The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, or approval of the manuscript; and decision to submit the manuscript for publication. Alexion Pharmaceuticals provided a courtesy medical review of the manuscript.

P491/1449

Prevalence and clinical significance of optic nerve lesions as detected by optical coherence tomography and MRI

Lilian Aly¹, Mirjam Beyrle², Fabian Lehmann¹, Anna Wild¹, Rebecca Wicklein¹, Mark Mühlau¹, Achim Berthele¹, Wiestler Benedikt², Jan Kirschke², Claus Zimmer², Bernhard Hemmer^1,3, David Schinz², Benjamin Knier¹

¹Klinikum Rechts der Isar, Department of Neurology, Munich, Germany, ²Klinikum Rechts der Isar, Department of Neuroradiology, Munich, Germany, ³Munich Cluster of Systems Neurology (SyNergy), Munich, Germany

Introduction: Optic neuritis (ON) is a frequent symptom in patients with multiple sclerosis (MS) that results in neuronal loss and visual impairment. While MRI of the optic nerve sensitively assess optic nerve morphology, retinal optical coherence tomography (OCT) precisely quantifies retinal layers. Thus, both are capable to detect tissue alterations typically occurring after acute ON. In both techniques, however, signal alterations suggestive of a history of ON may also be found in patients without any clinical ON episode.

Objectives/Aims: To assess the prevalence of clinical ON and subclinical ON-derived tissue damage detected by MRI and OCT in a big German MS cohort.

Methods: Cross-sectional cohort study involving patients with MS and clinically isolated syndrome (CIS) from a German academic MS center. Besides clinical examination and anamnesis, all patients received OCT and MRI on the exact same day between January and December 2021. OCT scans were analyzed for atrophy patterns suggestive of previous ON (5 µm peripapillary asymmetry of the retinal nerve fiber layer and 4 µm asymmetry of the combined ganglion cell and inner plexiform layer). Double-inversion recovery (DIR)-MRI was assessed for hyperintense optic nerve lesions suggestive of unilateral or bilateral ON. Clinical ON episodes were systematically extracted from the patients’ medical records as judged by the treating physicians.

Results: 432 Patients were included in the study. Patients were 40 (33-47) years old (median (25%-75% interquartile range)) and 62.5% female, disease duration at study inclusion was 6.8 (3.1-10.1) years. The prevalence of previous unilateral clinical ON was 31.0% (n=134) and 4.9% (n=21) for bilateral ON (simultaneously or sequentially). After clinical unilateral ON, MRI detected alterations in 74.6% (n=100; of these 58% were also detected by OCT) and OCT showed asymmetry in 54.5% (n=73; of these 79.5% were also detected by MRI). Among 277 patients without a history of clinical ON, MRI revealed alterations in 20.9% (n=58), and OCT found atrophy suggestive of unilateral ON in 11.9% (n=33). Of these, 20 patients were also detected by MRI. Visual acuity in eyes with hints for ON in MRI and OCT was reduced compared to the fellow eye.

Conclusion: A history of clinical ON broadly overlapped with ON suggestive findings in OCT and MRI. However, MRI and OCT alterations suggestive of ON also appear in eyes without a history of ON, suggesting the occurrence of a subclinical ON in up to 21% of MS patients.

Disclosure of interest: Lilian Aly received travel and research support by Novartis.

Mirjam Beyrle: nothing to disclose.

Fabian Lehmann: nothing to disclose.

Anna Wild reports: nothing to disclose.

Rebecca Wicklein received a poster grant from Novartis and an intramural research grant from the Technical University of Munich, School of Medicine and was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 - SyNergy ID 390857198).

Mark Mühlau received funding from the German Research Foundation, DFG Priority Programme 2177, Radiomics: Next Generation of Biomedical Imaging (project number 428223038), German Federal Ministry of Education and Research (BMBF), Medical Informatics Initiative (MII), Data Integration for Future Medicine (DIFUTURE) consortium (grants 01ZZ1603[A-D] and 01ZZ1804[A-I]), the National Institutes of Health (grant 1R01NS112161-01 [subinvestigator]), Bavarian State Ministry for Science and Art and the Collaborative Bilateral Research Program Bavaria – Québec: AI in medicine (project number F.4-V0134.K5.1/86/45)

Achim Berthele has received consulting and/or speaker fees from Alexion, Biogen, Celgene, Horizon, Novartis, Roche and Sandoz/Hexal. His institution has received compensation for clinical trials from Alexion, Biogen, Merck, Novartis, Roche, and Sanofi Genzyme.

Benedikt Wiestler reports no conflicts of interest.

Jan S Kirschke recieved personal fees (speakers services) from Novartis, research grants from the ERC, DFG and BMBF (not related).

Claus Zimmer has served on scientific advisory boards for Philips and Bayer Schering and has received speaker honoraria from Bayer-Schering and Philips. He or his institution has received research support and investigator fees for clinical studies from Biogen Idec, Quintiles, MSD Sharp & Dome, Boehringer Ingelheim, Inventive Health Clinical UK Ltd, Advance Cor, Brainsgate, Pfizer, Bayer-Schering, Novartis, Roche, Servier, Penumbra, WCT GmbH, Syngis, SSS International Clinical Research, PPD Germany GmbH, Worldwide Clinical Trials Ltd, Phenox, Covidien, Actelion, Medivation, Medtronic, Harrison Clinical Research, Concentric, Pharmtrace, Reverse Medical Corp., Premier Research Germany Ltd, Surpass Medical Ltd, GlaxoSmithKline, AXON Neuroscience, Bristol-Myers Squibb, Genentech, Acandis, EISAI, NeuroRx, Italfarmaco, Bioclinica, MIAC and IXICO.

Bernhard Hemmer has served on scientific advisory boards for Novartis; he has served as DMSC member for AllergyCare, Sandoz, Polpharma, Biocon and TG therapeutics; his institution received research grants from Roche for multiple sclerosis research. He has received honoraria for counseling (Gerson Lehrmann Group). He holds part of two patents; one for the detection of antibodies against KIR4.1 in a subpopulation of patients with multiple sclerosis and one for genetic determinants of neutralizing antibodies to interferon. All conflicts are not relevant to the topic of the study. He is associated with DIFUTURE (Data Integration for Future Medicine) [BMBF 01ZZ1804[A-I]]. Bernhard Hemmer received funding for the study by the European Union’s Horizon 2020 Research and Innovation Program [grant MultipleMS, EU RIA 733161] and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology [EXC 2145 SyNergy – ID 390857198].

David Schinz: nothing to disclose.

Benjamin Knier received travel support and speaking honoraria from Novartis and Teva. He was funded by the Else Kröner Fresenius-Stiftung (Else Kröner Fresenius Exzellenzstipendium 2019_EKES.09), the Gemeinnützige Hertie Foundation (medMS program) and received a research award from Novartis.

P492/907

Measuring spontaneous remyelination in a longitudinal multiple sclerosis cohort

Sam Hof¹, Pam Molenaar¹, J.A. Nij Bijvank^1,2, Ka Hoo Lam¹, Laurentius van Rijn^2,3, Axel Petzold^1,2,4, Joep Killestein¹, Bernard Uitdehaag¹

¹MS Center and Neuro-ophthalmology Expertise Center Amsterdam, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC location VUmc, Neurology, Amsterdam, Netherlands, ²Neuro-ophthalmology Expertise Center Amsterdam, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC location VUmc, Ophthalmology, Amsterdam, Netherlands, ³Onze Lieve Vrouwe Gasthuis, Ophthalmology, Amsterdam, Netherlands, ⁴Moorfields Eye Hospital, The National Hospital for Neurology and Neurosurgery and the UCL Queen Square Institute of Neurology, Ophtalmology, London, United Kingdom

Introduction: Remyelination trials are in need of a functional outcome measure. We propose that longitudinal measurement of oculomotor function may be used to measure and quantify spontaneous and therapeutic remyelination.

Objectives/Aims: We aimed to measure spontaneous remyelination with infrared oculopgraphy in a longitudinal multiple sclerosis (MS) cohort.

Methods: In a prospective, longitudinal, cohort study from the MS Center Amsterdam oculomotor function was measured and analysed using a validated standardized infrared oculography protocol (DEMoNS) at baseline, 3 months and 1 year follow-up. Presence of an internuclear ophthalmoplegia (INO) was defined by previously published cut-off levels of the versional dysconjugacy index (VDI). All subjects were also assessed for clinical function, including Expanded Disability Status Scale (EDSS), Nine Hole Peg Test (NHPT) and the visual functioning questionnaire (VFQ) and checklist individual strength (CIS).

Results: Among 80 individuals with MS, INO was persistent in 14 individuals and resolved in 7 individuals after a year of follow-up. Resolution of INO was consistent over time and occurred within 3 months in 3 participants and after 3-12 months in 3 participants. Compared to participants with persistent INO participants with resolved INO showed a 5.7% (95% CI 2.3-9.1%) reduction in VDI area under the curve (AUC) and a 10.7% (95% CI 5.0-16.0%) reduction in VDI peak velocity (pV/Am). Participants with resolved INO showed improved oculomotor function resulting in improved pro-saccadic latency (-33.3 ms; 95% CI [-66.2, -0.4]), fixational horizontal gaze stability (standard deviation -34%; 95% CI [-53%, -6%]), EDSS brainstem functional system (-0.75, 95% CI [-1.49, -0.02]), mental health symptoms due to vision (VFQ mental health +12, 95% CI 2-23) and driving difficulties (VFQ mental health +15, 95% CI 4-25) compared to participants with persistent INO. Participants with resolved INO also showed more improvement in NHPT (-3.47 sec, 95% CI [-6.68, -0.33]) and fatigue during physical activity (CIS activity -5; 95% CI [-1, -9]), compared to participants with persistent INO. There was no statistically significant difference in the presence of radiological disease activity among participants with resolved INO compared to participants with persistent INO (OR 0.24, 95% CI 0.004 - 2.878).

Conclusion: Spontaneous remyelination appearing as resolution of INO on longitudinal infrared oculography coincides with improvement of oculomotor function, clinical and subjective functioning.

Disclosure of interest: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. The APPS-MS study was co-funded by the PPP Allowance made available by Health Holland, Top Sector Life Sciences and Health (Grant No. LSHM16060-SGF) and Stichting MS Research (Grant No. 16-946 MS) to stimulate public–private partnerships and by a contribution from Biogen (unrestricted funding).

S.N. Hof, P.C.G. Molenaar, K.H. Lam and L.J. van Rijn declare no conflict of interest. J.A. Nij Bijvank is supported by the Dutch MS Research Foundation, grant nr. 18-1027. A. Petzold received grant support for remyelination trials in multiple sclerosis to the Amsterdam University Medicam Centre, Department of Neurology, MS Centre (RESTORE trial) and UCL, London RECOVER trial; Fight for Sight (nimodipine in optic neuritis trial); Royalties or licenses from Up-to-Date (Wolters Kluver) on a book chapter; Speaker fees for the Heidelberg Academy; participation on Advisory Board SC Zeiss OCTA Angi-Network, SC Novartis OCTiMS study; Leadership roles for Governing Board IMSVISUAL (until DEC-2022), Chairman ERN-EYE Neuro-ophthalmology (until OCT-2020), Board member of National Dutch Neuro-ophthalmology Association; Equipment: OCTA from Zeiss (Plex Elite); Medical writing: Support from Novartis for manuscript doi: 10.1002/acn3.51473. J. Killestein received research grants for multicentre investigator initiated trials DOT-MS trial, ClinicalTrials. gov Identifier: NCT04260711 (ZonMW) and BLOOMS trial (ZonMW and Treatmeds), ClinicalTrials. gov Identifier: NCT05296161); received consulting fees for F. Hoffmann-La Roche, Biogen, Teva, Merck, Novartis and Sanofi/Genzyme (all payments to institution); reports speaker relationships with F. Hoffmann-La Roche, Biogen, Immunic, Teva, Merck, Novartis and Sanofi/Genzyme (all payments to institution); adjudication committee of MS clinical trial of Immunic (payments to institution only). B.M.J. Uitdehaag reports research support and/or consultancy fees from Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, Teva, and Immunic Therapeutics.

P493/1238

Cancer and multiple sclerosis: 2023 recommendations from the French multiple sclerosis society

nicolas collongues¹, Françoise Durand-Dubief², Bertrand Bourre³, Helene ZEPHIR⁴, Kévin Bigaut¹, Xavier Ayrignac⁵, Christine Lebrun-Frenay⁶, Emmanuelle Leray⁷, Nathalie Morel⁸, Caroline BENSA⁹, JONATHAN CIRON¹⁰, Arnaud Kwiatkowski¹¹, Guillaume MATHEY¹², Chloé Pierret¹³, Julie Boucher⁴, Anne Kerbrat¹³, Pierre Branger¹⁴, Maxime Guillaume³, Alexis Montcuquet¹⁵, Benjamin Hebant³, Xavier Moisset¹⁶, boutiere clemence¹⁷, Perrine Schmitt¹⁸, Angélique Da Silva¹⁴, Julien Poupart¹¹, Chloé Prunis¹², Gilles Defer¹⁴, Eric Thouvenot¹⁸, Géraldine Androdias², Mikael Cohen⁶

Study Group: SFSEP, France4MS

¹CHRU de Strasbourg, Strasbourg, France, ²CHU de Lyon, Lyon, France, ³Hospital Center University De Rouen, Rouen, France, ⁴Hospital Center University De Lille, Lille, France, ⁵Hospital Center University De Montpellier, Montpellier, France, ⁶CRC SEP, UMRC UR2CA URRIS, CHU de Nice, Nice, France, ⁷Ehesp, Rennes, France, ⁸Centre Hospitalier Annecy Genevois, Epagny Metz-Tessy, France, ⁹Hospital Foundation Adolphe De Rothschild, Paris, France, ¹⁰Hospital Center University De Toulouse, Toulouse, France, ¹¹Group Des Hôpitaux University Catholic De Lille, Lille, France, ¹²Hospital Center Regional And University De Nancy Hospital Central, Nancy, France, ¹³CHU Rennes - Pontchaillou Hospital, Rennes, France, ¹⁴University Hospital Center of Caen, Caen, France, ¹⁵Hospital Center University De Bordeaux, Bordeaux, France, ¹⁶CHU Gabriel-Montpied, Clermont-Ferrand, France, ¹⁷Marseille University Hospital Timone, Marseille, France, ¹⁸University Hospital of Nimes, Nîmes, France

Introduction: The use of immunosuppressive drugs in patients with multiple sclerosis (MS) has dramatically increased over time. Additionally, epidemiological data reveal that around 45% of patients in France are older than 50. Thus, the question of a potential increased risk of cancer can be raised, as well as how MS patients should be screened and managed regarding cancer risk.

Objectives/Aims: These recommendations aim to help clinicians make decisions in patients with MS when considering the risk related to cancer and its treatments.

Methods: The French Group for Recommendations in Multiple Sclerosis (France4MS) reviewed articles from PubMed and university databases (January 1975 through June 2022). The RAND/UCLA appropriateness method, developed to synthesize the scientific literature and expert opinions on healthcare topics, was used to reach a formal agreement.

MS experts worked on the full-text review and initial wording of recommendations. A group of multidisciplinary healthcare specialists validated the final proposal of summarized evidence.

Results: A strong agreement was reached for all 31 proposed recommendations.

They cover diverse topics, such as cancer screening before introducing a disease-modifying treatment (DMT), recommended follow-up related to cancer under DMT, recommended attitude regarding MS management in the event of the discovery of cancer, and potential reintroduction of a DMT after initial cancer treatment. Details will be presented at the ECTRIMS congress.

Conclusion: Physicians and patients should be aware of the updated recommendations for cancer and MS.

Disclosure of interest: Nicolas Collongues: nothing to disclose

Françoise Durand Dubief: nothing to disclose

Bertrand Bourre: nothing to disclose

Hélène Zephir: nothing to disclose

Kevin Bigaut: nothing to disclose

Xavier Ayrignac: nothing to disclose

Christine Lebrun Frenay: nothing to disclose

Emmanuelle Leray: nothing to disclose

Nathalie Morel: nothing to disclose

Caroline Bensa: nothing to disclose

Jonathan Ciron: nothing to disclose

Arnaud Kwiatowkski: nothing to disclose

Guillaume Mathey: nothing to disclose

Chloé Pierret: nothing to disclose

Julie Boucher: nothing to disclose

Anne Kerbrat: nothing to disclose

Pierre Branger: nothing to disclose

Maxime Guillaume: nothing to disclose

Alexis Montcuquet: nothing to disclose

Benjamin Hebant: nothing to disclose

Xavier Moisset: nothing to disclose

Clémence Boutière: nothing to disclose

Perrine Schmitt: nothing to disclose

Angélique Da Silva: nothing to disclose

Julien Poupart: nothing to disclose

Chloé Prunis: nothing to disclose

Gilles Defer: nothing to disclose

Eric Thouvenot: nothing to disclose

Géraldine Androdias: nothing to disclose

Mikael Cohen: nothing to disclose

P494/681

Comorbidity in the aging population with multiple sclerosis – A nationwide cross-sectional study

Rolf Holm¹, Malthe Wandall-Holm¹, Melinda Magyari¹, Finn Sellebjerg²

¹Danish Multiple Sclerosis Registry, Glostrup, Denmark, ²Danish Multiple Sclerosis Center, Glostrup

Introduction: The influence of comorbidities on the disease course in patients with multiple sclerosis (MS) is widely debated. The likelihood of concomitant diseases increases with age, causing the elderly population to be at high risk of comorbidities.

Objectives/Aims: This study aims to assess the prevalence of chronic comorbidities and the incidence of acute comorbidities requiring hospitalization in elderly patients with MS compared to matched controls from the general population.

Methods: We conducted a matched, nationwide cross-sectional study in Denmark utilizing the Danish Multiple Sclerosis Registry to identify all living patients with MS ⩾ 50 years, alive, and residing in Denmark as of January 1^st, 2021. Patients were matched 1:10 by age, sex, and geographical residence to individuals from a 25% random sample of the entire Danish population. Information on all contacts with the Danish hospital system (secondary or tertiary care) was collected from the nationwide National Patient Register, including primary ICD10-diagnosis code, type of admission, and dates of admission and discharge. Chronic comorbidities were identified using ICD10-codes within broad disease domains (e.g., cancer, cardiovascular), while acute comorbidities were selected based on ICD10-codes with an admission type labeled 'acute', requiring hospitalization and a discharge at least one day after admission.

Results: Of 15,256 patients assessed for eligibility, 8,214 met the inclusion criteria. The mean age among these patients was 63.4 years (SD: 8.9), 68.3% were females, and 44.6% were categorized as RRMS at the reference date. The median latest Expanded Disability Status Scale score in the past two years was 3.5 (Q₁-Q₃= 2.0-6.0, n_miss=3,626).

We found patients with MS to be more prone to have one or more chronic comorbidities (MS: 37%; controls: 31%, P<0.001). The most frequent chronic comorbidity domains were cardiovascular (MS: 17.8%; controls: 16.2%, P=0.008) and cancer (MS: 7.5%; controls: 7.6%, P=0.9). MS patients were also at higher risk of one or more acute hospitalizations (MS: 16%; controls: 8%, P<0.001) with a high incidence of urinary infection (MS: 2.1%; controls: 0.2%, P<0.001) and urosepsis (MS: 0.9%; controls: 0.1%, P<0.001).

Conclusion: Elderly patients with MS have a significantly higher prevalence of chronic comorbidity and a higher incidence of acute hospitalizations compared to matched controls from the background population.

Disclosure of interest: Rolf Pringler Holm has served on scientific advisory board for Novartis and has received honoraria for lecturing for Novartis and Sanofi.

Malthe Faurschou Wandall-Holm has served on scientific advisory board for Sanofi and has received honoraria for lecturing for Novartis and Sanofi.

Finn Sellebjerg has served on scientific advisory boards for, served as consultant for, received support for congress participation or received speaker honoraria from Alexion, Biogen, Bristol Myers Squibb, H. Lundbeck A/S, Merck, Novartis, Roche, and Sanofi Genzyme. His laboratory has received research support from Merck, Novartis, Roche, and Sanofi Genzyme.

Melinda Magyari has served in scientific advisory board for Sanofi, Novartis, Merck, and has received honoraria for lecturing from Biogen, Merck, Novartis, Roche, Sanofi Genzyme, Bristol Myers Squibb.

Funding statement:

This study did not receive any funding.

P495/1234

Prevalence of comorbid autoimmune diseases in patients with first diagnosis of Multiple Sclerosis

Konstantin Fritz Jendretzky¹, Lisa-Marie Lezius¹, Thiele Thea², Witte Torsten², Franz Felix Konen¹, Martin W. Hümmert¹, Philipp Schwenkenbecher¹, Kurt-Wolfram Sühs¹, Mike Wattjes³, Stefan Gingele¹, Thomas Skripuletz¹

¹Hannover Medical School, Departement of Neurology, Hannover, Germany, ²Hannover Medical School, Department of Rheumatology, Hannover, Germany, ³Hannover Medical School, Institute of Diagnostic and Interventional Neuroradiology, Hannover, Germany

Introduction: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system that affects approximately 2.5 million people worldwide. Comorbid autoimmune diseases may further complicate the management and treatment of the disease. In MS, the most common comorbidities are thyroid disorders, inflammatory bowel disease, and rheumatoid arthritis. However, the prevalence and impact of these comorbidities on MS patients are still poorly understood. It is therefore crucial to further evaluate the prevalence of comorbid autoimmune diseases in MS patients and the potential impact on their clinical management.

Objectives/Aims: Data were retrospectively analysed to identify comorbid autoimmune diseases in patients newly diagnosed with MS or clinically isolated syndrome (CIS), to determine whether there is an increased prevalence and whether potential implications exist that might affect further clinical management.

The aim of this work was to evaluate the prevalence and character of comorbid autoimmune diseases in MS and CIS patients.

Methods: Data were collected retrospectively from all patients who were hospitalized for the first time at the Department of Neurology at Hannover Medical School between 2010 and 2018 for evaluation of possible MS.

Results: We were able to recruit a cohort of 508 patients. Of these patients, 338 (67%) were woman. The median age was 33. The cohort was divided into 315 (62%) patients with a diagnosis of MS and 193 (38%) patients with a diagnosis of CIS. Of the 508 patients, 76 (15%) were found to have at least one documented comorbid autoimmune disease, 42 (13%) of the MS patients and 34 (18%) of the CIS patients. By far the most common comorbid autoimmune disease was autoimmune thyroiditis with 53 (10%) patients. Other autoimmune diseases were chronic inflammatory skin diseases (n=7; 1,4%), arthritides (n=5; 1%), inflammatory bowel disease (n=4; 0,8%), diabetes mellitus type 1 (n=3; 0,6%), Sjögren's syndrome (n=2; 0,4%) and sarcoidosis (n=1; 0,2%).

Conclusion: Overall, this study showed a high prevalence of comorbid autoimmune diseases in patients with a first diagnosis of MS or CIS. While treatment of the most common comorbid disease, autoimmune thyroiditis, is usually carried out without immunosuppression, the treatment of MS should consider the other comorbid autoimmune diseases in the treatment decision.

Disclosure of interest: Konstantin Fritz Jendretzky received honaria and travel grants from Merck and Novartis; all outside the submitted work.

Lisa-Marie Lezius: nothing to disclose

Thea Thiele: received honaria and travel grants from Abbvie, Galapagos, Bristol Myers Squibb, Chugai, Roche, Boehringer Ingelheim, Novartis; all outside the submitted work.

Torsten Witte reports honoraria for lectures and travel grants from Abbvie, Biogen, Boehringer Ingelheim, Celgene, Chugai, CSL Behring, Euroimmun, Galapagos, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, Siemens, Takeda, UCB; all outside the submitted work.

Franz Felix Konen received travel grants from Merck and Novartis; all outside the submitted work.

Martin Werner Hümmert received research support from Myelitis e. V.; outside of the submitted work.

Philipp Schwenkenbecher received travel compensation and congress fee from Merck-Serono; all outside the submitted work.

Kurt-Wolfram Sühs received speaker`s honoraria or travel expenses from Biogen, Merck, BMS; all outside the submitted work.

MPW received royalties from Springer Healthcare and Elsevier; received consulting fees from Biogen, Roche, Biologix, Novartis, BMS-Celgene, Imcyse, Merck Serono, Sanofi Aventis, IXICO, and Icometrix; received honoraria from Bayer, Biogen, Biologix, Genilac, Novartis, Medison, Merck Serono, Roche, Sanofi Aventis, and BMS-Celgene; and participated on a data safety monitoring board for VU University Medical Center; all outside of the submitted work.

Stefan Gingele reports research support from Alnylam Pharmaceuticals, CSL Behring, Else Kröner Fresenius Foundation, Deutsche Forschungsgemeinschaft and Hannover Biomedical Research School (HBRS) and consulting and/or speaker honoraria from Alexion, Alnylam Pharmaceuticals, Pfizer and Merck all outside the submitted work.

Thomas Skripuletz reports research support from Alnylam Pharmaceuticals, Bristol-Myers Squibb Foundation for Immuno-Oncology, Claudia von Schilling Foundation, CSL Behring, Else Kröner Fresenius Foundation, Hannover Biomedical Research School (HBRS), Sanofi Genzyme, VHV Stiftung and honoraria for lectures and travel grants from Alexion, Alnylam Pharmaceuticals, Bayer Vital, Biogen, Celgene, Centogene, CSL Behring, Euroimmun, Janssen, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Siemens, Sobi; all outside the submitted work.

P496/1554

Mediterranean Diet is Associated with Cognition in Multiple Sclerosis

Ilana Katz Sand¹, James Sumowski¹, Kathryn Fitzgerald²

¹Corinne Goldsmith Dickinson Center for MS at Mount Sinai, Neurology, New York, United States, ²Johns Hopkins University, Baltimore, United States

Introduction: The MS community has a high interest in the interaction between diet and disease outcomes. We have previously noted relationships between Mediterranean diet alignment and 1) thalamic volume in early MS and 2) objectively captured MS-related disability (Multiple Sclerosis Functional Composite). Here we evaluated associations between Mediterranean diet score and cognition in a representative clinical MS cohort.

Objectives/Aims: To evaluate relationships between Mediterranean diet score and cognitive outcomes in multiple sclerosis (MS)

Methods: Persons with MS (n=563; 71% women; aged 44.2±11.3 years) completed the Mediterranean Diet Adherence Screener (MEDAS, scores 0-14) and an analogue of the BICAMS cognitive battery composed of Symbol Digit Modalities Test, Hopkins Verbal Learning Test, Revised, and CANTAB Paired Associate Learning. Normative z-scores were averaged into a composite cognitive z-score. Multiple regression investigated the independent contribution of MEDAS to cognition adjusting for demographic (age, sex, race, ethnicity, socioeconomic status) and health-related (BMI, exercise, sleep disturbance, hypertension, diabetes, hyperlipidemia, smoking) factors. Logistic regression predicted risk for cognitive impairment (<5^th percentile on 2-3 tasks) with MEDAS adjusting for aforementioned covariates.

Results: Mean (SD) cognitive z-score was -0.67 (0.95). Higher MEDAS independently predicted better cognition (B=0.08 [95%CI: 0.05, 0.11], β=0.20, p<0.001). Cognitive impairment was observed in 108 patients (19.2%). Higher MEDAS independently predicted 20% lower risk for cognitive impairment (Odds Ratio=0.80 [95% CI: 0.73, 0.89], p<0.001). MEDAS was by far the best health-related predictor of cognitive z-score and cognition impairment. Effect modifications indicated stronger relationships between diet and cognition (z-score and impairment) among persons with progressive (versus relapsing) disease.

Conclusion: After controlling for important potential confounders, we note a significant association between Mediterranean diet score and cognition in a representative sample of people with MS. The strength of the relationship in progressive disease suggests the possibility of a neuroprotective mechanism. Longitudinal studies and interventional clinical trials are needed.

Disclosure of interest: Dr. Katz Sand: nothing to disclose

Dr. Fitzgerald: nothing to disclose

Dr. Sumowski: nothing to disclose

P497/310

The Prevalence and Clinical Characteristics of Restless Legs Syndrome in Patients with Multiple Sclerosis

Aydanur Anaturk¹, Serkan Ozben¹

¹University of Health Sciences Antalya Training and Research Hospital, Neurology, Antalya, Turkey

Introduction: Although multiple sclerosis (MS) is one of the most common neurological disorders, sleep problems in MS have not been adequately addressed. Sleep disorders are common in the general population but have been reported to be more common in MS patients. Restless legs syndrome (RLS) is characterized by an uncomfortable sensation in the lower extremities with an irresistible urge to move the legs impairing sleep quality.

Objectives/Aims: As the diagnostic criteria for RLS changed in 2014, patients should develop difficulty in falling asleep or daytime symptoms secondary to RLS symptoms in order to diagnose RLS. There is a need for diagnostic prevalence studies according to the new criteria. Many existing prevalence studies still include individuals without these symptoms. Our study aimed to determine the prevalence of RLS in MS patients and examine its comorbidities and effects.

Methods: The patients were assessed using the RLS Severity Rating Scale, Pittsburg Sleep Quality Index (PSQI), Beck Depression Inventory, Beck Anxiety Inventory, Epworth Sleepiness Scale (ESS), Multiple Sclerosis Quality of Life-54 (MSQOL-54), and clinical disability by the Expanded Disability Status Scale (EDSS).

Results: 105 patients, mean age of 41.65±11, 78 female and 27 male, were included in the study. Totally 23 MS patients (20 female and 3 male) were diagnosed as RLS. Disease duration and EDSS severity were found to be higher in MS patients with RLS (p=0.025 and p=0.030). Beck depression and anxiety scores were found to be statistically higher in the MS patient group with RLS (p=0.005 and p=0.002). ESS (p<0.001), and PSQI (p=0.028) scale scores of patients with RLS were significantly higher in MS patients, MSQOL-54 physical (p=0.001), MSQOL-54 cognitive (p=0.018) and MSQOL-54total (p=0.002) scale scores were significantly lower. The rate of patients with bladder dysfunction was found to be higher in MS patients with RLS (43.5% vs 20.7%; p=0.007).

Conclusion: In our study, the prevalence of RLS in MS patients was shown to be approximately 22%. It has been observed that gender, disease duration, and disease severity affect the frequency of RLS. High depression and anxiety scores and low quality of life scores in patients with RLS were thought to be the effects of RLS. Therefore, patients should be questioned and treated for RLS.

Disclosure of interest: Aydanur Anaturk: Nothing to disclose

Serkan Ozben: Nothing to disclose

P498/1750

Incident epilepsy in multiple sclerosis: a meta-analysis of randomized clinical trials

Valeria Pozzilli¹, Carla Tortorella², Claudio Gasperini², Shalom Haggiag², Alessandro Cruciani³, Fioravante Capone¹, Vincenzo Di Lazzaro¹, Luca Prosperini²

¹Campus Bio-Medico University, Rome, Italy, ²San Camillo Forlanini Hospital, Rome, Italy, ¹Campus Bio-Medico University, Rome, Italy

Introduction: Epilepsy is reported to be more common in patients with multiple sclerosis (pwMS) compared to the general population, especially in those with advanced disability and progressive disease course, albeit with heterogeneous data across studies. Cortical/iuxtacortical lesions and brain atrophy are well-recognized pathological substrates associated with seizures in pwMS. However, available data about epilepsy in MS is mainly derived from observational studies, therefore susceptible to selection bias.

Objectives/Aims: To verify the hypothesis of an increased incidence of epilepsy in pwMS and find the associated risk factors.

Methods: We performed an extensive literature search to extract rates of adverse events (i.e. seizure, epilepsy or convulsion) from phase 3 randomized clinical trials (RCTs) in pwMS with ⩾18 years of age, and a duration ⩾48 weeks. A random-effect model was fitted to estimate the pooled incidence rate of seizures (effect size) in all study populations, regardless of arm allocation. Variables (moderators) affecting the pooled effect size were analyzed through meta-regressions. Given the rarity of the events of interest, estimates were inserted in equations as double arcsine transformed incidence rates.

Results: Data was extracted from 62 RCTs, with the pooled cohort consisting of 53,705 patients with an average follow-up of 2 years, yielding 105,818 patient-years. The pooled incidence rate for a new onset seizure was 34 (95% confidence intervals: 23 to 45) per 100,000 patient-years. Reporting of events of interest increased over the years (Beta = 0.06, p = 0.031). After correcting for the calendar year, higher incidence rates were observed in studies that enrolled patients with either a secondary progressive course (Beta = 0.043, p = 0.005), a greater EDSS (Beta = 0.042, p = 0.019), or a lower normalized brain volume (Beta = -0.24, p = 0.028). Out of 68 total events, 44 occurred in RCTs on sphingosine-1-phosphate agonists (S1Pa), resulting in an increased risk in treated arms versus placebo or the active comparator (odds ratio = 2.5, p=0.018).

Conclusion: Our study confirms a higher incidence of epilepsy in pwMS (34 versus 23-31 patient-years in the general population aged 30-60 years) and shows an association between incident epilepsy and both neurological disability and brain atrophy. Moreover, S1Pa would result in potentially epileptogenic agents, which needs further confirmation.

Disclosure of interest: VP has nothing to disclose.

LP received consulting fees and/or speaker honoraria from Biogen, Celgene, Genzyme, Merck-Serono, Novartis and Teva; travel grants from Biogen, Genzyme, Novartis and Teva; research grants from the Italian MS Society (Associazione Italiana Sclerosi Multipla) and Genzyme.

CT received honoraria for speaking and travel grants from Biogen, Sanofi-Aventis, Merck Serono, Bayer-Schering, Teva, Genzyme, Roche, Alexion, Horizon, Celgene, Almirall and Novartis.

CG received honoraria for speaking and travel grants from Biogen, Sanofi-Aventis, Merck Serono, Bayer-Schering, Teva, Genzyme, Roche, Alexion, Horizon, Celgene, Almirall and Novartis.

SH received honoraria from Biogen, Novartis, Genzyme and Merck Serono.

AC has nothing to disclose.

FC received travel grants from Sanofi, Genzyme, Merck, Roche, Biogen.

VDL has nothing to disclose related to this work.

P499/730

Konectom digital measures from the 6-minute walk test: reliability and association with clinical anchors and patient reported walking impairment

Aurelie Ruet¹, Angelos Karatsidis², Emmanuel Bartholomé², Marta RUIZ³, Gautier Cosne², Nolan Campbell², Matthew Scaramozza², Claudia Mazzà², Zhaonan Sun², Christian Barro²

¹CHU de Bordeaux, Bordeaux, France, ²Biogen, Cambridge, United States, ³Biogen, Paris, France

Introduction: In clinical trials, walking impairment in patients with multiple sclerosis (pwMS) is commonly quantified by Timed 25-Foot Walk (T25FW). Sensor based digital ambulation tests provide an opportunity to inform on different aspects of ambulatory impairment.

Objectives/Aims: To assess the reliability and convergent validity of walking measures from the Konectom digital 6-minute walk test (D6MWT).

Methods: The D6MWT, 6MWT and T25FW were performed on 72 pwMS in the DigiToms study. D6MWT measures were collected using the Konectom app on a smartphone secured to a walking belt. Digital measures covered domains of pace (step power, stride duration), balance & coordination (step regularity, stride regularity) and variability (stride duration variability). Self-reported walking impairment was collected by the 12-item Multiple Sclerosis Walking Scale (MSWS-12). Reliability was evaluated by intra-class correlation coefficient (ICC) over 7 remote assessments. Convergence was evaluated by Spearman correlations at a single in-clinic visit. The relationship to the MSWS-12 was modeled by multivariate linear regression including age, sex and height as covariates, measures were standardized by standard deviation to enable direct comparisons of the estimates, F-value and additional R-square compared to a reduced model without the measure.

Results: Digital measures showed a good reliability on repeated testing (ICC = 0.540 – 0.811), with step power showing the highest reliability (ICC = 0.811). Stride duration and step power were significantly correlated with the distance walked in the 6MWT (r_s=-0.83 and r_s=0.89, p<0.001 both), T25FW time (r_s=0.55 and r_s=-0.58, p<0.001 both) and MSWS-12 (r_s=0.49, r_s=-0.59, p<0.001 both). Stride duration variability and stride regularity were significantly correlated with balance assessed by the Romberg test (r_s = 0.39 and r_s = -0.41, p<0.001 both). In the multivariate model stride duration and step power showed a stronger association to the MSWS-12 (β = 0.142, F-value = 30.42, r2 = 0.30, p<0.0001 and β = -0.130, F-value = 22.03, r2 = 0.24, p<0.0001 respectively) than the T25FW (β = 0.112, F-value = 13.54, r2 = 0.16, p = 0.0005).

Conclusion: D6MWT measures had good reliability and logically correlated with accepted measures of ambulatory impairment. Stride duration and step power additionally showed a stronger association with patient reported walking impairment than the T25FW. The data support further Konectom D6MWT use in studies of pwMS to provide a more comprehensive assessment of ambulatory impairment.

Disclosure of interest: Aurélie Ruet: Dr Ruet has served on scientific advisory boards of Biogen and Merck and received funding for travel or speaker honoraria from Biogen, Novartis, Roche, Alexion, Sanofi-Genzyme, and Merck. My institution received research support from Biogen, Sanofi-Genzyme and Roche outside the scope of this study.

Angelos Karatsidis: Employee of and holds stock/stock options in Biogen.

Emmanuel Bartholomé:Employee of and holds stock/stock options in Biogen.

Marta Ruiz: Employee of and holds stock/stock options in Biogen.

Gautier Cosne: Employee of and holds stock/stock options in Biogen.

Nolan Campbell: Employee of and holds stock/stock options in Biogen.

Matt Scaramozza: Employee of and holds stock/stock options in Biogen.

Claudia Mazzà: Employee of and holds stock/stock options in Biogen.

Zhaonan Sun: Employee of and holds stock/stock options in Biogen.

Christian Barro: Employee of and holds stock/stock options in Biogen. Support: Biogen.

P500/2266

"Self-care selfies": Patient-uploaded videos capture meaningful changes in dexterity over 6 months

Arpita Gopal¹, wilson torres², Ilana Winawer¹, Shane Poole¹, Ayushi Balan², Hannah Stuart², Nora Fritz³, Jeffrey Gelfand¹, Diane Allen⁴, Riley Bove¹

¹UCSF Joan and Sanford I. Weill Neurosciences Building, San Francisco, United States, ²University of California, Berkeley, Berkeley, United States, ³Wayne State University, Detroit, United States, ⁴San Francisco State University, San Francisco, United States

Introduction: Upper extremity function reflects broader disease-related and quality of life progression in multiple sclerosis (MS). To capture these changes remotely, videos could offer strong accessibility benefits.

Objectives/Aims: To evaluate the feasibility of longitudinal collection of patient-uploaded videos and explore the validity of human pose estimation, a set of algorithms trained on images to detect body landmarks, in capturing changes in dexterity.

Methods: A single-center cohort of 50 participants with MS with moderate disability was enrolled for a 6-month study. Participants self-reported their dexterity using the ABILHAND survey, and periodically uploaded in-home videos of themselves performing 3 self-care tasks: buttoning, brushing teeth, and eating. Position and velocity kinematic data were extracted from the videos using open access MediaPipe Hand pose estimation software. In-clinic evaluations for validation at baseline and 6 months included: 9 hole peg test (9HPT), grip and pinch strength, and vibration sense. The Health Information Technology Usability Evaluation Scale (ITUES) framework was used to elicit participant feedback.

Results: Of the 50 enrolled participants, 44 (88%) completed at least 3 video uploads, and 37 (74%) completed the study (3 withrew due to relapse). Overall, 95% participants agreed/strongly agreed that the assessments were easy to access and 86% agreed/strongly agreed (0% disagreed) that the study tasks were representative of their daily activities. From the videos, buttoning task kinematic metrics showed the strongest correlation with 9HPT (nondominant: r=0.69, p=0.02; dominant: r=0.57, p=0.05) and ABILHAND (r=-0.48, p=0.05). Retest validity at 1 week was stable (r>0.8). Over 6 months, clinical reduction in pinch strength (5.8kg/cm² to 5.0kg/cm², p=0.05) was corroborated by self-reported change in ABILHAND. Metrics from the patient-uploaded buttoning videos were sensitive to changes in dexterity: 94% participants categorically worsened (48% worsened by >20%), compared to only 40% by 9HPT (6% by 20%).

Conclusion: Patient-uploaded videos represent a novel approach to capturing MS-related function. The validity and sensitivity to change of the measures collected, as well as their meaningfulness, suggests a possible benefit in detecting early progression. Their strong patient-centered benefits: accessibility, usability, acceptability, low cost and low-technological burden, enhance their potential for dissemination for disease monitoring and treatment.

Disclosure of interest: AG: nothing to disclose

WOT: nothing to disclose

IW: nothing to disclose

SP: nothing to disclose

AB: nothing to disclose

HSS: nothing to disclose

NEF: nothing to disclose

JMG: reports research support to UCSF from Roche/Genentech and Vigil Neurosciences and personal fees from medical legal consulting

DDA: nothing to disclose

RB: receives research support from NIH, DOD, National Multiple Sclerosis Society (Harry Weaver Award), NSF, as well as Biogen, Novartis and Roche Genentech. Scientific advisory board and consulting fees from Alexion, EMD Serono, Horizon, Janssen, Genzyme Sanofi, Novartis and TG Therapeutics.

P501/1330

Challenges and opportunities for the application of synthetic data in multiple sclerosis clinical research

Luca Carmisciano¹, Noemi Montobbio², Alessio Signori², Maria Pia Sormani²

¹University of Pisa, Pisa, Italy, ²Università degli studi di Genova, DISSAL, Genoa, Italy

Introduction: Synthetic data is an artificially generated set of observations with similar statistical properties and patterns of an existing real dataset. Privacy, data sharing and statistical models training improvements are among the most attractive applications of synthetic data in multiple sclerosis (MS) research. Technical literature is abundant on this topic but only a few practical use cases are available in MS.

Objectives/Aims: To explore the limits and the feasibility of conducting a statistical analysis with synthetic data, we replicated the results of SPI2.

Methods: SPI2 is a published, Phase III, clinical trial evaluating the effect of high-dose biotin on progressive MS. We generated synthetic data from the original SPI2 data set with five different strategies. Approaches were based on additive random noise, uni and multivariate distribution modeling or generative models. The proportion of patients improved on either Expanded Disability Status Scale (EDSS) or Time to Walk 25 Feet (TW25) was compared between treated and controls and Odds Ratios estimated using generalized linear models. Results were averaged among 20 syntheses and compared to the ones reported in the original SPI2 paper.

Results: All the synthetic data analyses, regardless of the generation strategy, concluded concordantly to the original SPI2 paper. For the primary SPI2 analysis the standardized mean difference of the treatment effect between the artificial and the real dataset analysis was lower than 9%. The mean confidence interval overlap over all coefficients between artificial and real dataset analysis was up to 85.0%.

Conclusion: It is feasible to use synthetic data generated from real clinical studies to perform exploratory analyses using common statistical tools without the need of sharing the original data source or other patient identifiable information. Caution is required since not all the data generation procedures capture all the statistical properties that are relevant to an arbitrary analytical method. Nevertheless, synthetic data is expected to improve global networking between MS researchers and to ease data sharing.

Disclosure of interest: LC, NM: nothing to disclose; AS: received teaching honoraria from Novartis; MPS: has received consulting fees from Biogen, Merck, Teva, Genzyme, Roche, Novartis, GeNeuro, and Medday.

P502/1195

Axonal damage in early MS lesions and white matter correlate with neurofilament light chains in serum

Anne-Sophie Beutler¹, Kruse Niels¹, Lidia Stork¹, Gloth Mareike¹, Wolfgang Brück¹, Imke Metz¹

¹Institute of Neuropathology, University Medical Center Göttingen, Göttingen, Germany

Introduction: Neurofilament light chains in serum (sNfL) are considered a biomarker for axonal damage, which is an important feature of multiple sclerosis (MS) pathology. Axonal damage occurs early in the MS disease course and is responsible for irreversible clinical deficits. sNfL have been shown to correlate well with MS clinical and MRI parameters of disease activity, but correlations with axonal damage in early MS lesions and sNfL are lacking.

Objectives/Aims: To analyse correlations of sNfL with axonal damage in early MS lesions as shown by histology.

Methods: We analyzed tissue samples from brain biopsies taken for differential diagnostics in 106 MS patients for their acute and chronic axonal damage, and correlated our findings with sNfL in blood samples. In addition, 26 follow-up samples were also included. Our findings were correlated with clinical parameters.

Results: APP-positive spheroids are known to indicate acute axonal damage; these were found to be highest in earliest lesion stages (median 130 spheroids/mm²). Higher levels of sNfL correlated with higher numbers of APP-positive spheroids in these early lesions (p<0.01). Axonal density could be determined using Bielschowsky silver staining. A significant negative correlation between sNfL levels in follow-up blood samples, taken independent of relapses, and axonal density in normal-appearing white matter (NAWM) was also observed (p=0.02). Finally, sNfL levels correlated with the Expanded Disability Status Score at at last clinical follow-up (p<0.01).

Conclusion: Our findings demonstrate that sNfL reflect the axonal pathology as shown by histology. On the one hand, sNfL correlated with acute axonal damage within the lesion, and on the other, with axonal reduction in NAWM. Our study thus emphasizes the relevance of relapse-associated lesional pathology for axonal damage, even for blood samples taken at a median of 9 months after biopsy. In addition, our results underline that axonal loss in normal-appearing white matter contributes to sNfL levels independent of relapses. Early axonal damage is clinically relevant, as shown by the correlations of sNfL levels with clinical disability found in this and in prior studies. sNfL are thus promising biomarkers that may help prognosticate patient disability and help with individualized treatment.

Disclosure of interest: ASD, NK, LS and MG have nothing to disclose. IM reports grants from Novartis Pharma GmbH, during the conduct of the study; personal fees from BiogenIdec, Bayer Healthcare, TEVA, Serono, Novartis Pharma GmbH, Genzyme, Roche, grants from BiogenIdec, Genzyme, outside the submitted work. WB has nothing to disclose related to this work.

This study was supported by Novartis Pharma GmbH.

P503/2252

Cell type-specific meningeal gene expression signatures in progressive multiple sclerosis

Tim Trobisch¹, Michael Kutza¹, Natalie Ludwig¹, Sven Wischnewski¹, Celia Lerma-Martin¹, Amel Zulji¹, Lucas Schirmer^1,2,3

¹Medical Faculty Mannheim, Heidelberg University, Division of Neuroimmunlogy, Department of Neurology, Mannheim, Germany, ²Mannheim Center for Translational Neuroscience and Institute for Innate Immunoscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany, ³Interdisciplinary Center for Neurosciences, Heidelberg University, Heidelberg, Germany

Introduction: Meningeal inflammation is a key feature of multiple sclerosis (MS), a prototypic inflammatory disease of the central nervous system (CNS) characterized by compartmentalized lesion pathology and progressive neurodegeneration. The meninges are an important tissue compartment consisting of both blood-brain and blood-cerebrospinal fluid barriers. Previous studies in progressive MS have highlighted that meningeal immune cell aggregates and subpial cortical pathology are often associated with each other. However, the current understanding of the homeostatic and MS meningeal tissue environment and how a disturbed microenvironment favors chronic inflammation and tissue damage in MS is still limited.

Objectives/Aims: To analyze cell type-specific meningeal gene expression signatures in tissues of healthy donors and people with MS (pwMS) with a focus on immune, stromal and vascular cell interactions.

Methods: We performed bulk and single-nucleus RNA sequencing of 14 meningeal tissue blocks obtained from 7 pwMS and 7 matched control donors. We utilized various bioinformatic tools including ligand-receptor and differential gene expression analyses and validated results with fluorescence multiplex in situ RNA hybridization and immunohistochemistry.

Results: We generated a comprehensive transcriptomic map of the human meninges focusing on stromal, vascular and immune cells. We identified distinct subtypes of each of these cell types including homeostatic and MS-enriched fibroblast subtypes, arterial, capillary and venous endothelial cell subtypes as well as myeloid and dendritic cells, CD4 and CD8 positive T cells, B cells and plasma cells. We verified their spatial expression with RNA and protein-based readouts. Further, with a focus on cell-cell-interaction analysis, we identified specific communication pathways between endothelial and immune cells, highlighting ACKR1 signaling among other pathways associated with a disturbed blood-brain barrier.

Conclusion: Our findings demonstrate specific ligand-receptor interaction pairs between endothelial and immune cells, which might play important roles in immune cell infiltration of the CNS and the promotion of chronic meningeal inflammation and subpial tissue damage. Further research on these interactions is needed to highlight their clinical significance and enable the development of new targeted therapies.

Disclosure of interest: LS: filed a patent for the detection of antibodies against KIR4.1 in a subpopulation of patients with multiple sclerosis (WO2015166057A1).

All other authors have nothing to disclose.

P504/1160

Lipocalin 2 reduces chemokine expression in endothelial cells and modulates immune cell migration

Natalie Gasterich¹, Florian Schmitz¹, Alexander Rantchev¹, Cordian Beyer¹, Tim Clarner²

¹Institute of Neuroanatomy, Uniklinik RWTH Aachen, Aachen, ²Institute of Anatomy, Universitätsmedizin Rostock, Rostock, Germany

Introduction: Multiple sclerosis (MS) is a debilitating disease that involves a complex interplay of immune cells and the blood-brain barrier (BBB). The BBB is composed of endothelial cells, pericytes, and astrocytes, and acts as a selective barrier, limiting the entry of immune cells into the CNS. However, in MS, this barrier is compromised, leading to the infiltration of immune cells and the subsequent destruction of myelin. Recent studies have identified LCN2 as a protective molecule in MS animal models, but its mechanisms of action are not fully understood.

Objectives/Aims: In this study, we aimed to investigate the role of LCN2 in reducing chemokine expression in endothelial cells and modulating immune cell invasion in vitro.

Methods: We used in vitro endothelial cell cultures and cytokines to induce an inflammatory reaction. We analyzed gene and protein expression levels of chemokines in response to inflammatory stimuli and/or LCN2 treatment. We also investigated the effect of LCN2 on immune cell migration through the endothelial cell barrier.

Results: We found that LCN2 treatment reduced endothelial chemokine expression under inflammatory conditions. Furthermore, LCN2 treatment reduced immune cell migration through the endothelial cell barrier in vitro. Our results suggest that LCN2 plays a role in reducing immune cell invasion during inflammatory lesion formation and progression in MS.

Conclusion: In conclusion, our study provides evidence for the protective role of LCN2 in MS by reducing endothelial chemokine expression and modulating immune cell invasion through the BBB. These findings suggest that LCN2 may be a potential therapeutic target for MS. Further studies are needed to fully elucidate the mechanisms of LCN2 action in MS and to evaluate its therapeutic potential.

Disclosure of interest: Natalie Gasterich: nothing to disclose

Florian Schmitz: nothing to disclose

Alexander Rantchev: nothing to disclose

Cordian Beyer: nothing to disclose

Tim Clarner: nothing to disclose

P505/1770

Aberrant iron deposition in the progressive Multiple Sclerosis spinal cord relates to neurodegeneration

Marco Pisa¹, Andrew Lockhart¹, Aimee Avery¹, Jonathan Pansieri¹, Alex Waldman¹, Clara Limbaeck^1,2, Gabriele De Luca¹

¹University of Oxford, Nuffield Department of Clinical Neurosciences, Oxford, United Kingdom, ²Oxford University Hospital, Neuropathology, Oxford, United Kingdom

Introduction: Iron accumulation in microglia-macrophages has been described in the multiple sclerosis (MS) brain, particularly in areas of demyelination. Iron-rimmed brain lesions strongly predict disability accumulation supporting iron metabolism as a crucial factor in MS pathology.

Objectives/Aims: Although spinal cord involvement is an important driver of disability in MS, iron accumulation in the MS spinal cord has not been characterised, and is the purpose of the present study.

Methods: Cervical, thoracic and lumbar spinal cord samples from 9 controls and 46 MS cases were labelled for iron (DAB-enhanced Turnbull protocol). Pre-treatment with either 0.1M citrate or EDTA buffer abolished the signal, confirming the specificity of the reaction. Two independent observers rated the extent and morphology of subpial, glial and axonal iron using semiquantitative scoring methods. Sections were labelled for myelin (PLP), axons (Palmgren silver), microglia-macrophages (TMEM119, Iba1, CD68), astrocytes (GFAP), and oligodendrocytes (OLIG2).

Results: Iron-positive glial cells with oligodendrocyte features were found throughout the parenchyma and subpial area in controls. In MS plaques, iron-positive foamy macrophages were common in acute (50%) and chronic active (56.4%) lesions, and were mainly distributed perivascularly rather than at the lesional edge. Iron-positive glial cells with an activated morphology were more commonly found in the normal-appearing-white matter (NAWM) in MS compared with controls (p<0.001); these cells co-labelled with Iba1 and correlated with Iba1- and CD68-macrophage inflammation (both ρ>0.3, p=0.001). In NAWM, 44.7% of samples showed iron-positive axons, mainly in the lateral corticospinal tracts, compared to only 13% of controls (p 0.005). Iron-positive axons and glia correlated with axonal counts (ρ -0.24, p=0.013 and ρ -0.27, p=0.005, respectively) and cord area (ρ -0.26, p=0.009 and ρ -0.25, p=0.013). MS cases exhibited a GFAP-positive fibrillar subpial pattern (32.6% vs. 2.4% in controls, p<0.001) that associated with higher glial and axonal iron staining.

Conclusion: We demonstrate that iron-positive foamy macrophages are commonly found in active spinal cord lesions, with features that differ from those observed in brain lesions. Importantly, we expand current knowledge on iron accumulation in MS by showing that it diffusely accumulates in NAWM in both axons and glia, and associates with axonal loss.

Disclosure of interest: MP is supported by Quinnipiac-Oxford partnership and has received honoraria from Biogen and the MS Academy. AL is supported by Quinnipiac-Oxford partnership. AA is supported by the MS Society. JP is supported by the MS Society. AW has nothing to disclose. CL has nothing to disclose. GDL has received support from the NIHR Biomedical Research Centre (BRC), Oxford, and research funding from the Oxford BRC, MRC(UK), UK MS Society, National Health and Medical Research (Australia), American Academy of Neurology, the Oxford-Quinnipiac Partnership, and Merck-Serono. He has received travel expenses from Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, MS Academy, and American Academy of Neurology (AAN); and honoraria as an invited speaker/faculty for Novartis, Roche, Merck Serono, the MS Academy, and AAN.

P506/1969

The first full histopathological description of monocytic myeloid-derived suppressor cells in the human brain: relationship to the severity of the clinical course in PPMS patients

MARIA CRISTINA ORTEGA MUÑOZ^1,2, Isabel Machín-Díaz^1,2, Michelle Naughton³, Jennifer García-Arocha¹, Víctor Quintanero-Casero¹, Celia Camacho-Toledano^1,2, Denise Fitzgerald³, Diego Clemente^1,2

¹Lab. Neuroinmuno-Reparación. Hospital Nacional de Parapléjicos, Toledo, Spain, ²Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Carlos III Health Institute, Madrid, Spain, ³Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen’s University Belfast, Belfast, United Kingdom

Introduction: Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells with a key regulatory role in multiple sclerosis (MS). Monocytic-MDSCs (M-MDSCs) have been investigated in the peripheral blood of MS patients with controversial results. Some authors described a little variation of M-MDSCs during MS clinical course, while others observed its increase at relapses. On the other hand, the function of M-MDSCs in MS is also a matter of debate, as they exhibit a suppressive activity in relapsing-remitting MS (RRMS), which is lost during progressive forms of the disease.

Objectives/Aims: There are no data about M-MDSC presence in the CNS of MS patients or about their relationship with MS clinical severity. In this sense, we will address the complete phenotypical identification and the expression pattern of the M-MDSCs in the CNS of MS patients.

Methods: We examined the M-MDSC presence by immunohistochemistry in CNS samples from 13 PPMS and 20 SPMS patients with different disease duration and 6 controls by using all the bona-fide markers previously described to classify M-MDSCs in blood, i.e: CD11b, CD33, HLA-DR, CD14 and CD15. We also explored the origin and the immunosuppressive function of these myeloid cells with TMEM119 and CD84 markers, respectively.

Results: We demonstrate for the first time the presence of cells exhibiting the complete M-MDSC phenotype, i.e. CD14⁺HLA-DR^-/lowCD15^-CD11b⁺CD33⁺ in the human CNS. M-MDSCs lacked TMEM119 expression and presented CD84 which confirmed their peripheral origin and their immunosuppressive activity, respectively. Our data show that myeloid cells expressing typical markers for M-MDSCs were mainly found in high inflammatory areas of both SPMS and PPMS, i.e. active lesions and the periplaque of mixed active/inactive lesions. Whereas their abundance was independent to clinical course duration in SPMS patients, a lower density of these regulatory cells as well as an exacerbated inflammatory context are directly correlated with shorter disease duration in PPMS patients.

Conclusion: For the first time, we described that M-MDSCs are present in the human CNS, associated to high inflammatory areas of MS lesions. Furthermore, M-MDSC abundance is directly related to a milder disease severity in PPMS patients. Our results open the door to use these regulatory cells as predictors of disease progression in PPMS patients.

Disclosure of interest: All authors: nothing to disclose.

P507/1572

Characterization of the transcriptional response of human brain derived endothelial cells to pro-inflammatory cytokines IFN-gamma and TNF-alpha in vitro

Skander Ben Ahmed¹, Stephanie Zandee¹, Olivier Tastet¹, Lyne Bourbonniere¹, Camille Grasmuck¹, Karine Thai¹, Fiona Tea¹, Antoine Fournier¹, Romain Cayrol¹, Martine Tetreault¹, Alexandre Prat¹

¹CRCHUM, Montreal, Canada

Introduction: Multiple sclerosis is an auto-immune disease of the central nervous system, characterized by a disruption of the blood-brain barrier and the meningeal brain barrier. The mechanisms leading to barrier degradation in MS involve effects of secreted cytokines/chemokines on the endothelial cells, thereby leading to CNS immune infiltration. Exposure of the endothelium to pro-inflammatory cytokines interrupts the homeostasis of the barriers by disrupting tight and adherent junctions, consequently increasing the permeability of the barrier. Cytokines secreted by different effectors of the immune system induce various functional responses in ECs, quantifiable through measurement of the transcriptome.

Objectives/Aims: 1: Compare the transcriptomes of BBB and BMB-associated ECs in steady-state

2: Identify the transcriptional response of ECs to cytokine stimulation

Methods: ECs from human brain tissue removed at surgery were put in culture and inflamed with cytokines. Bulk RNA-Seq was performed on treated and untreated EC with paired-end fragments on an Illumina NextSeq500 machine, at a targeted depth of 50M reads per sample. Reads were aligned to the human reference genome with STAR. Differential expression analysis was performed with R package limma. Biological insights from sets of differentially expressed genes were obtained through gene-set enrichment analysis.

Results: Preliminary analysis on three samples per group showed significant transcriptomic differences between the ECs forming the BBB and the BMB. We found that BMB and BBB differed in their immunological profiles for the expression of cell adhesion molecules, chemokines and cytokines such as IL11 and CCL26. Moreover, cytokine stimulation induced significant transcriptional changes in the BBB/BMB-associated ECs. These changes included genes such as SOD2 and IL32. Overall, ECs’ response to cytokine stimulation involved both immune pathways (e.g. defense response) and house-keeping functions (e.g. chromosome segregation).

Conclusion: Bulk RNA-Seq is a powerful sequencing approach for homogenous samples such as ECs in culture. This allowed to identify transcriptional signatures associated with the anatomical source of these cells, demonstrating that there are differences in the molecular properties of ECs depending on the structure they are forming. Gene expression changes induced by cytokine stimulation showed that ECs are highly responsive to cytokine stimulation, suggesting they are central to the processes that lead to immune infiltration.

Disclosure of interest: nothing to disclose

P508/1683

Multiple sclerosis patient lymphocytes induce smoldering like lesion in mouse spinal cord

Perrot Océane^1,2,3,4,5, Bachelin Corinne^1,2,3,4,5, Charles Sanson^1,2,3,4,5, Criniere-Boizet Baptiste^1,2,3,4,5, Elisabeth Maillart^1,2,3,4,5, Akbar David^1,2,3,4,5, Roussel Delphine^1,2,3,4,5, Sarrazin Nadège^1,2,3,4,5, Céline Louapre^1,2,3,4,5, violetta zujovic^1,2,3,4,5

¹ICM Institute for Brain and Spinal Cord, Paris, France, ²Sorbonne Université, Paris, France, ³INSERM, PAris, France, ⁴Centre national de la recherche scientifique, Paris, France, ⁵Aphp, Paris, France

Introduction: Mixed active inactive lesions are a hallmark of multiple sclerosis (MS) patients with severe disease and at risks of having higher disability.

Objectives/Aims: Therefore, understanding the generation of these mixed active/inactive or smoldering like lesions is of high importance.

Methods: We developed a new humanized mouse model where we grafted LY from MS patients (11 MS) or healthy donors (4 HD) in demyelinated lesion of the nude mouse spinal cord and followed the evolution of the lesion up to 3 months. We assessed the lesion volume and the extent of inflammation by electron microscopy and immunohistochemistry. We performed single cell RNA sequencing on control and grafted mice spinal cord. In parallel, we followed 1 week, 1, 2 and 3 months after the graft, mice behaviour (grip test, notched beam) and measured the somatosensory evoked potential to assess the physiological changes due to the persistence (or not) of the lesion.

Results: We observed 3 months after the grafting, only in mice grafted with MS LY, that human LY form perivascular cuffs contacting both the vascular wall and mouse immune cells. MS LY presence induced the development of a glial scar in the center of the lesion with a persistence of the demyelination process at the rim of the lesion. We detected in the rim of the lesion microglia cells loaded either with myelin or with iron. Single cell RNA-sequencing analysis provided evidence that microglial and oligodendroglial cells are the most impacted cells by MS LY graft. Behavioral analysis showed that while non-grafted mice and mice grafted with HD LY improved over time, probably due to remyelination, mice grafted with MS patient LY continued to make errors on the notched beam and had a weakened forelimb grip, probably due to the persistence of inflammation and demyelination. We also observed an increase of sensory evoked potential latency in mice grafted with MS patients LY.

Conclusion: Proposing such a novel humanized mouse model of mixed active inactive lesions will enable to comprehend how the shift from a focal demyelination to widespread demyelination and inflammation occurs.

Disclosure of interest: Perrot Océane: nothing to disclose

Bachelin Corinne: nothing to disclose

Sanson Charles: nothing to disclose

Criniere-Boizet Baptiste:nothing to disclose

Maillart Elizabeth: has received consulting or travel fees from Alexion, Biogen, Horizon, Janssen, Merck, Novartis, Sanofi and Teva, and research grant from Biogen, none related to the present work

Akbar David: nothing to disclose

Roussel Delphine: nothing to disclose,

Sarrazin Nadège: nothing to disclose

Louapre Céline: has received consulting, speaker or travel fees from Merck, Roche, Biogen, Novartis, Teva and Sanofi, and a IIT grant from Biogen none related to this work.

Zujovic Violetta: Nothing to disclose

P509/727

Age-dependent differences in remyelination: analysis of mRNA expression patterns to identify key factors during de- and demyelination in the cuprizone model of aged mice

Thiemo Möllenkamp¹, Stefan Gingele¹, Lara-Jasmin Schröder¹, Thomas Skripuletz¹, Martin Stangel^1,2, Viktoria Gudi¹

¹Hannover Medical School, Neurology, Hannover, Germany, ²Novartis Institute for Biomedical Research, Basel, Switzerland

Introduction: Remyelination represents an endogenous repair mechanism after myelin damage, but is often impaired in patients with multiple sclerosis (MS). For myelination studies, the cuprizone model has long been established: Here, young mice are fed the copper chelator cuprizone, which induces toxic demyelination of different brain structures. After cuprizone exposure, rapid and pronounced remyelination occurs immediately in young animals, so that investigation of remyelination failure is hampered.

Objectives/Aims: We established a modified model in aged mice (6 months). Here, remyelination occurred slower and incomplete, corresponding more closely to the impaired remyelination of MS patients.

Methods: Aged mice (6 months) were treated with a 0.4% cuprizone-containing diet for 6.5 weeks. After cuprizone cessation, remyelination was investigated for a period for up to 3.5 weeks for histology and 1.5 weeks for sequencing. In parallel, young mice (8-10 weeks) were treated with 0.2% cuprizone for 5 weeks and followed up for 1.5 weeks for sequencing. During different time points, myelination status, glial cell reaction, synaptic and dendritic density as well as cortical volume was assessed using novel image-analysis approaches. Additionally, relevant genes and their expression patterns were identified in the comparison of young and aged mice using RNAseq.

Results: Cuprizone treatment resulted in significant demyelination of all white and gray matter areas analysed in young and aged animals. Subsequently, pronounced and rapid remyelination occurred in young animals, whereas in aged animals it was slowed and incomplete, along with a prolonged microgliosis and astrogliosis. In neuronal, synaptic and dendritic density, a transient reduction was observed. Cortical volume and overall hippocampal neuronal volume decreased reversibly. Transcriptome analysis revealed differences in the expression of several factors between young and aged animals during de- and remyelination which will be presented in detail.

Conclusion: Detailed analysis of myelination processes is fundamental to understand remyelination failure in MS patients. We show that the use of a cuprizone protocol in aged mice mimics the impaired reparation capabilities seen in adult MS patients more closely than previous protocols with younger mice. We identified key differences in cellular reactions and gene expression, which may explain age-dependent remyelination differences and can therefore contribute to a better understanding of remyelination and its failure.

Disclosure of interest: TM: Work for Fraunhofer ITEM was independent of the research project shown here.

SG reports research support from Alnylam Pharmaceuticals, CSL Behring, Else Kröner Fresenius Foundation, Deutsche Forschungsgemeinschaft and Hannover Biomedical Research School (HBRS) and consulting and/or speaker honoraria from Alexion, Alnylam Pharmaceuticals, Pfizer and Merck all outside the submitted work.

LS: Work for Twincore, Centre for Experimental and Clinical Infection Research GmbH is not connected to his current functions.

TS reports honoraria for lectures and travel grants from Alexion, Alnylam Pharmaceuticals, argenx, Bayer Vital, Biogen, Celgene, Centogene, CSL Behring, Euroimmun, Janssen, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Siemens, Sobi, Teva, Viatris. His research is supported by the German Ministry for Education and Research (BMBF), Bristol-Myers Squibb Foundation for Immuno-Oncology, Claudia von Schilling Foundation for Breast Cancer Research, Else Kröner Fresenius Foundation, Hannover Biomedical Research School (HBRS), Alnylam Pharmaceuticals, CSL Behring, Novartis, Sanofi Genzyme, VHV Foundation.

MS is an employee of Novartis Institute for Biomedical Research, Basel. This research is not connected to his current functions.

There are no possible conflicts of interest for VG.

P510/1402

Pathogenic cerebrospinal fluid antibodies in oligoclonal band-negative primary progressive MS patients

Jamie Wong¹, Saud Sadiq¹

¹Tisch Multiple Sclerosis Research Center of New York, New York, United States

Introduction: Cerebrospinal fluid (CSF) oligoclonal bands (OCBs) are a hallmark diagnostic feature observed in the majority of multiple sclerosis (MS) patients. Prior studies have found an association between OCB absence and a lower disability score. We previously reported that pathogenic antibodies capable of inducing motor disability and hallmark MS pathology are present in the CSF of primary progressive MS (PPMS) patients, but not relapsing-remitting MS (RRMS) or secondary progressive (SPMS) patients. However, it remains unknown whether these pathogenic antibodies in PPMS CSF are only associated with patients who have OCBs.

Objectives/Aims: To determine if pathogenic antibodies in PPMS CSF correlate with the presence of OCBs.

Methods: CSF was obtained from OCB-positive and OCB-negative clinically definite PPMS patients. Adult C57BL/6J mice underwent laminectomies at cervical levels 4 and 5, then 3 µl CSF was injected into the cervical subarachnoid space. Mice were injected with either: 1) OCB-positive PPMS CSF, 2) OCB-negative PPMS CSF, 3) OCB-negative PPMS CSF passed through a 5 kDa MWCO tangential flow filtration system to remove all components larger than 5 kDa, or 4) OCB-negative PPMS CSF incubated with Dynabeads Protein A to deplete immunoglobulin G (IgG). At 1 day post injection (DPI), motor deficit scores were determined by evaluating forelimb reaching, gripping and tail rigidity. Forelimb grip strength was also assessed. Mice were then immediately perfused for histological analyses of the spinal cord.

Results: Mice injected with either OCB-positive or OCB-negative PPMS CSF developed significant forelimb motor disability by 1 DPI. However, mice injected with either filtered OCB-negative PPMS CSF or IgG-depleted OCB-negative PPMS CSF maintained normal motor function. Reactive astrogliosis and axonal damage, as indicated by increased GFAP and SMI-32 expression respectively, were observed in cervical spinal cords of both OCB-positive and OCB-negative PPMS CSF-injected mice, but not in mice injected with filtered or IgG-depleted OCB-negative PPMS CSF.

Conclusion: No differences in pathogenicity were observed between OCB-positive and OCB-negative PPMS CSF, suggesting that the presence of pathogenic antibodies in PPMS CSF does not correlate with the presence of OCBs.

Disclosure of interest: Jamie Wong: nothing to disclose.

Saud Sadiq: nothing to disclose.

P512/1151

Pioglitazone suppresses microglia-mediated neuroinflammation and ameliorates disease in a passive-transfer model of neuromyelitis optica spectrum disorder

Leung Wah Yick¹, Ethel Yin Ying Chan¹, Wenying Zou¹, Krystal Xiwing Yau¹, Jason Shing Cheong Kwan¹, Koon Ho Chan¹

¹The University of Hong Kong, Hong Kong, Hong Kong

Introduction: Neuromyelitis optica spectrum disorders (NMOSD) are autoimmune inflammatory demyelinating diseases characterized by recurrent attacks of acute neuroinflammation. Binding of pathogenic aquaporin-4 autoantibodies (AQP4-IgG) to AQP4 on astrocytes triggers lesion development that is driven by a crosstalk between astrocyte and microglia. Pioglitazone, an approved drug for type-2 diabetes, is a peroxisome proliferator activated receptor-γ (PPARγ) agonist that exerts neuroprotective effects in various experimental models of CNS insults.

Objectives/Aims: We examined whether oral pioglitazone treatment ameliorates motor impairments and pathologies via suppressing microglia-mediated neuroinflammation in mice which received human AQP4-IgG.

Methods: Adult C57BL/6 mice with disrupted blood-brain barrier were subjected to passive transfer of purified IgG from AQP4-IgG-seropositive NMOSD patients [IgG(AQP4+)], followed by oral gavage of 80 mg/kg pioglitazone or vehicle after the transfer and subsequently every day for 7 days.

Results: In the beam walking test, pioglitazone-treated IgG(AQP4+) mice took a shorter time to cross the beams and slipped less often than vehicle control. Immunofluorescence revealed that pioglitazone treatment profoundly alleviated NMOSD-like spinal cord pathologies including astrocytopathy, demyelination, and axonal loss in IgG(AQP4+) mice. Moreover, pioglitazone-treated IgG(AQP4+) mice displayed a reduction in microgliosis and levels of pro-inflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumour necrosis factor-α (TNF-α). The PPARγ inhibitor, GW9662, abolished the beneficial effects of pioglitazone. Microglia depletion with clodronate liposomes attenuated IgG(AQP4+)-induced motor impairments and spinal cord pathologies

Conclusion: PPARγ agonist can suppress microglia-mediated neuroinflammation induced by AQP4-IgG, and highlight the potential of repurposing pioglitazone as a therapeutic agent in NMOSD.

Disclosure of interest: No conflict of interest

P513/2297

A Humanized and Personalized model of Blood Brain Barrier to investigate leukocytes infiltration in Multiple Sclerosis

Margherita Maria Ravanelli^1,2, Giuseppe Liberatore², Claudia Cutellè², Francesca Calcaterra², Silvia Della Bella², Domenico Mavilio², Eduardo Nobile Orazio², Michela Matteoli^1,2,3, Eliana Lauranzano²

¹Humanitas University, Lab of Pharmacology and Brain Pathology, Rozzano (Milan), Italy, ²IRCCS Humanitas Clinical and Research Center, Rozzano (Milan), Italy, ³CNR Institute of Neurosciences, Milan, Italy

Introduction: The blood-brain barrier (BBB) is a highly specialized barrier composed of cerebral endothelial cells (ECs) surrounded by pericytes and astrocytic endfeet forming the neurovascular unit (NVU). Progressive BBB breakdown and infiltration of autoreactive leukocytes into the CNS are central features in the pathogenesis of neuroinflammatory diseases such as Multiple Sclerosis (MS).

Objectives/Aims: We aim at developing up a humanized NVU in vitro model for addressing MS pathogenic molecular mechanisms and to characterize the phenotype of specific T cells subsets transmigrating the BBB in MS patients and healthy controls (HCs).

Methods: Our model consists of a contact co-culture of primary ECs and human astrocytes. Specifically, as a source of ECs, circulating endothelial colony forming cells (ECFCs) are isolated from the peripheral blood of MS patients and HCs. Autologous lymphocytes are used to perform patient-specific transmigration studies across the BBB model.

Results: ECFCs’ phenotype was characterized by multi-colour flow cytometry, confirming the expression of typical endothelial epitopes: CD31, CD146, CD144, CD105, CD106, CD54, CD34, CXCR4 and GLUT1. Confocal microscopy confirmed ECFCs’ endothelial markers expression. ECFCs isolated from MS patients, expanded and cultured in vitro under pro-inflammatory conditions upregulate the expression of endothelial activation markers and adhesion molecules. Leukocytes transmigration across different NVU prototypes evidenced a significantly greater transmigration CD4+ T isolated from MS patients compared to HCs. Moreover, preliminary results highlighted the prevalent polarization of transmigrating CD4+ T cells toward a Th1, Th1* and Th17 phenotype in MS patients.

Conclusion: Our personalized NVU model demonstrated to be an interesting new tool to investigate the signature of T cells transmigrating the BBB in MS patients.

Disclosure of interest: FUNDING:

- Italian Multiple Sclerosis Foundation (FISM grant 2019/R-Single/032),

- Italian Ministry of Health (Ricerca Finalizzata, Young Researchers grant GR-2019-12370776 and GR-2018-12367117).

No potential competing interest was reported by the authors.

P514/332

Gender differences in an animal model of progressive Multiple Sclerosis with and without Vitamin D supplementation

Michaela Tanja Haindl¹, Muammer Üçal², Marta Nowakowska², Willibald Wonisch³, Christian Enzinger¹, Sonja Hochmeister¹

¹Medical University of Graz, Department of Neurology, Graz, Austria, ²Medical University of Graz, Department of Neurosurgery, Graz, Austria, ³Otto Loewi Research Center, Department of Physiological Medicine, Medical University of Graz, Graz, Austria

Introduction: Although Multiple Sclerosis (MS) is more prevalent among females, many male patients experience increased disease severity and progression. The basis for gender differences in MS is most likely a multifactorial contribution of immune bias and environment, e.g. vitamin D (VD)-levels and -responsiveness. While VD supplementation seems to be associated with a reduced risk for developing MS and reduced clinical activity, little is known about its effect on the progressive MS (PMS) phase.

Objectives/Aims: We investigated the effects of VD and the differences between male and female rats using our own developed model for PMS research (Üçal et al 2017).

Methods: All animals had ad libitum access to standard rodent food; VD+ animals received 400 IU VD per week from the weaning on. The brains were harvested on day (d) 15 and d30 after cytokine injection, and on d15 after a second cytokine injection on d30 (second disease phase = d45). Myelin preservation and microglial activation were assessed via immunohistochemistry of proteolipid protein (PLP) and Ionized calcium binding adaptor molecule 1 (Iba1), respectively. Total antioxidative capacity (TAC) was determined via colorimetric method in serum samples harvested at d1 and d3, as well as before sacrifice.

Results: The gender difference was most pronounced on d15 with a PLP loss of only 0.8 IQR 0.15 mm² in females, in comparison to males with a PLP loss of 1.7 IQR 0.77 mm² (p<0.004). Additionally, we observed a significantly higher TAC in females at d1 (p<0.05), d15 (p<0.028) and d30 (p<0.021). VD+ females exhibited a significant preservation of myelin at d15 compared with the untreated controls (p<0.030). VD+ males showed not only a more robust difference in PLP positivity at d15 (p<0.004), but also lower microglial activity at d30 (p<0.008) compared to the gender matched controls. Myelin preservation upon VD supplementation in males was further substantiated at d45 (p<0.009).

Conclusion: Female animals are more susceptible to experimental autoimmune encephalomyelitis, a common animal model for the relapsing remitting MS. Here we report for the first time, that male rats of our PMS model are more affected, which successfully recapitulates gender differences reported in human PMS. Interestingly, males seem to benefit more from VD supplementation, possibly in association with enhancing the comparably lower TAC at the baseline. We conclude that regular VD supplementation starting at juvenile phase could attenuate cortical damage in males possibly mediated by its antioxidant effects.

Disclosure of interest: Michaela Tanja Haindl: nothing to disclose

Muammer Üçal: nothing to disclose

Marta Nowakowska: nothing to disclose

Willibald Wonisch: nothing to disclose

Christian Enzinger: nothing to disclose

Sonja Hochmeister: nothing to disclose

This study was partially funded by Fresenius-Kabi (to Hochmeister S.).

P515/1149

B cell depletion by Ofatumumab exhibits central nervous system compartment specific effects, prevents the evolution of neurotoxic microglia and protects the visual system during experimental autoimmune encephalitis

Rebecca Wicklein¹, Christopher Sie², Daniel Anthony³, Bernhard Hemmer^1,4, Thomas Korn^1,2, Benjamin Knier¹

¹Klinikum rechts der Isar, TUM school of medicine, Technical University of Munich, Department of Neurology, Munich, Germany, ²Klinikum rechts der Isar, TUM school of medicine, Technical University of Munich, Institute for Experimental Neuroimmunology, Munich, Germany, ³University of Oxford, Department of Pharmacology, Oxford, United Kingdom, ⁴Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

Introduction: In patients suffering from multiple sclerosis, antibody-mediated depletion of B cells significantly reduces inflammatory disease activity, whereas its effect on neurodegeneration and disability progression is limited. In the current concept of multiple sclerosis pathophysiology, compartmentalized inflammation mainly driven by activated microglia is considered as one pathophysiological hallmark of disability progression.

Objectives/Aims: To assess the impact of Ofatumumab, a fully humanized type II anti-CD20 antibody, on neuroinflammation and neurodegeneration within different compartments of the central nervous system.

Methods: We induced experimental autoimmune encephalomyelitis (EAE) in human CD20 transgenic (huCD20tg) mice after immunization with myelin oligodendrocyte protein (MOG1-125). B cell depletion was initiated at EAE disease onset by subcutaneous application of Ofatumumab every 7 days. We assessed neuroinflammation and neurodegeneration in the brain, spinal cord, optic nerve and cerebrospinal fluid in mice at peak disease and recovery. Moreover, mice underwent longitudinal retinal optical coherence tomography (OCT) and OCT angiography (OCTA).

Results: After immunization with MOG1-125 protein, B cells were found most frequently within CSF, optic nerve and brain, but were barely detectable within the spinal cord as measured by flow cytometry. Ofatumumab treatment reduced B cell frequencies in the brain and optic nerve. Compared to the neurotoxic and activated microglial phenotype in control mice, B cell depleted mice exhibited greater portions of homeostatic and resting microglia. The phenotype of spinal cord microglia was unaffected by B cell depletion. Ofatumumab treatment ameliorated the EAE disease course and reduced EAE-associated mortality. OCT measurements revealed that inner retinal layer atrophy was reduced in the Ofatumumab treated cohort.

Conclusion: Ofatumumab may exhibit CNS compartment-specific therapeutical effects and may alter the phenotype of microglia during EAE. Examination of the visual system by OCT and OCTA may afford an opportunity to monitor the efficacy of B cell depleting therapy.

Disclosure of interest: This study was funded by Novartis Deutschland GmbH. Rebecca Wicklein received a poster grant from Novartis and an intramural research grant from the Technical University of Munich, School of Medicine and was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 - SyNergy ID 390857198). Christopher Sie hast nothing to disclose. Daniel C. Anthony has received research support from Novartis. Bernhard Hemmer has served on scientific advisory boards for Novartis; he has served as DMSC member for AllergyCare, Sandoz, Polpharma, Biocon and TG therapeutics; his institution received research grants from Roche for multiple sclerosis research. He has received honoraria for counseling (Gerson Lehrmann Group). He holds part of two patents; one for the detection of antibodies against KIR4.1 in a subpopulation of patients with multiple sclerosis and one for genetic determinants of neutralizing antibodies to interferon. All conflicts are not relevant to the topic of the study. He is associated with DIFUTURE (Data Integration for Future Medicine) [BMBF 01ZZ1804[A-I]]. Bernhard Hemmer received funding for the study by the European Union’s Horizon 2020 Research and Innovation Program [grant MultipleMS, EU RIA 733161] and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology [EXC 2145 SyNergy – ID 390857198]. Thomas Korn has nothing to disclose. Benjamin Knier received travel support and speaking honoraria from Novartis and Teva. He was funded by the Else Kröner Fresenius-Stiftung (Else Kröner Fresenius Exzellenzstipendium 2019_EKES.09), the Gemeinnützige Hertie Foundation (medMS program) and received a research award from Novartis.

P516/1552

Circulating monocytes implicate a demyelination at early stage of lesion on NMO-like mouse model

Moonhang Kim¹, Sung Min Kim²

¹Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea, ²Seoul National University Hospital, Department of Neurology, Seoul, South Korea

Introduction: Neuromyelitis optica (NMO) is an autoimmune inflammatory disease affected in the spinal cord and optic nerves of CNS and is basically seropositive for IgG against astrocyte aquaporin 4 (NMO-IgG). Microglia/macrophages are accumulated at the active injury site and play a role in the disease process. However, the detailed function of microglia/macrophage have not been studied on NMO. Therefore, in this study, we analyzed the functions of microglia/macrophage on the NMO-like mouse model by using homeostatic microglia-specific markers (P2ry12).

Objectives/Aims: We aimed to distinguish between monocytes and microglia using a microglia-specific marker and evaluate their functions.

Methods: NMO-like mouse model was made by intrastriatal injection of 3 ㎕ of isolated patient NMO-IgG (50mg/ml) with 5% of human complement. Mice were divided into 3 groups, normal, control-IgG and NMO-IgG for histological analysis, gene expression, FACS analysis and rotarod test, and sacrificed at 1 day, 3 days and 1 week after injection. To evaluate the function of macrophage, we depleted monocyte/macrophages by clodronate, and analyzed pro-inflammatory factors and demyelination by LFB stain. CD11b+P2ry12-Ly6G-Ly6C^high monocytes were sorted from blood and brain of normal and NMO mice, respectively, and analyzed by RNAseq.

Results: NMO groups showed lower latency to fall than other groups on the rotarod test at 1 day. The pro-inflammatory cytokine, TNFα and IL-1β was increased at 1 day. And, infiltration of CD11b+CD45high monocyte/macrophage was observed. RNAseq results showed that the infiltrating monocytes immediately differentiated into inflammatory macrophages, and treatment with clodronate reduced TNFa, IL1b expression, and demyelination, indicating their contribution to inflammation and demyelination. However, clodronate treatment did not affect the polarization and function of microglia, and the inflammatory function was performed at a high level regardless of the presence of monocytes.

Conclusion: In this study, we distinguished monocytes and microglia and analyze their functions using the microglia-specific marker, P2ry12. The results showed that the infiltrating monocytes played an important role in demyelination in the early stages of injury.

Disclosure of interest: Moonhang Kim: nothing to disclose

P517/1990

Major Histocompatibility Complex class II and co-stimulatory molecule analysis following adminitration of microbial antigens in Experimental Autoimmune Encephalomyelitis

Marina Boziki¹, Ilias Salamotas¹, Anastasia Chatziefstratiadou¹, Εleni Κarafoulidou¹, Paschalis Theotokis¹, Evangelia Kesidou¹, Olga Touloumi¹, Spandou Evangelia², Constantina Simeonidou², Nikolaos Grigoriadis¹

¹Aristotle University of Thessaloniki, 2nd Neurological University Department, Laboratory of Experimental Neurology and Neuroimmunology, Thessaloniki, Greece, ²Aristotle University of Thessaloniki, Laboratory of Experimental Physiology, School of Medicine, Thessaloniki, Greece

Introduction: Recently, the potential role of environmental factors in Multiple Sclerosis (MS) pathogenesis and triggering has been elucidated.

Objectives/Aims: The present study aims to explore the effect of microbial antigen administration in the expression pattern of Major Histocompatibility Complex class II (MHC-II) and of co-stimulatory molecules in the innate immune system in the Central nervous System (CNS) and in the periphery, in Experimental Autoimmune Encephalomyelitis (EAE).

Methods: Helicobacter Pylori (HP) Sydney Strain 1 (SS1) or escherichia coli (e.coli) sonicate in PBS, or PBS vehicle alone was intra-peritoneally administered to 6-8 week C57bl/6 mice in three weekly intervals, prior to the induction of MOG(35-55) EAE. CNS and peripheral lymphoid organs’ tissues were harvested for RT-PCR expression analysis, immunohistochemistry and fluorescent microscopy.

Results: A significant decrease in MHCII+TMEM119+ microglia was observed in both the e.coli- and HP-treated group, compared to the PBS (PBS: 42.67±3.12, e.coli: 28.36±2.53, HP: 15.88±2.77, p<0.001). Similar findings were observed in the number of Ly6C+MHCII+ infiltrating macrophages (PBS:78.46±4.47, e.coli: 42.13±5.37, HP: 13.23±1.89, p<0.001). In secondary lymphoid organs like the spleen, MHCII+F/480+ macrophages and MHCII+CD45R+ B cells were quantified, yielding a similar decrease, following pre-treatment with antigens from HP (PBS: 64.99±6.046, e.coli: 55.71±10.02, HP: 31.83±5.116, p<0.001 for macrophages; PBS: 1717±172.7, e.coli: 739.3±67.43, HP: 1106±125, p<0.001). Gene expression analysis for CD80, CD86 co-stimulatory molecules was performed in the CNS, spleen and intestine and normalized to β-actin and the PBS control group (times-x). In the brain, relative expression was significantly lower in the groups that received antigens from e.coli and HP (CD80-HP: times-0.08, CD86-HP: times-0.2, CD80- e.coli: times-0.25, CD86- e.coli: times-0.38). Interestingly, co-stimulatory molecules in the intestine were significantly upregulated after treatment with HP antigens (CD80-HP: times-6.34, CD86-HP: times-17.16) but not with e.coli antigens (CD80- e.coli: times-1.61, CD86- e.coli: times-0.53).

Conclusion: In this experimental setting, systemic administration of microbial antigens has been proven protective for EAE. Our results point towards a microbial antigen-specific protective effect that may be the result of modulation in antigen presentation.

Disclosure of interest: Boziki M.: Travel support and/or research grants and/or lecture fees and/or advisory services from The Hellenic Foundation for Research and Innovation (H.F.R.I.), the Ministry of Education’s Education and Lifelong Learning Program, the Hellenic Neurological Society, the Hellenic Academy of Neuroimmunology, Biogen Idec, Novartis, TEVA, Bayer, Genesis Pharma, Sanofi, Specifar, Roche and Merck.

Salamotas I.: nothing to disclose

Chatzieustratiadou A.: nothing to disclose

Karafoulidou E.: nothing to disclose

Theotokis P.: nothing to disclose

Kesidou E.: nothing to disclose

Touloumi O.: nothing to disclose

Spandou E.: nothing to disclose

Simeonidou K.: nothing to disclose

Grigoriadis N. : Travel support and/or research grants and/or lecture fees and/or advisory services from European Social Fund-ESF, Novartis, Bayer, Merck, Genesis, Sanofi, Specifar, Roche, Biogen, TEVA, Mylan.

P518/2211

Spatial transcriptomics of meningeal and spinal cord tissue identifies local associations between complement activation, neuroinflammation, tissue damage and disease progression in a progressive model of multiple sclerosis

Steven Pike^1,2,3, Nora Welsh^1,2, Michael Linzey^1,2, Lucas Salas^1,3, Francesca Gilli^1,2

¹Dartmouth College, Integrative Neuroscience, Hanover, United States, ²Dartmouth Hitchcock Medical Center, Neurology, Lebanon, United States, ³Dartmouth College, Epidemiology, Hanover, United States

Introduction: Although intrathecal production of immunoglobulins is a hallmark of multiple sclerosis (MS), it is still unclear how these molecules engage in MS pathogenesis. One potential mechanism is complement-dependent cytotoxicity (CDC) via the classical pathway in which antigen-bound antibodies complex with C1q to facilitate cellular toxicity and promote inflammation. Previous data from our laboratory has shown that in models of relapsing MS, i.e., PLP-induced experimental autoimmune encephalomyelitis (EAE), mice with worse clinical outcomes had a reduced activation of CDC in the spinal cord. Opposingly, in a model of progressive MS, i.e., Theiler’s murine encephalomyelitis virus-induced demyelinating disease, TMEV-IDD, we found that mice with worse clinical outcomes had increased activation of CDC.

Objectives/Aims: To identify how CDC correlates with clinical outcomes in a MOG-induced monophasic, sustained form of EAE.

Methods: Three female C57BL/6 mice were immunized with MOG_35-55 and monitored daily for clinical disability. Mice were sacrificed 37 days post-immunization and the spinal columns were removed for decalcification. The tissue was fixed, sectioned, hematoxylin and eosin stained, imaged, and prepared for spatial transcriptomics (ST) analysis (Visium, 10X Genomcis).

Results: Using ST, we captured a near transcriptome-wide assessment of gene expression, allowing us to correlate expression of key transcripts within regions of white matter, grey matter, or meninges. The ST data supports the presence of immune infiltration and gliosis near regions of complement expression. Evidence for CDC was observed in the white matter of all EAE mice. However, we found there was more CDC in the spinal cord of a mouse at a lower clinical score, compared to the other rodents. Histopathological validation of adjacent tissue sections is currently underway to validate the ST data. Together, the relationship between complement expression and clinical outcomes in chronic MOG-EAE follows what we observed in relapsing PLP-EAE.

Conclusion: Our results suggest that chronic EAE may better resemble a post-acute MS condition rather than a progressive model of MS. More work needs to be done to elucidate the protective and deleterious role of CDC across models of MS and why this relationship varies across models.

Disclosure of interest: None of the authors have anything to disclose

P519/366

A single cell multi-omics map of cell type specific mechanistic drivers of multiple sclerosis lesions

Maria Louise Elkjaer^1,2,3, Anne Hartebrodt⁴, Mhaned Oubounyt⁵, Anna Weber³, Lars Vitved³, Richard Reynolds⁶, Mads Thomassen¹, Richard Röttger⁷, Jan Baumbach^5,7, Zsolt Laszlo Illes^1,2,3

¹University of Southern Denmark, Department of Clinical Research, Odense C, Denmark, ²Odense University Hospital, Department of Neurology, Odense, Denmark, ³University of Southern Denmark, Institute for Molecular Medicine, Odense C, Denmark, ⁴Friedrich-Alexander-Universität Erlangen-Nürnberg, Biomedical Network Science Lab, Department Artificial Intelligence in Biomedical Engineering, Erlangen, Germany, ⁵University of Hamburg, Institute for Computational Systems Biology, Hamburg, Germany, ⁶Imperial College, London, Department of Brain Sciences, London, United Kingdom, ⁷University of Southern Denmark, Department of Mathematics and Computer Science, Odense C, Denmark

Introduction: Despite progress in understanding mechanisms of progressive MS pathogenesis, the drivers of sustained brain inflammation remain elusive.

Objectives/Aims: This study aimed to gain insight into the interplay between molecular mechanisms in progressive MS (PMS) at lesion sites. To achieve this, we integrated cell specific transcriptional signatures, regulatory cell programs, and the location of these cellular molecules in brain white matter (WM) lesions

Methods: We examined the cellular transcriptomes (snRNA-seq), epigenomes (snATAC-seq), and high-resolution capture of spatial context (spatial transcriptomics) of 16 microdissected WM lesion types from post-mortem PMS and control brains. We integrated MS-specific chromatin accessible regions, modulation of transcription factor footprints, and cell type-specific co-expression gene networks and interactions. We validated the enriched functional gene modules in bulk transcriptome from 73 MS WM tissues compared to 25 WM controls.

Results: The PMS-specific oligodendrocyte genetic program was governed by the KLF/SP gene family involved in myelination and stress-induced iron uptake. The transferrin gene (TF) and its receptor LRP2 were highly expressed across all lesion types in oligodendrocytes and were co-localized at the outer border of the chronic active lesion suggesting autocrine communication of iron uptake. The genomic accessibility of the structural protein (VIM) and the cystine/glutamate antiporter (SLC7A11) were significantly reduced, and the genes were downregulated in MS oligodendrocytes. We identified oligodendrocytes expressing genes of the osteopontin and complement factors at the outer edge of the chronic active lesion. We describe a metabolic astrocyte phenotype at the lesion border and an astrocytic-neuronal axis through FGF signalling (FGFR3-FGF13) inside the chronic active lesion. Finally, we identified two distinct B cell co-expression networks with different location and gene expression that prefer different lesion types.

Conclusion: Using single-cell multi-omics, we gained insight into cell type specific patterns with distinctive molecular signatures, pathways, interactions, and locations that can contribute to lesion fate in PMS.

Disclosure of interest: MLE is grateful for financial support from Lundbeckfonden (no. R347-2020-2454). ZI is grateful for financial support from Independent Research Fund Denmark (DFF 9039-00370B), Lundbeckfonden (R118-A11472), Scleroseforeningen (A25341, A29926, A31829, A33600), University of Southern Denmark (14/24200), Odense University Hospital (5798002573633). JB was partially funded by the European Union under grant agreement No. 101057619 (REPO4EU) and the NetMap project funded by the German Federal Ministry of Education and Research (BMBF) under grant number 031L0309B. MO work was funded by the German Science Foundation (DFG) via the Collaborative Research Center (SFB924) and the NetMap project funded by the German Federal Ministry of Education and Research (BMBF) under grant number 031L0309B. Other authors have nothing to disclose.

P520/677

Unravelling the Genetic Architecture of Time to Conversion to Multiple Sclerosis progression in Swedish Cohorts

Soumeen Jin^1,1, Klementy Shchetynsky¹, Adil Harroud², Lars Alfredsson¹, Tomas Olsson¹, Fredrik Piehl¹, Jan Hillert¹, Ali Manouchehrinia³, Pernilla Stridh¹, Ingrid Kockum¹

¹Karolinska Institute, Stockholm, Sweden, ²McGill University Health Centre and RI-MUHC, Montreal, Canada, ³The University of British Columbia, Vancouver, Canada

Introduction: Multiple sclerosis (MS) is a debilitating neurological disease affecting the central nervous system. It is characterised by inflammation, demyelination, and axonal damage, leading to various motor, sensory, and cognitive impairments. Different manifestations of disability progression are known in MS patients. Although genetic susceptibility of MS has been extensively studied, little is known about the genetic influence of rate of conversion to progressive disease.

Objectives/Aims: The aim of this study is to uncover the genetic architecture underlying the timing of conversion to the progressive stage of the disease.

Methods: People with MS were included from three Swedish nationwide cohorts: GEMS (Genes and Environment in Multiple Sclerosis), EIMS (Epidemiological Investigation of Multiple Sclerosis), and IMSE (Immunomodulation and Multiple Sclerosis Epidemiology Study) and one clinical-based local study cohort: STOP-MS. Genotyping was performed by deCODE Iceland using the Human OmniExpress (N=6,589) and the Global Screening (N=3,594) Arrays and the imputation was performed on the Haplotype Reference Consortium panel (release 1.1) using Minimac4 (v1.0.2).

We conducted preliminary genome-wide association studies (GWAS) of conversion to MS progression, with p=5*10^-8 set as a significance threshold, adjusted for sex, population structure and genotyping arrays, and later meta-analysed the GWAS results.

Results: Our preliminary analysis suggests a locus associated with the time of conversion to progressive MS. Although the genetic architecture is emerging, further analysis is required to refine the model and confirm our results in additional cohorts through collaboration within the MultipleMS consortia.

Conclusion: This study suggests that genetic variants contribute to the time required to advance the disease to the progressive phase of MS. Further investigation is currently in process to validate these findings and explore their potential clinical implication.

Disclosure of interest: Dr Hillert has no conflicts of interest. He received honoraria for serving on advisory boards for Biogen, Bristol-Myers-Squibb, Janssen, Merck KGaA, Novartis, Sandoz and Sanofi-Genzyme and speaker’s fees from Biogen, Janssen, Novartis, Merck, Teva, Sandoz and Sanofi-Genzyme. He has served as P.I. for projects sponsored by, or received unrestricted research support from,

Biogen, Bristol-Myers-Squibb, Janssen, Merck KGaA, Novartis, Roche, and Sanofi-Genzyme. His MS research is funded by the Swedish Research Council and the Swedish Brain foundation.

AM has no conflicts of interest. received funding from Margaretha af Ugglas Foundation

PS has no conflicts of interest and has funding from Margaretha af Ugglas Foundation, EU Horizon2020 MultipleMS, and NEURO Sweden.

LA has no conflicts of interest and has received honoraria for lectures from Biogen and Merck.

TO has no conflicts of interest and has received honoraria for lectures/advisory boards and unrestricted MS research grants from Biogen, Novartis, Merck and Sanofi.

FP has no conflicts of interest and has received research grants from Janssen, Merck KGaA and UCB, and fees for serving on DMC in clinical trials with Chugai, Lundbeck and Roche, and preparation of expert witness statement for Novartis.

Ingrid Kockum has no conflict of interest and has collaborative research agreement with Neurogene INC and has received lecture honoraria from Merck.

AH: nothing to disclose

KS: nothing to disclose

P521/334

genetic influences on disease course and severity, 30 years after a clinically isolated syndrome

Nitin Sahi¹, lukas haider^1,2, karen chung¹, Ferran Prados^1,3,4, Baris Kanber^1,3, Rebecca Samson¹, Alan Thompson¹, claudia wheeler-kingshott^1,5,6, anand trip¹, Wallace Brownlee¹, Olga Ciccarelli^1,7, Frederik Barkhof^1,3,7,8, Carmen Tur^1,9, Henry Houlden¹⁰, Declan Chard^1,7

¹UCL Queen Square Institute of Neurology, Queen Square MS Centre, London, United Kingdom, ²Medical University Vienna, Department of Biomedical Imaging and Image Guided Therapy, Vienna, Austria, ³UCL Centre for Medical Image Computing (CMIC), Department of Medical Physics and Biomedical Engineering, London, United Kingdom, ⁴Universitat Oberta de Catalunya, Barcelona, Spain, ⁵University of Pavia, Department of Brain and Behavioural Sciences, Pavia, Italy, ⁶IRCCS Mondino Foundation, Brain MRI 3T Research Centre, Pavia, Italy, ⁷National Institute for Health and Care Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre, London, United Kingdom, ⁸VU University Medical Centre, Department of Radiology and Nuclear Medicine, Amsterdam, Netherlands, ⁹Vall d'Hebron Institute of Research, MS Centre of Catalonia (Cemcat), Barcelona, Spain, ¹⁰UCL Queen Square Institute of Neurology, Department of Neuromuscular Diseases, London, United Kingdom

Introduction: Genetic contribution to multiple sclerosis (MS) severity remains unclear.

Objectives/Aims: To explore genetic influences on long-term disease course and severity, 30 years after a clinically isolated syndrome (CIS).

Methods: Sixty-one CIS patients underwent multiple clinical and MRI assessments over 30 years; 29 developed relapsing-remitting MS, 15 developed secondary progressive MS (SPMS) and 17 still had CIS. Twenty-seven genes were investigated for associations with clinical outcomes (including MS course and Expanded Disability Status Scale [EDSS]) and brain MRI (including white matter (WM) lesions, cortical lesions, and brain tissue volumes) at the 30-year follow-up. Genetic associations with changes in EDSS, relapses, WM lesions and brain atrophy (third ventricular and medullary measurements) over 30 years were assessed using mixed-effects models.

Results: HLA-DRB1*1501-positive (n=26) patients showed faster WM lesion accrual (+1.96 lesions/year [0.64-3.29], p=3.8x10^-3), greater 30-year WM lesion volumes (+11.60ml, [5.49-18.29], p=1.27x10^-3) and higher annualised relapse rates (+0.06 relapses/year [0.005-0.11], p=0.031) compared with HLA-DRB1*1501-negative patients (n=35). PVRL2-positive patients (n=41) had more cortical lesions (+0.83 [0.08-1.66], p=0.042), faster EDSS worsening (+0.06 points/year [0.02-0.11], p=0.010), greater 30-year EDSS (+1.72 [0.49-2.93], p=0.013; MS-only subgroup: +2.60 [1.30-3.87], p=2.02x10^-3), and greater risk of SPMS (OR=12.25 [1.15-23.10], p=0.031) than PVRL2-negative patients (n=18). In contrast, IRX1-positive (n=30) patients had preserved 30-year grey matter fraction (+0.76% [0.28-1.29], p=8.4x10^-3), lower risk of cortical lesions (OR=0.22 [0.05-0.99] p=0.049) and lower 30-year EDSS (-1.35 [-0.87,-3.44], p=0.026; MS-only subgroup: -2.12 [-0.87,-3.44], p=5.02x10^-3) than IRX1-negative patients (n=30). In MS cases, IRX1-positive patients also showed slower EDSS worsening (-0.07 points/year [-0.01,-0.13], p=0.015) and lower risk of SPMS (OR=0.19 [0.04-0.92], p=0.042).

Conclusion: These exploratory findings support diverse genetic influences on pathological mechanisms associated with MS disease course. HLA-DRB1*1501 influenced WM inflammation and relapses, while IRX1 (protective) and PVRL2 (adverse) were associated with grey matter pathology (cortical lesions and atrophy), long-term disability worsening and the risk of developing SPMS.

Disclosure of interest: N.S. has been a clinical research fellow in a post supported by Merck (supervised by S.A.T. and D.C.) and subsequently by MRC (MR/W019906/1).

K.C has received honoraria for participation and attendance of educational events from Novartis, Roche, Biogen and Merck; she has received honoraria for consultancy work from Novartis, Roche, Biogen, Merck and Viatris.

F.P received a Guarantors of Brain fellowship 2017-2020.

FP and BK are supported by the National Institute for Health Research (NIHR), Biomedical Research Centre initiative at University College London Hospitals (UCLH).

A.J.T. reports personal fees paid to his institution from Eisai Ltd; is an editorial board member for The Lancet Neurology receiving a free subscription; is Editor-in-Chief for Multiple Sclerosis Journal receiving an honorarium from SAGE Publications; receives support for travel as member, Clinical Trials Committee, International Progressive MS Alliance, and from the National MS Society (USA) as member, NMSS Research Programs Advisory Committee.

S.A.T. receives support from the UCLH Biomedical Research Centre; has received honoraria from Roche, Merck, Novartis, Sanofi-Genzyme and Biogen in the last 3 years and co-supervises a clinical fellowship at the National Hospital for Neurology and Neurosurgery, London, which is supported by Merck. W.J.B has received speaker honoraria for educational activities and/or acted as a consultant for Biogen, Janssen, Merck, Novartis, Roche, Sanofi-Genzyme and Viatris.

O.C. is a member of independent DSMB for Novartis, gave a teaching talk on McDonald criteria in a Merck local symposium, and contributed to an Advisory Board for Biogen; she is Deputy Editor of Neurology, for which she receives an honorarium.

C.T. is currently being funded by a Junior Leader La Caixa Fellowship (The project that gave rise to these results received the support of a fellowship from “la Caixa” Foundation (ID 100010434); fellowship code is LCF/BQ/PI20/117600080; She has also received the 2021 Merck’s Award for the Investigation in Multiple Sclerosis (Spain) and a grant from Instituto de Salud Carlos III (ISCIII), Spain (grant ID: PI21/01860); In 2015, she received an ECTRIMS Post-doctoral Research Fellowship and has received funding from the UK Multiple Sclerosis Society (grant number 77); She has also received speaker honoraria from Roche and Novartis; She serves on the Editorial Board of Neurology and Multiple Sclerosis Journal.

F.B. is supported by the UCLH biomedical research centre; He is a steering committee or iDMC member for Biogen, Merck, Roche, EISAI and Prothena; He is a consultant for Roche, Biogen, Merck, IXICO, Jansen, Combinostics; He has research agreements with Merck, Biogen, GE Healthcare, Roche; He is co-founder and shareholder of Queen Square Analytics LTD.

D.C. is a consultant for Hoffmann-La Roche; In the last three years he has been a consultant for Biogen, received research funding from Hoffmann-La Roche, the International Progressive Multiple Sclerosis Alliance, the Multiple Sclerosis Society, and the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre, and speaker’s honorarium from Novartis; He co-supervises a clinical fellowship at the National Hospital for Neurology and Neurosurgery, London, which is supported by Merck.

The remaining authors, L.H., R.S., C.A.M.G.WK. and H.H: nothing to disclose.

P522/1803

Circular RNA expression quantitative trait loci in multiple sclerosis revealed a new genetic variant located in chromosome 17 that is associated with multiple sclerosis and alters the expression of circular RNA hsa_circ_0106983

Saioa GS Iñiguez¹, Leire Iparraguirre^1,2, Eduardo Andrés-León³, Hirune Crespillo¹, Leire Romarate¹, Tamara Castillo Triviño^1,2,4, Elena Urcelay⁵, Manuel Comabella^6,7,8, Sunny Malhotra^6,7,8, Xavier Montalban^6,7,8, Lluis Ramio i Torrenta⁹, Ana Quiroga-Varela⁹, Koen Vandenbroeck¹⁰, Ane Aldekoa¹⁰, David Otaegui^1,2, Fuencisla Matesanz³, Maider Muñoz-Culla^1,2,11

¹Biodonostia Health Research Institute (HRI), Neuroscience Area, Multiple Sclerosis Group, Donostia-San Sebastian, Spain, ²Centro de Investigación Biomédica en Red (CIBERNED), Instituto de salud Carlos III (ISCIII)), Madrid, Spain, ³Parasitology and Biomedicine López Neyra Institute-CSIC, Granada, Spain, ⁴Donostia University hospital, OSI Donostialdea, Neurological Service, Donostia-San Sebastian, Spain, ⁵Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Laboratorio de Investigación en Genética de Enfermedades Complejas, Madrid, Spain, ⁶Centre d'Esclerosi Mútiple de Catalunya (Cemcat), Hospital Universitari Vall d'Hebron, Clinical-Neuroimmunology, Barcelona, Spain, ⁷Institut de Recerca, Hospital Universitari Vall d'Hebron (VHIR), Barcelona, Spain, ⁸Universitat Autónoma de Barcelona (UAB), Barcelona, Spain, ⁹Institut d’Investigació Biomèdica de Girona Dr.Josep Trueta (IDIBGI), Girona, Spain, ¹⁰Biocruces-Bizkaia Health Research Institute (HRI), Inflammation & Biomarkers Group, Barakaldo, Spain, ¹¹University of the Basque Country (EHU/UPV), Basic Psychological Processes and Their Development, Donostia-San Sebastian, Spain

Introduction: The dysregulation of the immune system has been shown to correlate with gene-expression changes. Among non-coding RNAs, circular RNAs (circRNAs) have emerged in recent years as a major player in the transcriptome regulation network.

The differential expression of circRNAs in multiple sclerosis (MS) patients has been previously reported. However, the impact of MS-associated genetic variants on circRNAs expression has not been extensively studied. Despite, these variants are known to influence gene expression.

Objectives/Aims: To study the effect of genetic variants that may regulate the expression levels of circRNAs in leukocytes of MS patients and Healthy controls (HC).

Methods: CircRNAs expression of 30 MS patients and 18 HC were screened by using RNA-Seq in leukocytes. The same samples were genotyped in the National Center of Genotyping in Spain (CEGEN) using the Illumina Infinium Global Screening array.

Circular RNA expression quantitative trait loci (CircQTL) analysis were carried out by correlating genotypes of 4,824,059 imputed variants with the expression levels of 22,308 circRNAs. Due to our cohort size, we established a minor allele frequency (MAF) threshold of >0.1. Best candidate circQTLs were crossed with 200 reported associated MS susceptibility variants.

We validated the potential circQTL candidates in an independent cohort of 68 MS patients and 64 HC. TaqMan genotyping assays were used for genotyping, while RT-qPCR was used to measure hsa_circ_0106983 expression levels.

Finally, to validate the previously reported SNP, we conducted a case-control association study in 2,831 MS patients and 3,191 HC.

Results: First circQTL analysis resulted in 42,077 circQTL candidates (FDR < 0.05); two of them were selected for further validation.

We validated rs7214410–hsa_circ_0106983 circQTL (p=3.99 x 10^-20) and rs11079784–hsa_circ_0106983 circQTL (p=1.34 x 10^-8). We found that rs7214410 SNP, which had not been previously described as a circQTL, has a functional effect on MS susceptibility and is related to hsa_circ_0106983 expression and regulation.

This rs7214410 SNP colocalizes with a MS-associated region, where rs11079784 was previously reported as the lead SNP. In our case-control association study, we found that rs7214410 shows a stronger association with MS (p=0.007) compared to rs11079784 (p=0.048), both with a dominant model.

Conclusion: Our study has identified a novel circQTL related to MS susceptibility and have a functional effect by changing hsa_circ_0106983 expression in leukocytes.

Disclosure of interest: Our source of founding are, Health Department from the Basque Government (2021333048),

Instituto de Salud Carlos III (PI20/01552 y PI20/00327)

Saioa GS Iñiguez: nothing to disclose

Leire Iparraguirre: nothing to disclose

Eduardo Andrés León: nothing to disclose

Hirune Crespillo: nothing to disclose

Leire Romarate: nothing to disclose

Tamara Castillo-Triviño: nothing to disclose

Elena Urcelay : nothing to disclose

Manuel Comabella: nothing to disclose

Sunny Malhotra: nothing to disclose

Xabier Montalban: nothing to disclose

Lluis Ramio i Torrenta: nothing to disclose

Anna Quiroga Varela: nothing to disclose

Koen Vandenbroeck: nothing to disclose

Ane Aldekoa: nothing to disclose

David Otaegui: nothing to disclose

Fuencisla Matesanz: nothing to disclose

Maider Muñoz-Culla: nothing to disclose

P523/228

Smoking affects epigenetic ageing of lunch bronchoalveolar lavage cells in Multiple Sclerosis

Dennis Klose¹, Maria Needhamsen¹, Mikael Ringh¹, Michael Hagemann-Jensen², Maja Jagodic¹, Lara Kular¹

¹Karolinska Institutet, Clinical Neuroscience, Stockholm, Sweden, ²Karolinska Institutet, Medicine, Stockholm, Sweden

Introduction: A compelling body of evidence implicates cigarette smoking and lung inflammation in Multiple Sclerosis (MS) susceptibility and progression. Previous studies have reported epigenetic age acceleration in blood immune cells and in glial cells of people with MS (pwMS) compared to healthy controls (HC).

Objectives/Aims: We aimed to examine biological aging in lung immune cells in the context of MS and smoking.

Methods: We analyzed age acceleration residuals (AARs) in lung bronchoalveolar lavage (BAL) cells from 17 pwMS and 22 HC in relation to smoking using eight DNA methylation- and two RNA-based clocks, which capture different aspects of biological aging.

Results: The pan-tissue (AltumAge, Horvath) and blood-specific (Zhang, SkinBlood, Hannum) clocks outperformed estimations from monocyte-specific and biological age (GrimAge, PhenoAge) clocks, whereas predictions from the RNA-based clocks did not pass quality control. After adjustment for covariates, Horvath, AltumAge and GrimAge clocks yielded significant differences between groups (P_adj < 0.05). Outcomes of the Horvath and GrimAge clocks uncovered the sole general effect of smoking irrespective of clinical groups, which exerted a significant epigenetic age reduction and increase, respectively. AltumAge clock indicated that BAL cells of non-smoking pwMS displayed a significant 5.4-year age acceleration difference compared to HC non-smokers (P_adj = 0.028). Surprisingly, smoking exhibited a negative effect on the AltumAge age acceleration in BAL cells of pwMS (P_adj = 0.0049). The differences between pwMS smokers and non-smokers could be attributed to differential methylation of 114 AltumAge-CpGs (P_adj < 0.05) affecting genes involved in innate immune processes such as cytokine production, defense response and cell motility. These changes functionally translate into transcriptional differences between pwMS smokers and non-smokers.

Conclusion: BAL cells of pwMS display inflammation-related and smoking-dependent changes associated to epigenetic aging.

Disclosure of interest: Lara Kular has received research grant from the Swedish Research Council, the Swedish Brain Foundation, the Swedish MS foundation, the Swedish Association for Persons with Neurological Disabilities, Åke Wiberg Foundation, Bergvals Foundation, Hedlunds Foundation and is supported by a fellowship from the Margaretha af Ugglas Foundation.

Maja Jagodic has received research grant from the Swedish Research Council, the Swedish Brain Foundation, the Stockholm County Council - ALF project, the European Union’s Horizon 2020 research and innovation program, the European Research Council (ERC) and the Knut and Alice Wallenberg Foundation.

Dennis Klose was supported by an Erasmus fellowship.

Maria Needhamsen: nothing to disclose.

Mikael Ringh: nothing to disclose.

Michael Hagemann-Jensen: nothing to disclose.

P524/1469

A preliminary genome-wide association study of MSIS-29 identifies three suggestive loci associated with either the physical or psychological subscales in people with multiple sclerosis

Pernilla Stridh¹, Klementy Shchetynsky¹, Adil Harroud^2,3,4, Ali Manouchehrinia¹, Jan Hillert¹, Lars Alfredsson⁵, Tomas Olsson¹, Fredrik Piehl¹, Ingrid Kockum¹

¹Karolinska Institutet, Center for Molecular Medicine, Department of Clinical Neuroscience, Stockholm, Sweden, ²McGill University, Department of Human Genetics, Montréal, QC, Canada, ³Montreal Neurological Institute-Hospital, The Neuro, Montréal, QC, Canada, ⁴McGill University, Department of Neurology and Neurosurgery, Montréal, QC, Canada, ⁵Karolinska Institutet, Institute of Environmental Medicine, Stockholm, Sweden

Introduction: Multiple sclerosis (MS) is a leading cause of neurological disability among younger adults, however, consequences of disease are multidimensional with differential impact on the daily lives of those affected. The Multiple Sclerosis Impact Scale-29 (MSIS-29) has emerged as a robust patient-reported outcome measure, reflecting how MS affects both physical and psychological functioning. Genome-wide association studies (GWAS) provides a unique tool to elucidate the intricate genetic architecture underlying aspects of disease severity. To our knowledge, no prior GWAS has focused specifically on the genetic determinants of MSIS-29 physical and psychological subscales in a large cohort of People with MS (PwMS).

Objectives/Aims: To conduct a GWAS investigating the genetic architecture of MSIS-29 in a large cohort of PwMS and to search for genetic loci associated with MS impact on physical and psychological sub-domain functioning.

Methods: MS cases were included from four Swedish studies and genotyped on Illumina Human OmniExpress chip (N=3,299) or Global Screening Array (N=3,096). After quality control and imputation, more than 7 million single nucleotide polymorphisms (SNPs) were analyzed. Clinical data including the MSIS-29 subscales was extracted from the Swedish MS Registry. We performed within-case GWAS and meta-analysis to examine the association between genetic variants and MSIS-29 physical and psychological subscale scores.

Results: In the preliminary analysis, we identified two suggestive loci associated with the physical subscale and one suggestive locus for the psychological subscale of MSIS-29, at p<1x10^-5. The genetic loci were distinct to either domain, suggesting that different biological mechanisms contribute to physical and psychological impact of the disease, and distinct from previously identified MS risk variants. We aim to add additional cohorts in the final analysis to assess whether the suggestive loci contribute to the experienced impact of MS.

Conclusion: Our findings provide novel insights into the genetic architecture of the variability in the impact of MS on patients' lives. Further replication and functional studies are warranted to validate our findings and elucidate the underlying biological mechanisms. The MSIS-29 is designed to assess impact on daily functioning and quality of life, and considering the affected persons experience will help us understand mechanisms contributing to disease severity in MS.

Disclosure of interest: PS has received funding from Margaretha af Ugglas Foundation, MS Research Fund, Horizon 2020 MultipleMS grant number 733161, and NEURO Sweden. KS has received funding from Horizon 2020 MultipleMS grant number 733161. AH has received consulting fees from Biogen, unrelated to the present work. AM has received funding from Margaretha af Ugglas Foundation. JH has received honoraria for serving on advisory boards for Biogen, Bristol-Myers-Squibb, Janssen, Merck KGaA, Novartis, Sandoz and Sanofi-Genzyme, speaker’s fees from Biogen, Janssen, Novartis, Merck, Teva, Sandoz and Sanofi-Genzyme, and funding from Swedish Research Council, the Swedish Brain foundation, Biogen, Bristol-Myers-Squibb, Janssen, Merck KGaA, Novartis, Roche, and Sanofi-Genzyme. LA has received honoraria for lectures from Biogen and Merck. TO has received honoraria for lectures/advisory boards and unrestricted MS research grants from Biogen, Novartis, Merck and Sanofi. FP has received research grants from Janssen, Merck KGaA and UCB, and fees for serving on DMC in clinical trials with Chugai, Lundbeck and Roche, and preparation of expert witness statement for Novartis. IK has received funding from Horizon 2020 MultipleMS grant number 733161 and Swedish Research Council.

P525/1508

Exploring genetic clustering of severity markers to identify groups with reduced heterogeneity in multiple sclerosis

Pernilla Stridh¹, Klementy Shchetynsky¹, Adil Harroud^1,2, Thomas Moridi¹, Sinead Moylett³, Albert Pukaj⁴, Federica Esposito⁵, Christiane Gasperi⁴, Narsis Kiani⁶, Hanne Flinstad Harbo⁷, janna saarela⁸, MARTINELLI BONESCHI FILIPPO GIOVANNI⁹, Lars Alfredsson¹, Jan Hillert¹, Tomas Olsson¹, An Goris³, Bernhard Hemmer⁴, Maja Jagodic¹, Chris Cotsapas¹⁰, Ingrid Kockum¹

¹Karolinska Institutet, Center for Molecular Medicine, Department of Clinical Neuroscience, Stockholm, Sweden, ²McGill University, Department of Human Genetics, Montréal, QC, Canada, ³KU Leuven, Leuven Brain Institute, Department of Neurosciences, Leuven, Belgium, ⁴Technical University of Munich, Department of Neurology, School of Medicine, Munich, Germany, ⁵IRCCS San Raffaele Scientific Institute, Neurology Unit and Laboratory of Human Genetics of Neurological Disorders, Milan, Italy, ⁶Karolinska Institutet, Center for Molecular Medicine, Department of Oncology-Pathology, Stockholm, Sweden, ⁷University of Oslo, Institute of Clinical Medicine, Oslo, Norway, ⁸University of Helsinki, Institute for Molecular Medicine Finland, Helsinki Institute for Life Sciences, Helsinki, Finland, ⁹University of Milan, Dino Ferrari Center, Department of Pathophysiology and Transplantation, Milan, Italy, ¹⁰Yale School of Medicine, Departments of Neurology and Genetics, New Haven, CT, United States

Introduction: Multiple sclerosis (MS) is a chronic, immune-mediated neurological disorder characterized by inflammation, demyelination, and axonal degeneration. MS is a complex disease with varying clinical manifestations and rate of disease progression, and is highly heterogeneous with respect to paraclinical findings, clinical outcomes, and response to treatment. The underlying etiology of MS is not yet fully understood, although both genetic and environmental factors contribute to the development and progression of the disease. Making a prognosis of severity and disease acceleration is essentially impossible at the time of diagnosis, leaving affected persons with substantial uncertainty for years. Here, we explore a genetic clustering approach to reduce the heterogeneity in MS.

Objectives/Aims: The aim of this study is to identify groups of MS cases who share sets of genetic, clinical and lifestyle similarities, and test if group characteristics can be used to predict clinical outcomes.

Methods: We explored genetic clustering in MS cases from Sweden, Germany, Norway, Belgium, and Italy who were part of the EU-funded MultipleMS project [EU RIA 733161]. More than 7 million variants were imputed from genotypes based on the Haplotype Reference Consortium. To nominate genetic risk variants for MS severity clustering, we performed rudimentary genome-wide association (GWA) analyses of 13 parameters capturing physical and cognitive disability, central nervous system inflammation, disease progression, and radiological findings. Suggestive risk variants were then used for principal component (PC) analysis, and patients were stratified into risk clusters based on the distribution of pairwise PC values. Clinical outcomes and environmental exposures were compared between the groups of cases.

Results: In total, 855 single nucleotide polymorphisms (SNPs) that survived suggestive p<1x10^-5 cut-off and clumping were selected for PC analysis. Although most MS cases occupied an overlapping PC space, we could separate out small clusters of MS cases with shared genetic loadings and specific medical history characteristics, such as past concussions.

Conclusion: We have explored clustering to identify groups of cases based on genetic markers of severity. The ability to separate out small clusters suggests that this approach can be expanded to reduce heterogeneity in MS and to identify outcome predictors to ultimately increase the ability to offer prognosis.

Disclosure of interest: PS has received funding from Margaretha af Ugglas Foundation, MS Research Fund, EU Horizon 2020 [grant MultipleMS, EU RIA 733161], and NEURO Sweden. KS has received funding from EU Horizon 2020 [grant MultipleMS, EU RIA 733161]. AH has received consulting fees from Biogen, unrelated to the present work. TM: nothing to declare. SM: nothing to declare. AP: nothing to declare. FE: nothing to declare. CG: nothing to declare. NK: nothing to declare. HFH: nothing to declare. JS has received research funding and honoraria from Sanofi-Genzyme. FMB: nothing to declare. LA has received honoraria for lectures from Biogen and Merck. JH has received honoraria for serving on advisory boards for Biogen, Bristol-Myers-Squibb, Janssen, Merck KGaA, Novartis, Sandoz and Sanofi-Genzyme, speaker’s fees from Biogen, Janssen, Novartis, Merck, Teva, Sandoz and Sanofi-Genzyme, and funding from Swedish Research Council, the Swedish Brain foundation, Biogen, Bristol-Myers-Squibb, Janssen, Merck KGaA, Novartis, Roche, and Sanofi-Genzyme. TO has received lecture/ advisory board honoraria and unrestricted MS research grants from Biogen, Novartis, Merck and Sanofi. AG: nothing to declare. BH has served on scientific advisory boards for Novartis; served as DMSC member for AllergyCare, Sandoz, Polpharma, Biocon and TG therapeutics; has received honoraria for counseling (Gerson Lehrmann Group); his institution received research grants from Roche for multiple sclerosis research; he holds part of two patents; one for the detection of antibodies against KIR4.1 in a subpopulation of patients with multiple sclerosis and one for genetic determinants of neutralizing antibodies to interferon; is associated with DIFUTURE (Data Integration for Future Medicine) [BMBF 01ZZ1804[A-I]]; has received funding from EU Horizon 2020 [grant MultipleMS, EU RIA 733161], and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology [EXC 2145 SyNergy – ID 390857198] (all conflicts are not relevant to the topic of the study). MJ: nothing to declare. CC: nothing to declare. IK has received funding from EU Horizon 2020 [grant MultipleMS, EU RIA 733161] and Swedish Research Council, has collaborative research agreement with Neurogene INC, and has received lecture honoraria from Merck.

P526/1784

Meningeal inflammation and disability accumulation: a candidate gene study

Ferdinando Clarelli¹, Silvia Santoro¹, Elisabetta Mascia¹, Kaalindi Misra¹, Laura Ferrè^1,2, Massimo Filippi^2,3,4,5, Federica Esposito^1,2

¹IRCCS San Raffaele Scientific Institute, Institute of Experimental Neurology, Division of Neuroscience, Laboratory of human genetics of neurological disorders, Milan, Italy, ²IRCCS San Raffaele Scientific Institute, Neurology and Neurorehabilitation Unit, Milan, Italy, ³Vita-Salute San Raffaele University, Milan, Italy, ⁴IRCCS San Raffaele Scientific Institute, Division of Neuroscience, Neuroimaging Research Unit, Milan, Italy, ⁵IRCCS San Raffaele Scientific Institute, Neurophysiology Service, Milan, Italy

Introduction: There is abundant evidence that cortical pathology has relevance in all multiple sclerosis (MS) courses. Multiple studies have further demonstrated a high correlation between cortical demyelination, meningeal inflammation and the rate of clinical progression, supporting the hypothesis that the inflammatory milieu generated by meningeal inflammation can be a driver of increased disability.

Objectives/Aims: To conduct a candidate gene study for the investigation of the role of genetic factors, linked to meningeal inflammation, in long-term disability progression.

Methods: Disability accumulation was measured with the Age Related Multiple Sclerosis Severity (ARMSS) score, considering a disease duration of at least 10 years. Findings from two post-mortem transcriptomic studies were leveraged to constitute a panel of candidate genes showing differential expression between patients with high and low grade of meningeal inflammation. Using the ChEA3 tool, we then performed transcription factor (TF) target over-representation analysis, to infer TFs putatively driving the observed change. To enhance power, we assigned SNPs to genes integrating regulatory annotation in brain tissues from four resources, using expression and splicing quantitative loci (eQTL, sQTL), enhancers and super-enhancers. Single variant association analysis was performed fitting linear regression models with normalized ARMSS as outcome, adjusted for suitable covariates and principal components to control population sub-structure. These statistics were then aggregated with MAGMA tool to yield gene-wise statistics.

Results: A cohort of 1686 Italian MS patients with long-term disability assessment was investigated. The panel of candidate genes was composed of 49 genes with expression change in the two studies and additional 20 linked TFs, with 11,711 mapped SNPs. Study-wise significance level was set to alpha=0.05/69=7.23E-03. The two top-associated genes were TFs: the first was NEUROD6 (p=6.13E-04), a basic TF involved in neuronal development, differentiation; the second was STAT3 (p=4.93E-03), a TF already linked to MS which is involved in multiple pathways. Colocalization analysis for NEUROD6 showed a moderate evidence of a shared causal locus between top-associated variant rs7801993 and eQTL signal in cerebellum (posterior probability=0.48).

Conclusion: We identified two genes with putative genetic involvement to meningeal inflammation and long-term disability. Replication of the detected signals is ongoing.

Disclosure of interest: Ferdinando Clarelli, Silvia Santoro, Elisabetta Mascia, Kaalindi Misra, Laura Ferrè: nothing to disclose

Massimo Filippi is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Associate Editor of Radiology, and Associate Editor of Neurological Sciences, received compensation for consulting services from Alexion, Almirall, Biogen, Merck, Novartis, Roche, Sanofi, speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA, participation in Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, Takeda, scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis, Sanofi-Genzyme, he receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA).

Federica Esposito received consulting and speaking fees from Novartis, Sanofi Genzyme

P527/403

SARS-CoV-2 mRNA vaccination affects antibody and cellular immune responses after B-cell depletion therapies

Erin Longbrake¹, Hiromitsu Asashima¹, Dongjoo Kim¹, Elliot Wang¹, Nikhil Lele¹, Nicholas Buitrago¹, Rachel Lutz¹, Isabella Cruz¹, Khadir Radassi¹, William Ruff¹, Michael Racke², Jodell Wilson², Tara Givens², Alba Grifoni³, Daniela Weiskopf³, Steven Kleinstein¹, Alessandro Sette³, Ruth Montgomery¹, Albert Shaw¹, Fangyong Li¹, Rong Fan¹, David Hafler¹, Mary Tomayko¹

¹Yale University, New Haven, United States, ²Quest Diagnostics, Secaucus, United States, ³La Jolla Institute for Immunology, La Jolla, United States

Introduction: B cell depletion therapy with anti-CD20 mAb is highly effective for many autoimmune disorders but increases risk for poor outcomes with SARS-CoV-2 infection. While B cell depletion is associated with markedly attenuated antibody responses to SARS-CoV-2 mRNA vaccination, responses vary among individuals. Thus, elucidating the factors that affect immune responses after repeated vaccination is important.

Objectives/Aims: To evaluate the cellular and humoral response to repeated SARS-CoV2 mRNA vaccination among B-cell depleted patients compared to immunocompetent controls.

Methods: Forty controls and 93 B-cell depleted patients contributed 492 samples at 7 different timepoints spanning 3 mRNA COVID-19 vaccinations, including the first vaccine. Spike and neutralizing antibodies were quantified, and flow cytometry was used to conduct detailed immunophenotyping of SARS-COV2 specific T- and B-cells. Multivariate logistic regression models were built to predict the likelihood of seroconversion.

Results: Approximately 26% of B-cell depleted patients mounted a serologic response to the primary series of mRNA vaccination against SARS-CoV2; this rose to 45% after 3 total vaccines. Multivariate regression models identified prior natural infection and cumulative exposure to anti-CD20 monoclonal antibodies as significant predictors of seroconversion at any time. Longer time since last anti-CD20 treatment and lower cumulative dose of anti-CD20 antibodies were independently associated with greater odds of serologic response to a 3^rd vaccine. Serologic responses to 3 vaccines were sustained for at least 24 weeks. All B-cell depleted patients mounted effective cellular responses to the primary vaccine series, and this response was further amplified by a third vaccination for B-cell depleted patients but not for controls. Interestingly, we observed a trend for a heightened spike-specific CD8+ T-cell response to third vaccination among B-cell depleted patients (p=0.07).

Conclusion: Serial vaccination strategies can be effective for generating a serologic response to mRNA COVID19 vaccinations among a subset of B-cell depleted patients. Natural infection, time from last anti-CD20 monoclonal antibody infusion and cumulative exposure to anti-CD20 monoclonal antibodies were independently associated with the subgroup of participants likely to benefit from repeated vaccination. These results will help to inform policy and generate evidence based recommendations among these high-risk, immunocompromised patients.

Disclosure of interest: DAH has received research funding from Bristol-Myers Squibb, Novartis, Sanofi, and Genentech. He has been a consultant for Bayer Pharmaceuticals, Bristol Myers Squibb, Compass Therapeutics, EMD Serono, Genentech, Juno therapeutics, Novartis Pharmaceuticals, Proclara Biosciences, Sage Therapeutics, and Sanofi Genzyme. Further information regarding funding is available on: https://openpaymentsdata.cms.gov/physician/166753/general-payments.

RF is a co-founder and scientific advisor of IsoPlexis, Singleron Biotechnologies, and AtlasXomics with financial interest.

SHK receives consulting fees from Peraton.

AS is a consultant for Gritstone Bio, Flow Pharma, Moderna, AstraZeneca, Qiagen, Avalia, Fortress, Gilead, Sanofi, Merck, RiverVest, MedaCorp, Turnstone, NA Vaccine Institute, Gerson Lehrman Group and Guggenheim.

LJI has filed for patent protection for various aspects of T cell epitope and vaccine design work.

WER is an employee of Repertoire Immune Medicines.

EEL has received research funding from Genentech and Biogen. She has been a consultant for EMD Serono, Bristol Myers Squibb, Genentech, Genzyme, NGM Bio, TG Therapeutics and Janssen.

MKR, JEW and TSG are employees of Quest Diagnostic

All other authors have nothing to disclose.

P528/232

Increase of chemokine receptor 6 on distinct T cell subsets in multiple sclerosis

Koroboshka Brand-Arzamendi¹, Raphael Schneider^1,2

¹St. Michael's Hospital, Unity Health Toronto, Toronto, Canada, ²Institute of Medical Science, University of Toronto, Toronto, Canada

Introduction: C-C chemokine receptor 6 (CCR6) positive T cells have been implicated in MS. Recently, an increase in CCR6+ T cells has been shown to precede MS disease activity. Chemokine ligand 20 (CCL20) binds to CCR6 to recruit CCR6+ T cells to sites of inflammation. Interestingly, CCL20 has been shown to be increased in the blood of people with MS (pwMS) and associated with higher disability scores. Whether CCL20 is already increased at the time of MS diagnosis and which specific CCR6-expressing T cell subsets may preferentially respond to CCL20 needs further study to clarify the potential role of the CCL20-CCR6 axis in MS.

Objectives/Aims: To measure CCR6 expression on T cell subsets and plasma CCL20 levels in a cohort of newly diagnosed pwMS.

Methods: For this cross-sectional study, 63 pwMS and 23 healthy controls (HCs) were recruited from the BARLO MS center, St. Michael’s Hospital, Unity Health, Toronto, at their time of diagnosis. The Simple PLEX microfluidic assay was used to detect CCL20. In a subset of 18 pwMS and 17 HCs, cytometry by time-of-flight (CyTOF) was used on whole blood to quantify the percentages of CCR6 positive T cells and their mean CCR6 expression levels.

Results: There was a significant increase of plasma CCL20 in pwMS compared to HCs (p<0.05). CCR6+ CXCR3- “Th17-like” cells were significantly increased in pwMS (p<0.05), as were CCR6 mean expression levels on additional CD4 T cell effector subsets and natural killer T (NKT) cells (p<0.05 and p<0.001). No such increase was seen on CD8 T cells.

Conclusion: We observed increased plasma levels of CCL20 in pwMS at the time of their diagnosis using a highly sensitive microfluidics assay. Moreover, using CyTOF, we found an increased number of CCR6+ CXCR3- “Th17-like” cells and increased mean CCR6 expression on several additional effector T cell subsets. This data suggests that the CCL20-CCR6 axis may play an important role in recruiting specific effector T cell populations early in MS.

Disclosure of interest: Raphael Schneider: has received consulting or speaking honoraria from Biogen, Novartis, Sanofi, and EMD Serono.

Koroboshka Brand-Arzamendi: nothing to disclose

P529/1018

Alpha crystallin B: EBNA1 antibody cross-reactivity and T cell responses in multiple sclerosis

Olivia Thomas¹, Mattias Bronge², Katarina Tengvall¹, Birce Akpinar¹, Ola Nilsson¹, Erik Holmgren¹, Tara Hessa¹, Guro Gafvelin¹, Mohsen Khademi¹, Lars Alfredsson³, Roland Martin¹, André Ortlieb Guerreiro Cacais¹, Hans Grönlund¹, Tomas Olsson¹, Ingrid Kockum¹

¹Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden, ²Karolinska Institutet, Stockholm, Sweden, ³Karolinska Institutet, Institute of Environmental Medicine, Stockholm, Sweden

Introduction: Epstein-Barr virus (EBV) is linked to MS development and molecular mimicry between autoantigens and viral proteins has been hypothesised to drive central nervous system (CNS) attack. EBNA1 antibodies have been the focus of cross-reactivity studies due to their elevation in MS sera, and alpha crystallin B (CRYAB) has been suggested for many years as an autoantigen in MS but its role in disease has been debated.

Objectives/Aims: To investigate adaptive immune responses to EBNA1 and CRYAB in MS patients

Methods: Overlapping peptide pools from CRYAB and EBNA1 were used in a multiplex bead assay to quantify IgG responses in plasma from population-based controls (Con, n=713) and persons with MS (pwMS, n=720). Competition assays were used to determine whether homologous peptides from EBNA1 and CRYAB could reciprocally block peptide binding peptide to IgG. Peripheral blood mononuclear cells (PBMC) from controls, individuals with other neurological disease (OND) and pwMS were stimulated using full-length EBNA1 and CRYAB antigen-coupled beads. Responding T cells were analysed by FluoroSpot and flow cytometry. Mice were immunised with CRYAB or EBNA1 antigen and T cells from draining lymph nodes were examined for reactivity to bead bound antigen by flow cytometry.

Results: CRYAB aa2-16 had the highest proportion of positive IgG responses, with 27.6% positive pwMS and 16.9 % positive Con (OR 1.88, 95% CI 1.45 – 2.43, p=3.6 x 10-5). The highest odds ratio (OR) for pwMS was for CRYAB aa3-17 reactivity (OR 1.98, 95% CI 1.40 – 2.82, p=0.0041) with 13.3% positive pwMS and 7.2% positive Con respectively, and combination of high EBNA1 responses with CRYAB positivity dramatically increased disease risk (OR=9.0). Reciprocal blocking experiments showed that spike in of EBNA1 peptides with CRYAB homology blocked antigen-specific IgG binding. Evidence for T cell cross-reactivity was obtained in mice between EBNA1 and CRYAB, and increased CRYAB and EBNA1 CD4+ T cell responses were detected in Natalizumab-treated pwMS.

Conclusion: We detected increased anti-CRYAB antibody levels in pwMS and reciprocal blocking experiments demonstrated antibody cross-reactivity between EBNA1 (aa399-415) and CRYAB (aa8-27). Investigation of cellular immunity showed CRYAB to elicit a strong T cell response in pwMS, and further investigation of these cells is warranted to determine their relevance in MS disease pathology.

Disclosure of interest: OT has nothing to disclose. MB has nothing to disclose. KT has nothing to disclose. MK has nothing to disclose. LA has nothing to disclose. AO has nothing to disclose. IK has nothing to disclose. HG is the inventor of a current patent related to antigen-beads filed by NEOGAP Therapeutics AB. HG is the founder and co-owner of the company NEOGAP Therapeutics AB. BA, ON, EH, TH and GG hold positions at NEOGAP Therapeutics AB. TO has received unrestricted MS research grants and/or lecture/advisory board honoraria from Biogen, Novartis, Genzyme, Merck, and Roche, of which none are applicable to this study. RM received unrestricted grants from Biogen and Novartis and personal compensation for lecture or advisory board functions from Biogen, Merck, Novartis, Roche, Sanofi Aventis, Teva, Cell-Protect, Neuway, and Third Rock Ventures. He is a co-founder, co-owner and an employee of Cellerys, a startup company of the University of Zürich. He is a coinventor and patent holder on patents related to antigen-specific tolerization, treatment/vaccination of PML, and the use of daclizumab as a treatment of MS.

P530/1426

Cervical lymph nodes in patients with multiple sclerosis show an overrepresentation of memory B cells and a disturbed germinal center reaction

Joona Sarkkinen¹, Dawit Yohannes¹, Maria Perdomo², Pia Dürnsteiner¹, Goran Kurdo³, Riikka Linden³, Pentti Tienari^1,4, Eliisa Kekäläinen¹, Sini Laakso^4,5

¹University of Helsinki, Translational Immunology, Helsinki, Finland, ²University of Helsinki, Virology, Helsinki, Finland, ³Helsinki University Hospital, Medical Imaging, Helsinki, Finland, ⁴Helsinki University Hospital, Neurology, Helsinki, Finland, ¹University of Helsinki, Translational Immunology, Helsinki, Finland

Introduction: Early adulthood Epstein Barr virus (EBV) infection increases the risk of multiple sclerosis (MS) by 32-fold. Part of the B cells remain latently infected by EBV, and B cells found from the central nervous system have been shown to activate in the cervical lymph nodes (cLN).

Objectives/Aims: To investigate cLNs in MS patients at the diagnostic phase and compare with those of healthy controls.

Methods: We have studied cLNs of newly diagnosed MS patients (N=7) and healthy controls (N=6) accessed by fine-needle-aspirations (FNA). We characterized the cellular composition using scRNAseq and CITEseq and traditional FACS. We studied the targets of the B cell and T cell responses using TCR and BCR single cell analysis tools. Viral persistence was addressed using NGS and multiplex qPCR methods on both cLN aspirates and saliva.

Results: cLNs of newly diagnosed MS patients show increased numbers of memory B cells. BCRs in GC B cells show lack of clonality seen in healthy controls. TCR specificity in cLNs was overall similar between patients and controls. MS patients but not controls showed active secretion of EBV but not other herpesviruses in the saliva.

Conclusion: Fine-needle-aspirations (FNA) are a suitable approach to study GC reactions in lymph nodes. Polyclonal GC BCR finding in MS patients is in line with EBV-driven unlimited expansion, giving possibly rise also to uncontained autoreactive B cell responses. Even though MS patients had signs of EBV re-activation, T cells were not differentially targeting EBV or other common viruses compared to healthy controls, thus providing further evidence for the role of EBV as a transformer of B cells in MS disease pathogenesis.

Disclosure of interest: Joona Sarkkinen: nothing to disclose

Dawit Yohannes: nothing to disclose

Maria Perdomo: nothing to disclose

Pia Dürnsteiner: nothing to disclose

Goran Kurdo: nothing to disclose

Riikka Linden: nothing to disclose

Pentti Tienari: lecture fees Biogen, Roche, Novartis, Sanofi-Genzyme, Merck, Teva, Orion, Santen, Alexion; congress expenses Biogen, Novartis, Merck KGaA

Eliisa Kekäläinen: lecture fees Merck, Astra Zeneca; congress expenses Roche; scientific advisor Janssen-Cilag

Sini M Laakso: lecture fees UCB Pharma, Merck, Biogen, Janssen-Cilag, Novartis, Argenx; expenses related to scientific congresses Roche, Merck, Novartis, UCB Pharma; scientific advisor Janssen-Cilag, Argenx, Novartis, Roche; investigator for the clinical study Clarion (Merck) and subinvestigator for the clinical study Fenhance (Roche)

P531/1703

AXL+SIGLEC6+ dendritic cells in cerebrospinal fluid and brain tissues of patients with autoimmune inflammatory demyelinating disease of CNS

Junho Kang¹, Moonhang Kim², Da-Young Yoon², Won-Seok Kim², Seok-Jin Choi², Young Nam Kwon³, Woo Seok Kim¹, Sung-Hye Park⁴, Jung-Joon Sung², Myungsun Park¹, Jung Seok Lee¹, Sang Beom Kim⁵, Jong-Eun Park¹, Sung Min Kim²

¹Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejon, South Korea, ²Seoul National University Hospital, Seoul, South Korea, ³Severence Hospital, Seoul, South Korea, ⁴Seoul National University Hospital, Pathology, Seoul, South Korea, ⁵Kyung Hee University Hospital at Gangdong, Seoul, South Korea

Introduction: Inflammatory demyelinating disease of the CNS (IDD) is a heterogeneous group of autoimmune diseases, and multiple sclerosis is the most common type. Dendritic cells (DCs), major antigen-presenting cells, have been proposed to play a central role in the pathogenesis of IDD. The AXL⁺SIGLEC6⁺ DC (ASDC) has been only recently identified in humans and has a high capability of T cell activation. Nevertheless, its contribution to CNS autoimmunity remains still obscure.

Objectives/Aims: We aimed to identify the ASDC in diverse sample types from IDD patients and experimental autoimmune encephalomyelitis (EAE).

Methods: We analyzed the single cell RNA sequencing data of paired CSF-blood samples from 9 patients with inflammatory demyelinating disease of the CNS and dataset of multiple sclerosis (MS) patients from published studies. Presence of ASDC was re-confirmed in brain biopsy tissue of MS patients and in an experimental autoimmune encephalomyelitis model.

Results: A detailed analysis of DC subpopulations using single-cell transcriptomics for the paired cerebrospinal fluid (CSF) and blood samples of IDD patients (total n = 9) revealed that three subtypes of DCs (ASDCs, ACY3⁺ DCs, and LAMP3⁺ DCs) were overrepresented in CSF compared with their paired blood. Among these DCs, ASDCs were also more abundant in CSF of IDD patients than in controls, manifesting poly-adhesional and stimulatory characteristics. In the brain biopsied tissues of MS patients, obtained at the acute attack of disease, ASDC were also frequently found in close contact with T cells. Lastly, the frequency of ASDC was found to be temporally more abundant in acute attack of disease both in CSF samples of IDD patients and in tissues of EAE, an animal model for CNS autoimmunity.

Conclusion: Our analysis suggests that the ASDC can be involved in the pathogenesis of CNS autoimmunity.

Disclosure of interest: This work is supported by Grant No. HI21C0539 from the Korea Health Industry Development Institute Research Fund. Some of the biospecimens for this study were provided by the Seoul National University Hospital Human Biobank, a member of the Korea Biobank Network, which is supported by the Ministry of Health and Welfare. Junho Kang was supported by a grant of the MD-PhD/Medical Scientist Training Program through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea. Jong-Eun Park was supported by the POSCO Science Fellowship.

P532/1782

immunosennescence trajectories in multiple sclerosis and diverse controls reveal cytotoxic effector granzyme b ifn-g nk cell signatures as a hallmark of aging

Hanane Touil¹, masashi fujita¹, tain luquez², annie lee³, adam brickman⁴, christian habeck⁵, Vilas Menon⁶, yaakov stern⁷, Donna L Farber⁸, Amit Bar-Or⁹, Philip De Jager¹⁰

Study Group: MS pathogenesis

¹Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, Neurology, New York, United States, ²Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, United States, ²Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, United States, ⁴Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology, College of Physicians and Surgeons, Columbia University, taub, New York, United States, ⁵Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology, College of Physicians and Surgeons, Columbia University, Taub, New York, United States, ⁶Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, Neurology, new york, United States, ⁷3Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology, College of Physicians and Surgeons, Columbia University, taub, New York, United States, ⁸4Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, microbiology immunology, New York, United States, ⁹Department of Neurology and Center for Neuroinflammation and Experimental Therapeutics (CNET), Perelman School of Medicine, University of Pennsylvania, neurology, philadelphia, United States, ¹⁰Columbia Multiple Sclerosis Center, Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, new york, United States

Introduction: The natural aging of the immune system (Immunosenescence ISC), involves gradual adaptation of immune-cell composition and functions. Multiple Sclerosis (MS) is a lifelong inflammatory chronic disease whereby premature ISC is associated with disease progression and poor prognosis. However, defined multi-modal ISC trajectories remain unclear due to studies mostly centered on European-ancestry populations.

Objectives/Aims: To examine age-associated cellular and functional changes in peripheral mononuclear blood cells (PBMC) in MS patients and controls with diverse ancestries.

Methods: Cellular, functional and transcriptomic changes of PBMCs derived from untreated RRMS (n=21, age 50-74 years) and ethnically-diverse controls (n=250, age 20-84 years) were measured using multiparametric flow-cytometry, single-cell-RNA-sequencing.

Results: We describe a mature (NKG2A⁺NKG2C⁺) and senescent (CD62L⁺KLRG⁺) CD56⁺PD-L1⁺NK cell-subset increasing in frequency with age (p=0.0011) in MS and controls, abundant in older Hispanics (p=0.001). Senescent CD56⁺PD-L1⁺NK cells harbor effector cytotoxic functions (IFNγ⁺, granzyme B⁺ & perforine⁺), while in older controls they acquire regulatory functions (IL-10⁺). We also uncovered 10 cell-subsets newly associated with advancing age: naïve CD20⁺CD4⁺ (p=0.0028) and CD20⁺CD8⁺ (p=0,0032) T-cells, activated IgD^lowCD4 central memory T-cells (p=0.0079).

Unbiased clustering of single-cell data revealed age-associate changes within cytotoxic CD4⁺CTLT-cells (p=0.009), mucosal associated invariant T-cells (MAIT) (p=0.0013), regulatory T-cells (p=0.006) and δγ-T-cells (p=9.51x10^-5) compartments. Overall, we report reciprocal effector (ISC NK, MAIT) vs. regulatory (ISC NK and T cells) changes with advancing age. Using these findings, our estimate of immunological-age captured 58.4% of variance in chronological-age, and is related to brain atrophy on MRI – an established feature of progressive MS.

Conclusion: We shed light on novel ISC trajectories in MS and diverse controls triggers of disease-progression, including effector cytotoxic CD56⁺PD-L1⁺IFNγ+GranzymeB⁺ NK-cells and regulator CD56⁺PD-L1⁺IL-10⁺NK cells, their lack of regulation might lead to aberrant inflammation in MS and support tumor environment. Our findings informed accurate immunological age estimates, contributing to an ongoing effort to personalized medicine for MS.

Disclosure of interest: HT was funded by the Canadian MS society and the FRQS (Fonds de recherche du Québec en santé) for a post-doctoral fellowship.

P533/1961

a peripheral cytotoxic nk-like cd eight t-cell subset predicts at onset an aggressive course of multiple sclerosis

David Axel Laplaud^1,2,3, Sita Shah⁴, Emilie Dugast⁴, Alexandra Garcia⁴, fourgeux cynthia⁴, gourain victor⁴, boussamet leo⁴, Fabienne Lefrère², melinda moyon², FLORA LEJEUNE^2,3,4, Sandrine Wiertlewski^2,3,4, Eric Thouvenot^5,6, hanane agherbi⁶, Romain Casey⁷, Sandra Vukusic^7,8, Aurelie Ruet^9,10, Emmanuelle Le Page¹¹, Pierre Labauge¹², Guillaume MATHEY¹³, Helene ZEPHIR¹⁴, Arnaud Nicot⁴, jeremie poschmann⁴, LAURELINE BERTHELOT⁴

¹CR2TI, Neurology - MS center, Nantes, France, ²Inserm CIC 1413, Nantes, France, ³Service de Neurologie, CHU Nantes, Nantes, France, ⁴CR2TI, Nantes, France, ⁵Service de Neurologie, CHU de Nîmes, Nîmes, France, ⁶INSERM U1191 / UMR 5203 / Institut de Génomique Fonctionnelle, Montpellier, France, ⁷Observatoire Français de la Sclérose en Plaques, Centre de Recherche en Neurosciences de Lyon, INSERM 1028 et CNRS UMR 5292, Lyon, France, ⁸Université Claude Bernard Lyon 1, Faculté de Médecine Lyon Est, Lyon, France, ⁹Service de Neurologie, CHU de Bordeaux, Bordeaux, France, ¹⁰Université de Bordeaux, INSERM, Neurocentre Magendie, U1215, Bordeaux, France, ¹¹Centre Hospitalier Universitaire Pontchaillou, Centre d'Investigation Clinique 1414 Institut National de la Santé et de la Recherche Médicale, Rennes, France, ¹²Service de Neurologie, CHU de Montpellier, Montpellier, France, ¹³Service de neurologie, Centre Hospitalier Régional Universitaire de Nancy - Hôpital Central, Nancy, France, ¹⁴Pôle Des Neurosciences Et de L'appareil Locomoteur, CRC-SEP, Hôpital Roger Salengro, Université de Lille, Inserm U1172, Lille, France

Introduction: Multiple sclerosis (MS) is an autoimmune disease due to chronic inflammation in the central nervous system (CNS) whose prognosis is still uncertain at disease onset.

Objectives/Aims: In an effort to anticipate disease severity, we founded the OutcoMS project, in which we aim to unravel mechanisms behind a poor outcome in MS, through the use of transcriptomics at disease onset. For that, we classified patients in aggressive or non-aggressive disease according to the use of high efficacy treatments during the two first years of the disease.

Methods: In a first cohort, we collected peripheral blood mononuclear cells (PBMCs) from 22 patients at their first clinical episode during clinically isolated syndrome (CIS). After >2 years, patients were sorted into 11 non-aggressive MS and 11 aggressive MS. Samples were matched with PBMCs from 11 healthy volunteers (HV) and sequenced using scRNAseq technology. Transcriptomic results were then confirmed at the protein level in a second larger cohort of 60 CIS patients composed of 29 evolving toward a non-aggressive and 31 toward an aggressive MS, and 30 HV from the OFSEP cohort with a flow cytometry assay performed on PBMCs.

Results: While subsets of CD4+ T cells discriminate MS patients and HV well, we identified a subset of CD8+ T cells that is increased in CIS patients that later convert to aggressive MS compared to non-aggressive MS. This CD8+ T cell population displays a memory phenotype and cytotoxic activity similar to natural killer cells. The increase in this subset in aggressive MS was confirmed using flow cytometry on the OFSEP cohort. Furthermore, a high frequency of these cells showed predictive value for aggressive MS at onset (AUC of 0.673). When combined with sNfL(serum neurofilament light chain) and sGFAP (serum glial fibrillary acidic protein), the AUC increased to 0.843.

Conclusion: Our data suggests that severe forms of MS may be driven by a subset of cytotoxic memory CD8+ T cells with NK-like properties. The frequency of this subset of cells in the blood of MS patients, in association with sNfL and sGFAP, can be used as a predictive tool at the first demyelinating event to identify patients who will require high efficacy treatment.

Disclosure of interest: David LAPLAUD: board membership, consultancy, and grants from Alexion, Actelion, BMS, Biogen, Merck, Novartis, Roche, and Sanofi.

Sita SHAH: nothing to disclose

Emilie DUGAST: nothing to disclose

Alexandra GARCIA: nothing to disclose

Cynthia FOUGEUX: nothing to disclose

Victor GOURAIN: nothing to disclose

Leo BOUSSAMET: nothing to disclose

Flora LEJEUNE: nothing to disclose

Fabienne LE FRERE: nothing to disclose

Melinda MOYON: nothing to disclose

Sandrine WIERTLEWSKI: nothing to disclose

Eric THOUVENOT: nothing to disclose

Hanane Agherbi: nothing to disclose

Romain Casey: nothing to disclose

Sandra VUKUSIC: nothing to disclose

Aurelie RUET: nothing to disclose

Emmanuelle LE PAGE: nothing to disclose

Pierre LABAUGE: nothing to disclose

Guillaume MATHEY: nothing to disclose

Hélène ZEPHIR: nothing to disclose

Arnaud NICOT: nothing to disclose

Jeremie POSCHMANN: nothing to disclose

Laureline BERTHELOT: nothing to disclose

P534/2183

B cell disruption in MS revealed by a genomewide circular RNA profilling

Marcin Mycko¹, Anna Zurawska¹, Igor Selmaj², Krzysztof Selmaj^1,2

¹Department of Neurology, Laboratory of Neuroimmunology, University of Warmia and Mazury, Olsztyn, Poland, Olsztyn, Poland, ²Center of Neurology, Lodz, Poland

Introduction: Multiple sclerosis (MS) is highly heterogenic disorder with respect to clinical course, diagnosis and treatment response. B cell have been known to propagate autoimmune demyelination but their exact role in MS remains unknown. Circular non- coding RNA (circRNA) emerge as a promising candidates for a molecules signifying the MS status and the analysis of their changes can provide an insight into the mechanisms of this condition.

Objectives/Aims: To assess the significance of the genome-wide expression changes of the circRNA in relapsing-remitting MS patients.

Methods: We have profiled circRNAa samples of peripheral blood mononuclear cells (PBMC) from 104 MS patients and age and sex matched controls. We analyzed close to 14000 individual circRNA per sample. The discovery set data were validated using quantitative reverse transcription polymerase chain reaction (qRT-PCR) with an independent cohort of RRMS patients and HC. The power of the validation study has been calculated according to the number of the samples and determined as a parameter alpha=0.9.

Results: A genomewide discovery analysis revealed 246 circRNA differentially downregulated (P < 0.05) in RRMS patients versus HC. A validation cohort analysis positively validated three circRNA showing highest levels (hsa_circRNA_101348, hsa_circRNA_102611 and hsa_circRNA_104361) and two circRNA showing lowest levels (hsa_circRNA_101145 and hsa_circRNA_001896) of differential expression in the RRMS remission versus HC group: hsa_circRNA_101145 and hsa_circRNA_001896. The expression of these molecules was found to be a marker of the disease clinical status (relapse, p= p=0.0002 or remission p=0.0000332) as well as showed a correlation with a presence of the gadolinium-enhancing lesions in brain MRI (p=0.0039) The in silico analysis of the miRNA interacting with these circRNA and positively validated 3 protein-coding mRNA likely to be affected by the expression these circRNAs. Intriguingly a changes of the MS marker circRNA were most likely to lead to a disturbed B cell activity. A B cell expressed genes that has been revealed to be affected by the MS related circRNA included AK2 and IKZF3, a genes that encode a molecules involved in production of a high-affinity antibodies.

Conclusion: We have described a previously unknown changes of the circRNA during RRMS and revealved a circRNA-miRNA pathways operating in the MS pathogenesis.

Disclosure of interest: Study supported by by NCN grant OPUS nr 2016/23/B/NZ6/02541

P535/819

Platelet dense granule secretion promotes autoimmune neuroinflammation in an animal model of multiple sclerosis

Niklas Huntemann¹, Susann Eichler², Anna Vogelsang², Lara Preuth², Tobias Ruck¹, Sven Meuth¹

¹Department of Neurology, Medical Faculty, Heinrich Heine University Duesseldorf, Duesseldorf, Germany, ²Department of Neurology with Institute for Translational Neurology, University Hospital Muenster, Muenster, Germany

Introduction: Patients suffering from multiple sclerosis (MS) are at increased risk for cardiovascular diseases related to abnormal platelet function. However, the contribution of platelets to inflammatory disorders of the central nervous system (CNS), such as experimental autoimmune encephalomyelitis (EAE), a model used to study MS, remains poorly understood. Nevertheless, there is growing evidence indicating an interplay between platelets and immune cells that promotes aberrant immune responses: During neuroinflammation, platelets accumulate in the CNS, where they release a variety of soluble factors stored in alpha and dense granules upon activation.

Objectives/Aims: In this study, EAE was used to investigate the impact of platelet dense granule secretion on neuroinflammation.

Methods: Therefore, we performed EAE in Munc13-4-deficient (Munc13-4^-/-) mice as they show an attenuated dense granule release.

Results: We found that a lack of platelet dense granule secretion significantly delayed disease onset (15.7 vs 12.1 days after immunization; p=0.0001) and ameliorated disease progression in experimental neuroinflammation (cumulative EAE scores: 1.59 vs 3.26; p=0.0003). Furthermore, immunohistochemical as well as flow cytometric analyses revealed a reduction in CNS infiltration (infiltrated leukocytes per 10,000 beads: 2,703 vs 9,668; p=0.007) and demyelination (demyelinated area: 12.9% vs 18.8%; p=0.028) compared to wild type mice at disease maximum. Remarkably, we particularly observed reduced diapedesis of pathogenic T helper 17 cells (35.9% vs 42.6%; p=0.1605). Moreover, in vivo assessment of blood-brain barrier (BBB) integrity showed reduced cerebral vascular leakage during EAE in Munc13-4^-/- mice through diminished upregulation of endothelial adhesion molecules. Of particular importance from a translational perspective, we demonstrated that inhibition of platelet activation and thus degranulation by approved agents such as acetylsalicylic acid and P2Y12 receptor inhibitors significantly ameliorated the EAE course.

Conclusion: Overall, we were able to demonstrate that compounds secreted from platelet dense granules contribute to neuroinflammation, as Munc13-4^-/- mice show an attenuated EAE progression. Furthermore, we provided evidence that platelet-derived contents modulate BBB function and promote lymphocyte diapedesis during neuroinflammation. Nevertheless, further studies are needed to identify the underlying pathways that mediate the role of platelets as inflammatory amplifiers.

Disclosure of interest: N.H. received travel reimbursements from Alexion and meeting attendance fees from Novartis. S.E.: nothing to disclose. A.V.: nothing to disclose. L.P.: nothing to disclose. T.R. reports grants from the German Ministry of Education, Science, Research and Technology, grants and personal fees from Sanofi-Aventis and Alexion, personal fees from Biogen Idec, Roche, and Teva, and personal fees and nonfinancial support from Merck Serono, outside the submitted work. S.G.M. received honoraria for lecturing and travel expenses for attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen Idec, Celgene, Diamed, Sanofi-Aventis, MedDay, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Chugai Pharma, QuintilesIMS, and Teva. His research is funded by the German Ministry for Education and Research (BMBF), Bundesinstitut für Risikobewertung (BfR), Deutsche Forschungsgemeinschaft (DFG), Else Kröner Fresenius Foundation, Gemeinsamer Bundesausschuss (G-BA), German Academic Exchange Service, Hertie Foundation, Interdisciplinary Center for Clinical Studies (IZKF) Muenster, German Foundation Neurology, and by Alexion, Almirall, Amicus Therapeutics Germany, Biogen Idec, Diamed, Fresenius Medical Care, Sanofi-Aventis, HERZ Burgdorf, Merck Serono, Novartis, ONO Pharma, Roche, and Teva.

P536/1228

Single cell spatial characterisation of axillary lymph nodes reveals increased abundance of T follicular and memory B cells in multiple sclerosis

Joona Sarkkinen¹, Leo Hannolainen², Eliisa Kekäläinen^1,3, Mikko Mäyränpää⁴, Maria Perdomo², Sini Laakso^1,5

¹University of Helsinki, Translational Immunology Program, Helsinki, Finland, ²University of Helsinki and Helsinki University Hospital, Helsinki, Finland, Department of Virology, Helsinki, Finland, ³Helsinki University Central Hospital, HUS Diagnostic Center, Clinical Microbiology, Helsinki, Finland, ⁴Helsinki University Hospital and University of Helsinki, Helsinki, Finland, Department of Pathology, Helsinki, Finland, ⁵Helsinki University Central Hospital, Department of Neurology, Helsinki, Finland

Introduction: High efficacy of CD20 monoclonal antibodies in preventing relapses and disability accumulation in multiple sclerosis (MS) has placed B cells and their interaction with T cells in the center of attention for disease pathogenesis. Follicular T helper cells (Tfh) are crucial in directing B cell maturation in germinal centers (GCs) within lymph nodes. The ratio of Tfh and regulatory T follicular cells (Tfr) in blood has been reported to be increased and to correlate with intrathecal IgG production in MS patients.

Objectives/Aims: We sought to explore the landscape of immune interaction within lymph nodes of MS patients and control subjects with no neuroimmunological diseases.

Methods: Formalin fixed-paraffin embedded axillary lymph nodes of MS patients and controls were retrieved from Helsinki Biobank. The samples had been collected during operation for a suspected breast tissue malignancy, with no finding of cancer cells in the lymph nodes studied. We analyzed cell abundancies and spatial connections of Tfh cells and B cell subsets in axillary lymph nodes of 44 MS patients and 44 controls by extracting spatial topology information from highly multiplexed in-situ cellular imaging using cyclic immunofluorescence (CyCIF). To assess the presence of Epstein Barr virus (EBV) in the samples, EBER in situ hybridization and EBV-qPCR were utilized.

Results: Lymph nodes of MS patients contained increased frequency of memory B cells compared to control subjects. Tfh cells were increased in frequency also within the B-cell follicle area of the GCs, suggesting underlying disturbance of GC reaction.

Conclusion: Perturbed GC reaction appears a prominent feature of lymph nodes in MS patients, in line with a key role in disease pathogenesis. Our findings warrant further studies on lymph nodes also with potential for novel treatment discoveries.

Disclosure of interest: Joona Sarkkinen, Leo Hannolainen, Eliisa Kekäläinen, Maria Perdomo: nothing to disclose

Sini M Laakso: lecture fees UCB Pharma, Merck, Biogen, Janssen-Cilag, Novartis, Argenx; expenses related to scientific congresses Roche, Merck, Novartis, UCB Pharma; scientific advisor Janssen-Cilag, Argenx, Novartis, Roche; investigator for the clinical study Clarion (Merck) and subinvestigator for the clinical study Fenhance (Roche)

Mikko Mäyränpää: lecture and/or advisory board fees from Boehringer Ingelheim, Bristol-Myers Squibb, MSD, Takeda, Bayer, Amgen, Roche, and Aiforia technologies oy

P537/1305

the immune landscape of antiviral responses in multiple sclerosis

Silvia D'Orso¹, gisella guerrera¹, Mario Picozza², Alice Verdiani², Marta Pirronello³, Silvia Corbisiero², Carla Tortorella⁴, Marco Salvetti⁵, Rosella Mechelli⁶, chiara buscarinu⁷, Serena Ruggieri⁸, Claudio Gasperini⁸, Bruno Gran⁹, Luca Battistini², Giovanna Borsellino²

¹Neuroimmunology Unit, Santa Lucia Foundation, Rome, Italy, ²Neuroimmunology Unit, Santa Lucia Foundation, roma, Italy, ³Neuroimmunology Unit, Santa Lucia Foundation, Roma, Italy, ⁴San Camillo hospital, Roma, Italy, ⁵Neurology and Centre for experimental Neurological therapies (CENTERS), S. Andrea Hospital, Roma, Italy, ⁶Neurology and Centre for experimental Neurological therapies (CENTERS), S. Andrea Hospital, roma, Italy, ⁷Sant' Andrea Hospital, Roma, Italy, ⁸San Camillo hospital, roma, Italy, ⁹Division of Clinical Neurology, School of Clinical Sciences, University of Nottingham, UK., Nottingham, United Kingdom

Introduction: Multiple sclerosis (MS) is an immune-mediated chronic inflammatory disease of the central nervous system.MS is defined as a multifactorial disease, occurring in genetically susceptible individuals exposed to environmental trigger(s). There is a long-lasting association between MS and viral infections, which have profound influences on the immune system. The strong correlation between Epstein-Barr virus (EBV) and MS has recently gained more support. The allostatic perturbation resulting from viral infection is capable of triggering specific antiviral responses that can cause autoimmune reactions and support neuroinflammation through direct and indirect mechanisms.

Objectives/Aims: Fourteen newly diagnosed, untreated pwMS with a clinical diagnosis of relapsing-remitting MS and 14 healthy donors. A fresh heparinized venous blood sample was drawn for the parallel study of both innate and adaptive immunity.

Methods: For the study of innate immunity, whole blood was stimulated with R848, mimicking a viral infection and acting through the activation of TLR 7/8. The responses of the innate immune cells were studied by multiparametric flow cytometry analysis, that allowed to investigate 10 myeloid subpopulations and the release of 8 different cytokines. For the study of adaptive immunity, freshly drawn Peripheral Blood Mononuclear Cells (PBMCs) were isolated from whole blood. To fully capture the antigen-specific T cell response and to maximize sensitivity, two separate assays for the detection of the expression of surface activation-induced markers (AIM) and for intracellular cytokine staining (ICS) were set up to evaluate the immune antiviral responses against Epstein-Barr, Cytomegalovirus (CMV), Influenza and Sars-Cov-2 viruses.

Results: This study revealed that the frequency of subpopulations of innate immunity did not change between HD and MS patients. However, following stimulation with viral mimics, monocytes of pwMS produced significantly higher levels of pro-inflammatory cytokines compared to healthy donors while dendritic cells responded less. Regarding adaptive immunity, we CD4+ T cells of pwMS responded more vigorously in pwMS referred to HD.

Conclusion: Collectively, these preliminary findings highlight that pwMS have a vigorous innate immune response to viral mimics, and that the adaptive immune reactivity to these three different viruses shows different patterns of responsiveness both between viruses and between HD and pwMS.

Disclosure of interest: Silvia D’Orso nothing to disclose

Gisella Guerrera nothing to disclose

Mario Picozza nothing to disclose

Alice Verdiani nothing to disclose

Marta Pirronello nothing to disclose

Silvia Corbisiero nothing to disclose

Claudio Gasperini Claudio Gasperini has received consulting fees from Biogen, Novartis, Roche, Sanofi, Merck, Bristol; speaker honoraria from Biogen, Sanofi, Merck, Novartis, Bristol, Janssen, Sandoz; travel grants from Roche, Biogen, Sanofi, Novartis

Carla Tortorella received honoraria for speaking and travel grants from Biogen, Sanofi-Aventis, Merck Serono, Bayer-Schering, Teva, Genzyme, Roche, Alexion, Horizon, Celgene, Almirall and Novartis.

Marco Salvetti received research support and consulting fees from Biogen, Merck, Novartis, Roche, Sanofi, Teva.

Luca Battistini received honoraria for seminars, advisory boards and/or research grants from: Merck, Roche, Novartis, Baxter, Genzyme, Biogen, Bristol, Janssen, Horizon e Sanofi.

Maria Chiara Buscarinu speaking honoraria or research support from Merck, Sanofi, Roche, Novartis, Alexion, Viatris, BMS, Biogen.

Serena Ruggieri has received honoraria from Biogen, Merck Serono, Novartis and Teva for consulting services, speaking and/or travel support.

Rosella Mechelli nothing to disclose

Giovanna Borsellino nothing to disclose

Bruno Gran nothing to disclose

P538/1328

Expanded T lymphocyte clones in the cerebrospinal fluid of multiple sclerosis patients are specific for autologous Epstein-Barr virus infected B lymphocytes

John Lindsey¹, Assaf Gottlieb²

¹University of Texas Health Science Center at Houston, Neurology, Houston, United States, ²University of Texas Health Science Center at Houston, School of Medical Bioinformatics, Houston, United States

Introduction: Epstein-Barr virus (EBV) infection has long been associated with multiple sclerosis (MS), but a mechanism by which EBV infection might contribute to the pathogenesis of MS has not been demonstrated.

Objectives/Aims: Our objective was to determine the fraction of T cells in the cerebrospinal fluid (CSF) of MS patients that is specific for EBV and compare to other common antigens.

Methods: We obtained blood and CSF samples from 8 newly presenting, untreated relapsing-remitting MS patients. We isolated mononuclear cells from the blood and stimulated with autologous EBV-infected lymphoblastoid cell lines (LCL), EBV, varicella zoster virus (VZV), influenza, and candida. We sorted the responding T cells with flow cytometry after 6 days. We sequenced T cell receptors (TCR) from CSF, unselected blood cells, and the antigen-specific cells. We used the TCRbeta CDR3 sequences from the antigen-specific cells to assign antigen specificity to the TCR sequences from the CSF and blood.

Results: LCL-specific cells comprised 13.0% of the total reads present in CSF and 13.3% of the reads present in blood. The next most abundant antigen specificities were influenza (4.7% in CSF and 9.3% in blood) and EBV (4.3% in CSF and 5.5% in blood). The dominance of LCL-specific TCR was even more marked in the expanded clones. For the most abundant 1% of clones in CSF, 51.6% were specific for LCL as compared to 21.2% of the most abundant clones in the blood.

Conclusion: LCL-specific sequences form a major portion of the TCR repertoire in both CSF and blood. A large fraction of the most abundant clones in the CSF are specific for LCL. These T cells most likely recognize EBV antigens expressed during latent infection, but they could also target human proteins expressed by LCL. The role of these LCL-specific T cells in the pathogenesis of MS requires further investigation.

Disclosure of interest: J. W. Lindsey: nothing to disclose. A. Gottlieb: nothing to disclose.

P539/1908

Identification of brain-reactive CD8+ T cells in multiple sclerosis using autologous stem cell-derived brain cells

Samuel Jones¹, Sylvain Perriot¹, Mathieu Canales¹, Larise Oberholster¹, Marie Gimenez¹, Marie Théaudin², Caroline Pot^1,2, Amandine Mathias¹, Renaud Du Pasquier^1,2

¹Laboratories of Neuroimmunology, Neuroscience Research Centre, Department of Clinical Neurosciences, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland, ²Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland

Introduction: Multiple sclerosis (MS) is widely regarded as an autoimmune disease driven by autoreactive immune cells infiltrating the brain and inducing inflammatory demyelinating lesions. CD8+ T cells are the most predominant lymphocytic population in these lesions and are clonally expanded suggesting an antigen-driven proliferation. However, brain antigens targeted by these CD8+ T cells have yet to be formally identified.

Objectives/Aims: Our objective is to screen for the presence of autoreactive CD8+ T cells recognizing autologous neurons and astrocytes.

Methods: We have developed a co-culture assay between CD8+ T cells and autologous human-induced pluripotent stem cell (hiPSC)-derived neurons and astrocytes. This allows to specifically expand brain-reactive CD8+ T cells present in peripheral blood mononuclear cells (PBMCs) at a frequency below detection levels of conventional methods. First, an expansion step is initiated where ex vivo PBMCs and autologous HLA-I enhanced neurons or astrocytes are cultured together for 14 days. Second, expanded CD8+ T cells are isolated and incubated overnight with fresh HLA-enhanced neurons and astrocytes. Finally, neuron- or astrocyte-reactive CD8+ T cells are detected by secretion of IFN-y using flow cytometry.

Results: First, we have generated and characterized hiPSCs from a cohort of 8 MS patients and 6 age- and sex-matched healthy donors (HDs). Second, we demonstrated that hiPSC-derived neurons and astrocytes efficiently upregulate HLA class I expression upon exposure to IFN-γ and TNF-α and activate cognate CD8+ T cells. Finally, using our system, we were able to successfully expand and identify brain-reactive CD8+ T cells from ex vivo PBMCs. Of the 3 HDs and 2 MS patients assayed to date, we detected neuron-reactive CD8+ T cells in one HD and one MS patient as well as astrocyte-reactive CD8+ T cells in one MS patient but not in HDs.

Conclusion: Overall, we now have at hand a co-culture system allowing us to successfully expand and identify autoreactive CD8+ T cells from any donor. We have already performed this assay for 3/6 HDs and 2/8 MS patients of our cohort and could successfully identify brain-reactive CD8+ T cells in 2/5 donors (1 HD, 1 MS) for neurons and 1/5 donors (0 HD, 1 MS) for astrocytes. We are now screening the whole cohort to assess if we identify significant differences between HDs and MS patients. Ultimately, our novel hiPSC-based platform will offer unique perspectives in identifying TCRs and ultimately antigens that would be pathogenic in MS patients.

Disclosure of interest: Samuel Jones: nothing to disclose.

Sylvain Perriot: nothing to disclose.

Mathieu Canales: nothing to disclose.

Larise Oberholster: nothing to disclose.

Marie Gimenez: nothing to disclose.

Amandine Mathias: nothing to disclose.

Marie Théaudin received travel grants, advisory board/lecture and consultancy fees from Biogen, Sanofi, Novartis, Merck and Roche. None related to this work.

Caroline Pot reports that the Lausanne University Hospital received speaker honoraria and travel grants for her activities with Novartis, Roche, Biogen, Merck and Sanofi. None related to this work.

Renaud Du Pasquier reports that the Lausanne University Hospital received speaker honoraria and travel grants for his activities with Biogen, Genzyme, Merck, Novartis, Roche, and Sanofi. None of them were related to this work.

P540/287

The link between metabolic effects of obesity and multiple slcerosis. Hyperinsulinemia impairs regulatory T-cell activity

Jorge Correale^1,2, Mariano Marrodan¹, Maria Piedrabuena¹

¹Fleni, Neurology, Buenos Aires, Argentina, ²University of Buenos Aires, Institute of Biological Biochemistry and Biophysic (IQUIFIB), Buenos Aires, Argentina

Introduction: One of the hallmarks of obesity is a marked increase in blood insulin levels. The canonical role of insulin is to promote cell glucose uptake via the AKT pathway. However, this pathway also affects regulatory T (Treg) cell development and function.

Objectives/Aims: To study whether hyperinsulinemia in obese MS (ObMS) patients influences Treg cell function, by altering immune homeostasis.

Methods: Thirty ObMS patients (body mass index [BMI] > 30 kg/m²), 30 non-obese MS (nObMS) subjects, and 30 healthy age and sex-matched controls (HC) were studied. CD4⁺CD25⁺FoxP3⁺ (Treg) and CD4⁺CD25^-FoxP3^- (Tconv) T cells were isolated from peripheral blood using magnetic beads. Serum levels of insulin, phosphorylation of AKT ^Ser473, and ribosomal protein S6 ^Ser235/236 were assessed by ELISA. RT-PCR and flow cytometry were used to measure insulin receptor expression. IL-10 and TGF-β produced by different cell populations after stimulation with anti-CD3/CD28 monoclonal antibodies and IL-2, in the presence of increasing insulin concentrations, were quantified using ELISA. Ex vivo release of IL-6, IL-17, TNF-α, IFN-γ, and IL-10 was assessed using an ELISPOT assay. Treg cells were induced in vitro from naive CD4⁺ T cells using TGF-β, rapamycin, butyrate, and retinoic acid, in the presence and absence of insulin.

Results: ObMS patients showed higher serum insulin levels than nObsMS patients and HC. Treg and Tconv cells expressed similar receptor levels, ex vivo and after activation. Insulin-induced AKT and S6 ^Ser235/236 phosphorylation were significantly higher in Treg cells than in Tconv cells. Higher AKT activity was associated with suppression of IL-10 production in Treg cells, and lack of expression of FoxP3, these effects were reversed by AKT inhibitors. However, insulin did not alter CD25, LAP, CD39, or CTL4 expression, nor TGF-β secretion. In addition, Treg cell dysfunction was associated with increased numbers of ex vivo IFN-γ, TNF-α, IL-17, and IL-6 positive cells in ObMS patients. Values showed a positive correlation with BMI and a negative correlation with ex vivo IL-10-positive cell numbers.

Conclusion: The presence of hyperinsulinemia in ObMS patients suggests a link exists between metabolism and autoimmunity. Increased insulin levels limit the differentiation of naïve CD4+ T cells to Treg cells, which also acquire a specific defect in IL-10 production.

Disclosure of interest: JC: Received financial compensation for research grants, institutional honoraria, academic presentations, and attended advisory boards from

Biogen, Merck, Novartis, Roche, Bayer, Sanofi-Genzyme, Gador, Raffo, Bristol Myers Squibb, and Janssen.

MM: Received fees for educational presentations and/or conference attendance from Merck-Serono Argentina, Biogen-Idec Argentina, Novartis Argentina,

Gador, and Roche Argentina.

MAP: Has nothing to disclose related to this article.

P541/637

T cells from newly diagnosed MS patient have enhanced responsiveness to CD46 activation and with a skewing towards CD46 CYT-2 isoforms

Linda Sundvall¹, Litten Rossen², Vivien Schack², Bettina Bundgaard², Peter Rasmussen¹, Thor Petersen^3,4, Per Höllsberg^2,5,6

¹Department of Neurology, Aarhus University Hospital, Aarhus, ²Department of Biomedicine, Aarhus University, Aarhus, Denmark, ³Neurology Research Unit, University Hospital of Southern Denmark, Sønderborg, Denmark, ⁴Department of Regional Health Research, University of Southern Denmark, Odense, Denmark, ⁵Department of Clinical Medicine, Aarhus University, Aarhus, Denmark, ⁶NIDO | Centre for Research and Education, Gødstrup Hospital, Herning, Denmark

Introduction: The ubiquitously expressed membrane protein CD46 is a regulator of innate and adaptive immune responses and is a receptor for several pathogens. In adaptive immunity, CD46 co-activated T cells may shift towards an IL-10-regulatory phenotype. Because insufficient IL-10 responses may be involved in chronic inflammation in MS, we hypothesized that MS patients have an altered CD46 response.

Objectives/Aims: We studied CD46-driven cytokine responses and IL-10 phenotypes in a cohort of untreated MS patients and examined whether they correlated with the expression of CD46 isoforms.

Methods: Treatment-naïve MS-suspected patients admitted for diagnostic investigations were consecutively offered participation. Diagnosis was subsequently made according to the 2017 McDonald criteria. Data were performed on n=37 MS patients and n=28 controls. The MS patients and controls were similar in age (36.2 vs 37.9 years) and gender distribution. Briefly, purified CD4⁺ T cells were stimulated with immobilized anti-CD3/CD46, or anti-CD3/isotype control, in the presence of IL-2. Supernatants were harvested at 48 and 72 hrs and analyzed by Cytometric Bead Array for IL-10, IFN-γ, TNF-α, IL-17 IL-13 or Cytokine Secretion Assay for IFN-γ and IL-10. RNA was extracted from resting T cells and prepared for reverse transcriptase and real-time PCR to determine the relative expression of CD46 isoforms (BC1, C1, BC2, C2).

Results: Without CD46 co-engagement, CD3-activated MS T cells survived at lower rates and mounted weaker cytokine responses of IL-10 (p=0.03), IFN-γ (p=0.002) at 48 hrs and IFN-γ, (p=0.02) and TNF-α (p=0.03) at 72 hrs when compared with controls. Noticeably, CD46-coactivation demonstrated that MS T cells survived at normal rates, mounted a switch towards an IL-10 phenotype and showed a reduced IFN-γ:IL-10 ratio when compared with control T cells. Analyses of CD46 isoform expression indicated that CD46 high-responding MS T cells had a predominance of CYT-2 compared with controls. The level of surface CD46 was similar in MS and control T cells.

Conclusion: We conclude that T cells from newly diagnosed MS patients are more responsive to CD46-signaling. The skewing towards CYT-2 containing isoforms in MS T cells may indicate that these cells have been preactivated in vivo. Since CD46 activation increased the level of all the measured cytokines particularly in MS T cells, we hypothesize that CD46 in vivo binding ligands, either natural or pathogens, may be more proinflammatory in MS patients.

Disclosure of interest: Sundvall, Linda: Nothing to disclose.

Rossen, Litten: Nothing to disclose.

Schack, Vivien: Nothing to disclose.

Bundgaard, Bettina: Nothing to disclose.

Rasmussen, Peter: Nothing to disclose.

Petersen, Thor: Nothing to disclose.

Höllsberg, Per: Nothing to disclose.

P542/1584

characterisation of b-cell subsets during pregnancy and postpartum in relapsing-remitting multiple sclerosis

Malik Seals¹, Stefanie Gamradt¹, Linda El-Ahmad¹, Caren Ramien², Christoph Heesen², Manuel Friese², Stefan Gold¹

¹Charité - Universitätsmedizin Berlin, Neuropsychiatry, Berlin, Germany, ²University Medical Centre Hamburg-Eppendorf, Institute of Neuroimmunology and Multiple Sclerosis, Hamburg, Germany

Introduction: Pregnancy is characterised by a pronounced reduction in relapse risk for patients with multiple sclerosis (MS). The underlying mechanisms for this phenomenon, however, remain incompletely understood. Emerging data have suggested that B-cells and autoantibodies contribute to disease onset, propagation, and progression in MS. However, few studies have attempted to characterise the changes within peripheral B-cell populations throughout pregnancy and post-partum.

Objectives/Aims: To characterise changes within peripheral B-cell populations across pregnancy and post-partum.

Methods: Peripheral blood mononuclear cells of 15 pregnant patients with relapsing-remitting (RR) MS were isolated and analysed with flow cytometry for B-cell subsets. Patients selected had single pregnancies and were not on any prescribed disease-modifying therapeutics during pregnancy or postpartum. Samples were collected in trimester (Tri-1) between weeks 10 and 14 of gestation, Tri-2 between weeks 22 and 24, Tri-3 between weeks 30 and 36-, and three months post-partum (Post).

Results: From Tri1 to Tri3, we observed a significant decrease in transitional B cells [p=0.002], whereas from T3 to Post, we saw a significant increase in numbers [p=0.0002]. Double-negative 2 (BN2) B-cells were also significantly decreased from Tri1 to Tri3 [p=0.055], with a significant increase from Tri3 to Post [p=0.004]. From Tri3 to Post, we also observed a considerable decrease in unswitched and switched memory B-cells [p=0.03]; there is also an increased number of (total) and early Plasmablasts [p=0.04]. From Tri1 to Tri3, we observed a downregulation of CD21 and CD23; however, post-partum, CD21 and CD23 markers are upregulated.

Conclusion: Our data suggest that during pregnancy in RRMS patients, B-cell populations undergo significant modulation, indicating a shift towards less activated, anti-inflammatory phenotypes. Further research, with larger cohorts, is required to explore these changes' functional relevance and identify subpopulations that may be used as prognostic biomarkers for disease activity.

Disclosure of interest: Malik Seals: nothing to disclose

Stefanie Gamradt: nothing to disclose

Linda El-Ahmad: nothing to disclose

Caren Ramien: nothing to disclose

Christoph Heesen: nothing to disclose

Manuel A. Friese: nothing to disclose

Stefan M. Gold: nothing to disclose

P543/2015

CSF-related metabolic switch with specific clonal amplification of pathogenic T and B cell subsets in early MS patients

Marion Mandon^1,2, Leonard Simon¹, Monvoisin Celine¹, Jean Rachel^1,2, Emmanuelle Le Page³, Gilles Edan³, Tarte Karin^1,2, Ame Patricia^1,2, Delaloy celine¹, Stephane Rodriguez¹, LAURE MICHEL^1,2,3

¹1 INSERM, Unité Mixte de Recherche U1236, Université Rennes, Etablissement Français du Sang Bretagne, Rennes, France, ²Pole Biologie-CHU Rennes, Rennes, France, ³Neurology Department, Rennes Clinical Investigation Centre, Rennes, France

Introduction: Although the primary event(s) triggering RRMS are still under investigation, disease maintenance requires a recurrent infiltration of immune cells from the periphery to the CNS. There, immune cells interplay with cells from local and peripheral origins dictate their functions and phenotype, polarizing them toward a pathological or a suppressive subset. Together with this polarization, cell metabolism is shaped to adapt cells to their new microenvironment, favour their maintenance as their activity, stressing the need to consider it in association with cell phenotype.

Objectives/Aims: In this study we aimed to decipher specific immune cell polarization within the CSF, to describe their interplay with other immune infiltrating subsets and to check for potentially associated metabolic switch.

Methods: Immune cells from Cerebro Spinal Fluid (CSF) and paired blood (n=5) of RRMS patients were sampled at diagnosis and used for scRNAseq analysis. Gene expression profile, cells interactome, clonal amplification and metabolome were specifically assessed and compared between CSF and blood cells by the use of dedicated informatic tools.

Results: Immune cells recruitment to the CSF was associated to an upregulation of activation markers at their surface and to a strong shift of their metabolism toward higher cholesterol biosynthesis, potentially participating to tissue and effector function adaptation as to cell proliferation. In accordance, enrichment in pro-inflammatory cell populations comprising antigen presenting monocytic cells, GzmK CD4 T cells as well as Tbet B cells was observed within the CSF. Increased frequency of these T and B subsets was partly explained through their clonal amplification which was found exclusive to the CSF. Finally, interactome analysis demonstrated differential crosstalk properties among infiltrating cells with Tbet B cells specific expression of CD22, a BCR signalling attenuator engaged during T/B interactions and potentially reflective of recurrent BCR stimulation, while CCL5 expression found mostly restricted to GzmK CD4 T cells may contribute to proinflammatory cells recruitment.

Conclusion: Altogether, these results highlighted that at diagnosis, RRMS patient’s CSF is already enriched with pro-inflammatory cells which had experienced a metabolic switch. Among these subsets, Tbet B cells and GzmK CD4 T cells demonstrated clonal expansion and peculiar interacting properties illustrative of their central role in disease course and maintenance.

Disclosure of interest: Marion Mandon: nothing to disclose

Simon Léonard: nothing to disclose

Céline Monvoisin: nothing to disclose

Rachel Jean: nothing to disclose

Emmanuelle Le Page: nothing to disclose

Gilles Edan: nothing to disclose

Karin Tarte: nothing to disclose

Patricia Amé: nothing to disclose

Céline Delaloy: nothing to disclose

Stéphane Rodriguez: nothing to disclose

Laure Michel: nothing to disclose

P544/2451

Expansion of EBV peptide-specific CD8 T cells from multiple sclerosis patients and healthy donors reveals dysregulation of effector responses that may be associated with disease pathogenesis

Maria Chiara Monaco¹, Lauren Suarez², William Frazier¹, Ruipeng Wang², Jack Ragheb², Mathias Oelke², Steven Jacobson¹

¹NINDS, NIH, Bethesda, United States, ²NexImmune, Inc., Gaithersburg, United States

Introduction: Although 90% of adults are infected with EBV, recent studies have rekindled a role for this ubiquitous agent in the pathogenesis of MS.

Objectives/Aims: To assess whether MS is associated with defective T cell control of EBV-infected B cells, we employed a nanoparticle (np) based Artificial Immune Modulation (AIM) platform consisting of a cocktail of six EBV peptides presented on np decorated with HLA-A2 and anti-CD28 molecules to enrich, expand, and characterize EBV specific CD8⁺ T cells from healthy and MS HLA-A*02:01 donors.

Methods: After 14 days, expanded cells were assessed for specificity and functionality as measured by intracellular cytokine staining and killing of EBV peptide loaded target cells.

Results: The expanded CD8⁺ T cells showed significant antigen specificity as shown by intracellular cytokine release and/or cytotoxic activity, which is consistent with previously published data. Interestingly, compared to heathy donors, such cells from MS patients exhibited functional defects in their responses to select EBV peptides.

Conclusion: These results, analyzing the functional responses of EBV specific CD8 ⁺ T cells expanded from healthy donors and patients with MS, represent our initial effort to interrogate the hypothesis that MS may be associated with defective T cell control of EBV infected cells, which is consistent with a number of reports suggesting that a dysregulation of EBV specific immune responses is associated with the pathogenesis of MS creating potential opportunities for new therapeutic approaches in MS.

Disclosure of interest: 1. Authors funding are from the intramural research program (IRP), NINDS, NIH

2. Authors funding from NexImmune, Inc.

P545/429

Novel insights into the role of Epstein-Barr virus in the pathogenesis of multiple sclerosis using a rabbit model

Gulfaraz Khan¹, Asma Hassani², Narendran Reguraman³, Safa Shehab³

¹United Arab Emirates University, College of Medicine and Health Sciences, Medical Microbiology & Immunology, Al Ain, United Arab Emirates, ²Harvard Medical School, Beth Israel Deaconess Medical Center, Dept. of Neurology, Division of Movement Disorders, Boston, United States, ³United Arab Emirates University, College of Medicine and Health Sciences, Anatomy, Al Ain, United Arab Emirates

Introduction: Multiple sclerosis (MS) is a chronic autoimmune disorder affecting the central nervous system (CNS), characterized by inflammation and demyelination. What causes MS remains unknown. An accumulating body of evidence implicates Epstein-Barr virus (EBV) in the pathogenesis of MS. Our previous study on over 1000 brain samples revealed the presence of EBV in the brain of 90% of MS cases. However, how EBV induces the neuropathology seen in MS has been frustratingly difficult to address, primarily due to the lack of a naturally susceptible small animal model of EBV infection.

Objectives/Aims: We have recently established a novel rabbit model of EBV infection which recapitulates EBV infection in humans. In the current study, we aimed to address some of the prominent questions on the role of EBV in MS pathogenesis using the rabbit model.

Methods: To determine the impact of peripheral EBV infection on dissemination of the virus to the CNS and its potential pathological consequences, we injected EBV intravenously in one group of animals, and isotonic saline in another. Animals were sacrificed at 2-4 weeks post infection and all major organs were collected. Histopathological changes and viral dynamics were examined in peripheral blood, spleen, brain, and spinal cord, using a range of molecular and histopathology techniques.

Results: Our findings revealed that: (1) intravenous administration of EBV resulted in widespread infection, and the virus was readily detectable in the plasma, peripheral blood lymphocytes, and the spleen, (2) circulating infected cells and not free virus correlated with CNS infection, (3) peripheral infection induced the formation of distinct inflammatory cellular aggregates in the brain and spinal cord, (4) the aggregates consisted of a range of inflammatory cells, (5) demyelination was present within the inflammatory aggregates, (6) the expression of EBV latent transcripts, EBER1 and EBNA1, correlated with the levels of expression of proinflammatory cytokines such as IL1β and IL6.

Conclusion: Taken together, our findings provide direct evidence that peripheral EBV infection can lead to the virus traversing into the CNS and inducing neuroinflammation and demyelination, two hallmarks of MS.

Disclosure of interest: Gulfaraz Khan: nothing to disclose

P546/2339

Epstein-Barr Virus infection of primary human naive B cells induces a transient, T-bet+/CXCR3+ atypical B cell phenotype

Gillian Horn¹, Nicolas Reinoso-Vizcaino², Elliott SoRelle^2,3, Micah Luftig²

¹Duke University, Integrative Immunobiology, Durham, United States, ²Duke University, Molecular Genetics & Microbiology, Durham, United States, ³Duke University, Biostatistics & Bioinformatics, Durham, United States

Introduction: Epstein-Barr virus (EBV) infects human B cells and is present in 90% of the world’s adult population. This prevalence primarily arises from the ability of EBV to access lifelong latent infection in memory B cells by co-opting B cell immune response mechanisms. EBV has the ability to promote survival of autoreactive memory B cell clones which is noteworthy given EBV is associated with multiple sclerosis (MS). Despite these associations, the extent to which EBV is mechanistically involved in MS development remains incompletely understood.

Objectives/Aims: The objective was to use EBV as a model to study heterogeneous B cell fates, specifically the formation of CXCR3+ B cells which have been described to have trafficking ability to the central nervous system and detected in MS patient brain lesions.

Methods: Single cell RNA sequencing and flow cytometric analysis was used to study EBV-driven formation of CXCR3+ B cells.

Results: In vitro EBV infection induces the mimicry of a pre-germinal center activated precursor to early memory B cells and infection of naïve B cells yields a distinct CXCR3+ population that expands then contracts, remaining present in EBV-immortalized lymphoblastoid cell lines. Further analysis revealed EBV-induced CXCR3+ population was CD27-/IgD-/CD21-/T-bet+. These cells were found to have upregulated TLR7, IL21R, and IFNGR1 expression, suggesting “innate-like” activation consistent with characteristics of atypical B cells known to be expanded during chronic infection and autoimmunity. Our mechanistic characterization identified a critical, though not completely essential, role for T-bet in driving the expansion of CXCR3+ B cells. Also, we observed a temporal relationship between early T-bet+/CXCR3+ followed by T-bet-/CXCR3+ cells. Towards defining the regulation of T-bet in EBV-infected B cells, we observed ChIP-sequencing peaks for EBV nuclear antigen 2 (EBNA2) with its co-activator RPBJ at both the TBX21 and CXCR3 loci.

Conclusion: These findings demonstrate the ability of EBV to drive the transient differentiation of naïve B cells to become CXCR3+ B cells in vitro and suggest this precursor may both remain present in the EBV-infected memory B cell pool in vivo and persist in tissues. Additionally, these findings warrant further investigation into EBV-mediated differentiation of CXCR3+ B cells as it provides the potential for trafficking of latently infected autoreactive B cell clones that could elicit a pathogenic or poorly targeted immune response aiding in the development or exacerbation of MS.

Disclosure of interest: Gillian Q. Horn: Gillian Q. Horn is funded by Duke University T32 Immunology Basic Immunology Training Program Grant (5T32AI052077-18).

Micah A. Luftig: Dr. Micah A. Luftig is a consultant for Evrys Bio and Moderna and receives the following NIH grant funding (5R01DE025994-08, 5R01CA234348-04, 5R01CA140337-12, 1U01CA275306-01).

Nicolas M. Reinoso-Vizcaino: Dr. Nicolas Reinoso-Vizcaino receives Post-doctoral funding from the NIH (5R01DE025994-08).

Elliott D. SoRelle: Elliott D. SoRelle is a recipient of the American Cancer Society Postdoctoral Fellowship.

P547/427

Unfermented dietary B-fructan fibres worsen multiple sclerosis outcomes, mediated by altered gut microbiota

Reihane Khorasaniha¹, Stephanie Tollenaar², Juan Jovel³, Ismaila Ba⁴, Athalia Voisin¹, Richard Miller¹, Ramsha Mahmood¹, Michael Bording-Jorgensen⁵, Christopher Cheng², Charles Bernstein¹, Natalie Knox¹, Amit Bar-Or⁶, Ruth Ann Marrie¹, E. Ann Yeh⁷, Yinshan Zhao⁸, Brenda Banwell⁶, Emmanuelle Waubant⁹, Feng Zhu⁸, Ali Mirza⁸, Soheila Karimi-Abdolrezaee¹, Helen Tremlett⁸, Kevin McGregor⁴, Ben Willing², Heather Armstrong¹

¹University of Manitoba, Bannatyne Campus, Winnipeg, Canada, ²University of Alberta, Edmonton, Canada, ³University of Calgary, Calgary, Canada, ⁴York University, Toronto, Canada, ⁵McMaster University, Hamilton, Canada, ⁶University of Pennsylvania, Philadelphia, United States, ⁷The Hospital for Sick Children, Toronto, Canada, ⁸The University of British Columbia, Vancouver, Canada, ⁹University of California San Francisco, San Francisco, United States

Introduction: Dietary fibres are not digested in the gut; they are fermented by microbes, typically promoting health. We showed if fibre fermenting microbes are decreased, specific unfermented fibres (β-fructans) can induce inflammation and gut damage in inflammatory bowel diseases (IBD). This occurred via TLR2 and the NLRP3 inflammasome, increasing cytokine secretion (eg. IL-1β, IL-23, IL-5). Similar to IBD, multiple sclerosis (MS) patients display changes in their gut microbiota and worsened symptoms and quality of life scores following a high-fibre diet.

Objectives/Aims: We hypothesize unfermented β-fructans induce inflammation in MS, mediated by decreased fibre-fermenting gut microbiota.

Methods: Study I: Stool samples were collected along with participant diet data (Block Kids Food Screener) from the Canadian Pediatric Demyelinating Disease Network (n=17 MS, n=20 healthy controls; <22 years age and sex matched) at a single time point. We calculated approximate daily fibre subtype intakes. Gut microbiota abundance and functions were determined (shotgun metagenomics; Kraken2 and HUMAnN3) and correlated with fibre consumption between patients and controls. Study II: Direct response to unfermented β-fructans was examined in a germ-free EAE mouse model of MS (unable to ferment fibres). Mice were fed β-fructans (n=7) or control fibre diet (n=8) beginning at symptom onset (day 14) until 28 days. EAE scores and weights were recorded daily. Intestinal and CNS tissues were collected (day 28) to examine inflammation and demyelinating lesions (LFB-HE, H&E).

Results: Study I: Children and youth with MS consumed significantly less β-fructans (2.4g/day; S.D. 0.32; p<0.05) than healthy participants (3.6g/day; S.D. 0.39) which was associated with altered gut microbiota, reflecting decreased fibre fermenting abilities (taxonomic and metabolic). Study II: Unfermented β-fructans sustained worsened EAE symptoms in mice following symptom peak (day 20-28; p<0.05) and increased demyelinating lesions in the CNS, compared to control diet.

Conclusion: Results from Study II where unfermented β-fructans sustained worsened symptoms and MS specific CNS damage in mice supported Study I findings that decreased fibre fermenting microbiota was associated with decreased β-fructan consumption in MS patients. Perhaps this is a learned behavior related to β-fructan intolerance and avoidance. Personalized dietary fibre guidelines, reducing consumption of detrimental fibres and increasing consumption of safe fibres, could improve outcomes in MS.

Disclosure of interest: Reihane Khorasaniha is funded by a James Gordon Fletcher Ph.D Fellowship for Research in Functional Foods and Nutraceuticals.

Stephanie Tollenaar is funded by a Weston Family Foundation grant held by BW.

Juan Jovel is a scientific advisor for Dayhoff Technologies.

Ismaila Ba has no conflicts to disclose

Athalia Voisin is funded by a Canadian Institutes of Health Research Canada Graduate Scholarship

Richard Miller is funded by grants from the Health Science Centre Foundation and Weston Family Foundation held by HA.

Ramsha Mahmood is funded by grants from Natural Sciences and Engineering Research Council of Canada and University of Manitoba Graduate Enhancement of Tri-Agency held by HA.

Michael Bording-Jorgensen is funded by a Mitacs fellowship.

Chris Cheng has no conflicts to disclose

Charles Bernstein is supported by the Bingham Chair in Gastroenterology. Dr. Bernstein has served on advisory Boards for AbbVie Canada, Amgen Canada, Bristol Myers Squibb Canada, Roche Canada, Janssen Canada, Sandoz Canada, Takeda Canada, and Pfizer Canada; Consultant for Mylan Pharmaceuticals and Takeda; Educational grants from Abbvie Canada, Bristol Myers Squibb Canada, Pfizer Canada, Takeda Canada, and Janssen Canada. Speaker’s panel for Abbvie Canada, Janssen Canada, Pfizer Canada, and Takeda Canada. Received research funding from Abbvie Canada, Amgen Canada, Pfizer Canada, Takeda Canada, Sandoz Canada

Amit Bar-Or A. Bar-Or has Received fees for advisory board participation and/or consulting from Accure, Atara Biotherapeutics, Biogen, BMS/Celgene/Receptos, GlaxoSmithKline, Gossamer, Janssen/Actelion, Medimmune, Merck/EMD Serono, Novartis, Roche/Genentech, Sanofi-Genzyme; and has received grant support to the University of Pennsylvania from Biogen Idec, Roche/Genentech, Merck/EMD Serono and Novartis. A. Bar-Or receives research funding from the National Institutes of Health (NIH), The National MS Society (NMSS), the Juvenile Diabetes Research Foundation (JDRF), the Canadian Institutes of Health Research, Multiple Sclerosis Society of Canada, Multiple Sclerosis Scientific Foundation and Melissa and Paul Anderson Chair in Neuroinflammation. A. Bar-Or served on the Board of Directors of the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) and the Federation of Clinical Immunology Societies (FOCIS), where he continues as a long-standing member of the Education Committee. He currently serves on the International Advisory Committee on Clinical Trials in Multiple Sclerosis and on the Steering Committee of the NIH Immune Tolerance Network (ITN) and is co-PI of the NIH Autoimmunity Center of Excellence (ACE), and member of the Leadership Council of the Colton Center for Autoimmunity at the University of Pennsylvania

Ruth Ann Marrie receives research funding from: CIHR, Research Manitoba, Multiple Sclerosis Society of Canada, Multiple Sclerosis Scientific Foundation, Crohn’s and Colitis Canada, National Multiple Sclerosis Society, CMSC, the Arthritis Society and the US Department of Defense, and is a co-investigator on studies receiving funding from Biogen Idec and Roche Canada. She holds the Waugh Family Chair in Multiple Sclerosis.

E. Ann Yeh research funding from NMSS, CMSC, CIHR, NIH, OIRM, SCN, CBMH Chase an Idea, SickKids Foundation, Rare Diseases Foundation, MS Scientific Foundation, McLaughlin Centre, Leong Center, Peterson Foundation. Investigator initiated research funding from Biogen. Scientific advisory: Hoffman-LaRoche. Speaker honoraria: Biogen, Saudi Epilepsy Society, NYU, MS-ATL; ACRS, PRIME, CNPS.

Brenda Banwell serves as a consultant for clinical trial design for Novartis, Sanofi Biogen, UCB, Roche, and Teva Neuroscience. The study was contributed to by the Canadian pediatric demyelinating disease, Network and supported by the Canadian multiple sclerosis society.

Emmanuelle Waubant is funded by the NIH, NMSS, DoD, CMSC, Race to Erase MS and PCORI. She is a site investigator for trials with Biogen, Alexion, Roche. She has received honoraria for talks from Yoga moves MS, Neurology Live and Advanced Curriculum.

Natalie Knox is funded by the Ontario Ministry of Food, Agriculture, Rural Affairs.

Feng Zhu is funded through research grants held by HT, including The Multiple Sclerosis Scientific and Research Foundation (PI: Tremlett, EGID: 2636).

Ali Mirza is funded by MS Society Canada

Helen Tremlett has received research support in the last 3 years from the: Canada Research Chair Program, National MS Society, Canadian Institutes of Health Research, Canada Foundation for Innovation, MS Society of Canada, MS Scientific Research Foundation and the EDMUS Foundation (‘Fondation EDMUS contre la sclérose en plaques’).

Kevin McGregor is funded by NSERC Discovery Grant and funding from the CANSSI Distinguished Postdoctoral Fellowship Program

Benjamin Willing receives funding from: CIHR, NSERC, Alberta Innovates, Results Drive Agricultural Research, Weston Family Foundation, and the Canada Research Chairs program.

Yinshan Zhao is funded through research grants held by HT, including The Multiple Sclerosis Scientific and Research Foundation (PI: Tremlett, EGID: 2636).

Soheila Karimi-Abdolrezaee is supported by research grants from the Canadian Institutes of Health Research (CIHR), MS Society of Canada and University of Manitoba.

Heather Armstrong is the PI on research grants from Weston Family Foundation, NSERC, HSC Foundation, Crohn’s Colitis Canada, CHRIM, MMSF, MS Society, Canada Research Chairs, and University of Manitoba, and is a scientific advisor for Dayhoff Technologies. She holds a Tier 2 Canada Research Chair in integrated biosciences.

P548/2034

In vitro infection of CNS-derived cells with Epstein-Barr virus using a B-cell transfer method

Roberto Alfonso¹, Nicolas Daviaud², Vanessa Kirschner¹, Joyce Lei¹, Antonia De Oliveira¹, Saud Sadiq¹

¹Tisch MS Research Center of New York, New York, United States, ¹Tisch MS Research Center of New York, New York, United States

Introduction: Epstein-Barr Virus (EBV) is a lymphotropic gammaherpesvirus known to infect around 95% of the general population. The host’s memory B-cells are the main cellular target of EBV where it establishes lifelong latency. Infection of epithelial cells through a lytic phase is also fundamental for the normal life cycle of the virus, and additional cellular targets such as T-cells and NK-cells have been described in the context of pathogenesis. Best known for causing infectious mononucleosis and contributing to the development of several types of cancers, EBV has also been recognized as an important driver of multiple sclerosis (MS) disease. However, much of the molecular mechanisms underlying MS and drivers of pathogenesis remain to be elucidated. A question of pressing importance is how this lymphotropic virus might contribute to a disease mostly affecting the central nervous system (CNS).

Objectives/Aims: Here, we consider the possibility of EBV directly infecting CNS-derived cells by applying different in vitro infection models.

Methods: Results: Direct exposure of primary astrocytes with cell-free virus resulted in minimal levels of infection (less than 1 GFP+ astrocyte per 5x10^4 cells). In contrast, co-culture conditions with EBV+ B-cells allowed for an increased rate of astrocyte infection, including: i) “cell-to-cell” contact with an EBV-producing cell line or Lymphoblastoid Cell Lines (LCLs) derived from EBV-GFP recombinant virus infections (0.1-0.25% GFP+ astrocytes); and ii) “cell-transfer” method using primary B-cells loaded with EBV virions (1.5-5%). Cell to cell interaction between astrocyte and EBV-infected B-cells was necessary for infection. Importantly, we were able to recapitulate positive infection in co-culture conditions using human induced Pluripotent Stem Cells (iPSC)-derived monolayer brain cells and cerebral organoids.

Conclusion: Overall, these results present in vitro evidences of an EBV - B cell - CNS interaction network which could be of relevance to understand how this virus contributes to MS disease.

Disclosure of interest: Roberto Alfonso: nothing to disclose

P549/2194

Gut microbiome signature in North Indian people with Multiple Sclerosis

Gurkeerat Kaur¹, Dheeraj Khurana¹, Rajesh Pandey², Pallawi Kumari², Priti Devi², Aparna Swaminathan², Ashok Kumar³, Usha Dutta⁴, Poonam Khanna⁵, Deepak Sharma⁶, Pallab Ray⁷

¹Postgraduate Institute of Medical Education and Research (PGIMER), Neurology, Chandigarh, India, ²Integrative Genomics of Host-PathogEn (INGEN-HOPE) laboratory Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB), Delhi, India, ³Postgraduate Institute of Medical Education and Research (PGIMER), National Institute of Nursing Education (NINE), Chandigarh, India, ⁴Postgraduate Institute of Medical Education and Research (PGIMER), Gastroenterology, Chandigarh, India, ⁵Postgraduate Institute of Medical Education and Research (PGIMER), Department of Community Medicine and School of Public Health, Chandigarh, India, ⁶CSIR-Institute of Microbial Technology (CSIR-IMTECH), G. N. Ramachandran Protein Centre (GNRPC), Chandigarh, India, ⁷Postgraduate Institute of Medical Education and Research (PGIMER), Medical Microbiology, Chandigarh, India

Introduction: Gut microbiome dysbiosis has been linked to Multiple Sclerosis (MS) through bi-directional gut-brain axis. Western studies have established that certain taxa may be mediating immune, metabolic and neuroendocrine factors that are associated with either disease pathogenesis or progression. Gut dysbiosis in Indian MS patients has not been characterized.

Objectives/Aims: To characterize the gut microbiome profile in North Indian MS patients.

Methods: 84 MS patients (both untreated and treated) from outpatients’ department and MS clinic were recruited along with age-gender matched 106 healthy controls (HCs). Major inclusions were RRMS patients as per 2017 Mc Donald’s criteria with an Expanded Disability Status Score (EDSS) < 5.5 and exclusions were progressive forms of MS and no associated co-morbidities. Demographics, MS characteristics and detailed dietary characteristics were recorded. Stool samples were taken for 16S rRNA sequencing and 5 ml of blood samples were taken to quantify serum zonulin levels.

Results: The median (IQR) age of RRMS patients was 32.8 (27.9 - 38.6) years, with 63 (75%) females and 21 (25%) males. Median (IQR) of body mass index (BMI) was 23.9 (20.6 - 27.1) kg/m² in RRMS patients and 23.2 (20.9 - 25.2) kg/m² in HCs (p=0.266). Food frequency based dietary analysis revealed significantly less consumption of dietary fibres by MS patients 8.7 (6.3 - 11) g/d than HCs 9.6 (7.8 - 12.7) g/d (p=0.012). Firmicutes was the most abundant and dominant phylum observed in our population (47.06% HCs vs 48.47% MS patients). Significantly reduced differential abundance of bacterial species such as Bacillus species of probiotic potential, Monoglobus pectinilyticus (pectin-degrading bacteria) and Faecalibacterium prausnitzii (commensal, probiotic, and butyrate-producing bacteria) were observed in MS patients. Metabolic pathways such as (5Z)-dodec-5-enoate biosynthesis I, oleate biosynthesis IV, palmitoleate biosynthesis I, stearate biosynthesis II, and mycolate biosynthesis involved in the generation of long chain fatty acids (LCFAs) were significantly enriched in MS patients. Moreover, MS patients had significantly higher serum zonulin concentrations [median (IQR), 233.5 (109.5 - 360.8) ng/mL] than HCs [median (IQR), 124.8 (73.3 - 251.2) ng/mL] (p=0.001).

Conclusion: Gut dysbiosis exists in North Indian MS patients which has a distinct microbiome signature compared to Western MS patients and it may be linked to a low dietary fibre intake.

Disclosure of interest: This study was supported by Departmental Research funds.

Kaur. G, Khurana. D, Pandey. R, Kumari. P, Devi. P, Swaminathan. A, Kumar. A, Dutta. U, Khanna. P, Sharma. D and Ray. P : nothing to disclose

P550/1229

Modifiable risk factors for MS are consistent across diverse ethnic backgrounds

Benjamin Jacobs¹, Pooja Tank¹, Jonathan Bestwick¹, Alastair Noyce¹, Charles Marshall¹, Rohini Mathur¹, Professor Gavin Giovannoni¹, Ruth Dobson¹

¹Queen Mary University of London, London, United Kingdom

Introduction: Multiple Sclerosis is a leading cause of non-traumatic neurological disability among young adults worldwide. Prior studies have identified modifiable risk factors for Multiple Sclerosis in cohorts of White ethnicity, such as infectious mononucleosis, smoking, and obesity during adolescence/early adulthood. It is unknown whether modifiable exposures for Multiple Sclerosis have a consistent impact on risk across ethnic groups.

Objectives/Aims: To determine whether modifiable risk factors for Multiple Sclerosis have similar effects across diverse ethnic backgrounds.

Methods: We conducted a nested case-control study using data from the UK Clinical Practice Research Database. Multiple Sclerosis cases diagnosed from 2001 until 2022 were identified from Electronic Healthcare Records, and matched to unaffected controls based on year of birth. We used stratified logistic regression models and formal statistical interaction tests to determine whether the effect of modifiable risk factors for Multiple Sclerosis differed by ethnicity.

Results: We included 9,662 Multiple Sclerosis cases and 118,914 age-matched controls. The cohort was ethnically diverse (MS: 277 South Asian [2.9%], 251 Black [2.6%]; Controls: 5043 South Asian [5.7%], 4019 Black [4.5%]). The age at MS diagnosis was earlier in the Black (40·5 [SD 10.9]) and Asian (37·2 [SD 10·0]) groups compared with White cohort (46·1 [SD 12.2]). There was a female predominance in all ethnic groups, however the relative proportion of males was higher in the South Asian population (proportion of women 60.3% vs 71% [White] and 75.7% [Black]). Established modifiable risk factors for Multiple Sclerosis – smoking, obesity, infectious mononucleosis, low vitamin D, and head injury - were consistently associated with Multiple Sclerosis in the Black and South Asian cohorts. The magnitude and direction of these effects were similar across all ethnic groups examined. There was no evidence of statistical interaction between ethnicity and any tested exposure, and no evidence to suggest that differences in area-level deprivation modifies these risk factor-disease associations. These findings were robust to a range of sensitivity analyses.

Conclusion: Established modifiable risk factors for Multiple Sclerosis are applicable across diverse ethnic backgrounds. Efforts to reduce the population incidence of Multiple Sclerosis by tackling these risk factors need to be inclusive of people from diverse ethnicities.

Disclosure of interest: BMJ has received speaker honoraria from Biogen & Roche. RM has received consulting fees from AMGEN. PT has no interests to declare. RD has received speaker honoraria from Biogen Idec, Teva, Merck, Janssen, Roche and Sanofi Genzyme; sat on advisory boards for Roche, Merck, Novartis, Janssen and Biogen; and received research support from Biogen,

Merck and Celgene. GG has received speaker honoraria from AbbVie, Actelion, Biogen, Celgene, Sanofi-Genzyme, Genentech, Merck-Serono, Novartis, Roche and Teva; sat on advisory boards for AbbVie, Actelion, Biogen, Celgene, Sanofi-Genzyme, Genentech, GlaxoSmithKline, Merck-Serono, Novartis, Roche and Teva; and received research support from Sanofi-Genzyme, Takeda, and Merck SJ has received support for conferences, speaker, advisory boards, trials, Data and Safety Monitoring Boards, and projects with CSL Behring, Takeda, Swedish Orphan Biovitrum, Biotest, Binding Site, Grifols, BPL, Octapharma, LFB, Pharming, GSK, Weatherden, Zarodex, Sanofi, and UCB Pharma. None of these conflicts relate to the current work. AN reports consultancy and personal fees from AstraZeneca, AbbVie, Profile, Roche, Biogen, UCB, Bial, Charco Neurotech, uMedeor, Alchemab, and Britannia, outside the submitted work. None of these conflicts relate to the current work. CM reports personal fees from Biogen and GE Healthcare, outside the submitted work.

P551/1528

Inverse association between mediterranean diet and risk of multiple sclerosis

Lars Alfredsson¹, Tomas Olsson¹, Anna Karin Hedström¹

¹Karolinska Institutet, Stockholm, Sweden

Introduction: There is some evidence implicating diet in the development of inflammatory diseases.

Objectives/Aims: We aimed to study the influence of dietary habits on the risk of developing multiple sclerosis (MS).

Methods: We used a population-based case-control study recruiting incident cases of MS (1953 cases, 3557 controls). Subjects with different dietary habits five years prior to diagnosis were compared regarding MS risk by calculating odds ratios (OR) with 95% confidence intervals (CI) using logistic regression models. Adjustment was made for a large number of environmental and lifestyle habits, including ancestry, smoking, alcohol consumption, body mass index, physical activity and sun exposure habits.

Results: Mediterranean diet was associated with lower risk of developing MS (adjusted OR 0.59, 95% CI 0.38-0.93), compared to western-style diet. There was no significant association between vegetarian/vegan diet and MS risk (adjusted OR 0.93, 95% CI 0.73-1.22), nor between diet with low glycemic index and MS risk (adjusted OR 0.96, 95% CI 0.64-1.44). The association between MD and reduced MS risk remained significant when subjects with low fish consumption were excluded (OR_adj 0.54, 95% CI 0.32-0.90), and when non-drinkers were excluded (OR_adj 0.53, 95% CI 0.29-0.96).

Conclusion: Mediterranean diet appears to exert a protective influence regarding the risk of subsequently developing MS compared to western-style diet. The inverse association was also observed among those with adequate fish consumption, indicating that MD may have effects beyond that from fish consumption. The dietary lipids used in MD may be involved in explaining the inverse relationship between MD and risk of MS. Olive oil has a high content of monosaturated fatty acids which play an important role in immune function. Minor components in olive oil, such as polyphenols, may also contribute to the antioxidant and anti-inflammatory capacities.

Disclosure of interest: Alfredsson reports grants from Swedish Research Council, grants from Swedish Research Council for Health Working Life and Welfare, grants from Swedish Brain Foundation, during the conduct of the study; personal fees from Teva, personal fees from Biogene Idec, outside the submitted work. TO has received lecture/advisory board honoraria, and unrestricted MS research grants from Biogen, Novartis, Sanofi and Merck. Hedström has nothing to disclose.

P552/1370

Gut, skin and oral microbiome in Multiple Sclerosis: a Mendelian Randomization analysis

Valeria Zancan¹, Gianmarco Bellucci¹, Rachele Bigi^1,2, Virginia Rinaldi¹, Martina Nasello¹, Maria Chiara Buscarinu^1,2, Rosella Mechelli^3,4, Giovanni Ristori^1,2, Marco Salvetti^1,5

¹Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, Rome, Italy, ²Neuroimmunology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, Rome, Italy, ³IRCCS San Raffaele Pisana, Rome, Italy, ⁴San Raffaele Roma Open University, Rome, Italy, ⁵Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Neurologico Mediterraneo Neuromed, Pozzilli, Italy

Introduction: Accumulating evidence links the microbial communities inhabiting the gut and other body surfaces, such as the skin and the oral mucosa, to pathophysiological processes underlying Multiple Sclerosis (MS). However, most of studies on microbiome in MS are correlative in nature, thus being prone to confounding and reverse causality.

Objectives/Aims: The study’s objective was to assess causality between the gut, skin and oral microbiome and MS, by performing Mendelian Randomization (MR) analyses. MR represents an epidemiological study design that allows to estimate the causal relationship between a risk factor and an outcome of interest using genetic variants as proxies for environmental exposures.

Methods: We extracted genetic instruments from summary statistics from 3 large genome-wide association studies (GWAS) on gut microbiome (18340, 8959 and 7738 subjects), 1 GWAS on skin flora (1656 skin samples), and 1 GWAS on oral microbiome (1915 subjects). Exposure data derived from the latest GWAS on MS susceptibility (47429 patients and 68374 controls).

Results: We found that genetically predicted abundance of Ruminococcus (Odds Ratio, OR=2.89, p=0.001), Bacteroides (OR= 1.16, p=0.02), Actinobacteria (OR 1.48, p=0.02) and Bifidobacteriaceae (OR= 1.46, p=0.01) in the gut, Veillonella species in the skin (OR=1.06, p=0.02), Lachnospiraceae (OR=1.41, p=0.02) and Saccharimonadaceae (OR=0.66, p=0.04) in saliva are causally linked with MS.

Conclusion: Our findings provide evidence for a causal relationship between the microbiome from diverse body sites and MS risk, reinforcing the relevance of the microbiome-gut-brain axis in disease etiology and opening wider perspectives on host-environmental interactions in MS.

Disclosure of interest: MS receives research support and has received fees as speaker from Sanofi, Biogen, Roche, Novartis, Bayer Schering, and Merck Serono. MB has received fees as speaker from Sanofi, Biogen, Roche, Merck Serono and Novartis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest

P553/1114

Smoking status in relation to fluid biomarkers in acute optic neuritis

Moschoula Passali^1,2, Maria Knudsen^2,3, Mathias Schmidt^1,2, Josefine Britze^1,2, Jette Lautrup Frederiksen^1,2

¹Optic Neuritis Clinic, Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital Rigshospitalet-Glostrup, Glostrup, Denmark, ²Department of Clinical Medicine, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark, ³Functional Imaging Unit, Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital Rigshospitalet-Glostrup, Glostrup, Denmark

Introduction: Smoking has been linked to accelerated disease progression in multiple sclerosis (MS), but the involved mechanisms remain unclear. As smoking cessation is associated with normalised rates of progression, we hypothesise that a better understanding of the effects of smoking may reveal modifiable drivers of MS progression.

Objectives/Aims: The aim of this study is to elucidate the potential mechanisms driving smoking-induced disease exacerbation in MS.

Methods: Questionnaires were used to classify patients with acute optic neuritis (ON) that had a lumbar puncture performed in the years 2018-2021 as daily smokers, occasional smokers, former smokers or never smokers. Furthermore, data on cerebrospinal fluid (CSF) white blood cell counts (WBCs), IgG-index, Qalb (albumin quotient between CSF and serum x 10^-3) and serum 25-hydroxy-vitamin-D were collected. Results are presented as medians with interquartile range. Wilcoxon rank sum test and multiple regression were used to study the effects of smoking.

Results: We recruited 75 patients with acute ON (61% MS-converters, 65% women, age: 32 (27-40) years) with the following distribution among the smoking status groups: 19 daily smokers, 5 occasional smokers, 15 former smokers and 36 never smokers. We found no differences in CSF WBCs and IgG-index among groups. Daily smokers had higher Qalb (5.6 (4.3-6.8)) compared to never smokers (4.1 (3.2-4.8), p=0.005) and former smokers (3.7 (3.0-5.3), p=0.03). We found no difference in Qalb between never smokers and former smokers (p=0.96). Daily smokers had much lower serum IgG (9.4 (8.4-10.2 g/L) compared to never smokers (11.7 (10.4-12.9) g/L, p=0.00002), but not significantly lower than former smokers (10.0 (8.8-11.7) g/L, p=0.09). The difference in serum IgG between former smokers and never smokers did not reach significance (p=0.06). Daily smokers had lower serum vitamin D (37 (25-49) nmol/L) compared to never smokers (48 (32-70) nmol/L, p=0.029) and former smokers (62 (36-78) nmol/L, p=0.024). We found no difference in serum vitamin D between former smokers and never smokers (p=0.41). The effects of smoking on Qalb, serum IgG and serum vitamin D were still significant after adjusting for MS-diagnosis, age and gender.

Conclusion: The above data suggest that smoking is associated with increased permeability between the blood and the CSF, reduced systemic humoral IgG immunity and lower levels of serum vitamin D in acute ON. Future studies should investigate the relationship between the suggested mechanisms and disease progression in MS.

Disclosure of interest: Moschoula Passali: nothing to disclose

Maria H. Knudsen: nothing to disclose

Mathias F. Schmidt: nothing to disclose

Josefine Britze: nothing to disclose

The above authors have been funded from the Danish Multiple Sclerosis Society during their contribution to this work.

Jette Frederiksen has received no funding to support the presented work. She has served on scientific advisory boards for and received funding for travel related to these activities as well as honoraria from Merck Serono, Sanofi-Aventis, Roche, Novartis and Chiesi.

P554/535

Neuronal intracellular calcium storage release upon direct T-cell-neuron interaction

Anna-Lena Schlegelmilch¹, Miriam Schillner¹, Frauke Zipp¹, Stefan Bittner¹

¹University Medical Center of the Johannes Gutenberg University, Department of Neurology, Mainz

Introduction: Neurodegeneration is a central pathology in multiple sclerosis (MS), which is especially present in the progressive phase of disease. However, currently there is no therapy targeting the neurodegenerative aspects of MS. Glutamate excitotoxicity has been discussed as a crucial factor in neuronal damage during chronic inflammatory processes. Upon direct contact with neurons, T-cells showed to secrete glutamate via a vesicular release, resulting in intracellular calcium increase, excitotoxicity and neuronal damage (Birkner et al., J Clin Invest 2020). Identifying the physiological pathway of T cell mediated excitotoxicity is a promising therapeutic approach to target neurodegeneration in MS.

Objectives/Aims: We now aim to investigate the effects of T-cell-neuron interaction, focusing on neuronal activity and the underlying molecular pathways for neuronal calcium increase.

Methods: Murine organotypic hippocampus slice cultures (OHSCs) were used to investigate the effects of T-cell-neuron-interaction in an ex vivo three-dimensional system. Organotypic hippocampus slices were cultured and transfected with the calcium sensitive protein Gcamp6. Additionally T lymphocytes were added to the culture. Two-photon imaging was performed to analyse the interaction of neurons and T lymphocytes.

Results: Exclusively T helper 17 (Th17) cells cause neuronal hyperexcitability in a model of OHSCs, which was indicated by an increase of intracellular calcium concentration. This increase is mediated by a direct cell-cell contact of Th17 and neurons. Using different receptor antagonists, we were able to identify NMDA (MK801) and Ryanodine receptors (Dantrolene) to be involved in the Th17 cell meditated increase of neuronal activity.

Conclusion: Our findings provide an insight into the glutamate related pathways of T-cell mediated neuronal hyperexcitability and demonstrate a therapeutic potential of a neuroprotective therapy in MS.

Disclosure of interest: Anna-Lena Schlegelmilch: nothing to disclose

Miriam Schillner: nothing to disclose

Frauke Zipp has recently received research grants and/or consultation funds from Biogen, Ministry of Education and Research (BMBF), Bristol-Meyers-Squibb, Celgene, German Research Foundation (DFG), Janssen, Max-Planck-Society (MPG), Merck Serono, Novartis, Progressive MS Alliance (PMSA), Roche, Sanofi Genzyme, and Sandoz.

Stefan Bittner has received honoria and compensation for travel from Biogen Idec, Bristol Meyer Squibbs, Merck Serono, Novartis, Sanofi-Genzyme, Roche and Teva.

P555/404

Neuroprotective and anti-inflammatory effects of dimethyl fumarate, monomethyl fumarate and cannabidiol in neurons and microglia

Alicia Sánchez-Sanz¹, María José Coronado-Albi², JULIA SABIN MUÑOZ³, RUTH GARCIA HERNANDEZ¹, Ofir Rodríguez-De la Fuente³, Juan Antonio Garcia Merino^1,4, Antonio J Sánchez-López⁵

¹Instituto de Investigación Sanitaria Puerta de Hierro-Segovia de Arana, Neuroimmunology Unit, Madrid, Spain, ²Instituto de Investigación Sanitaria Puerta de Hierro-Segovia de Arana, Confocal Microscopy Unit, Madrid, Spain, ³Hospital Universitario Puerta de Hierro, Madrid, Spain, ⁴Hospital Universitario Puerta de Hierro, Neuroimmunology Unit, Madrid, Spain, ⁵Instituto de Investigación Sanitaria Puerta de Hierro-Segovia de Arana, Biobank, Madrid, Spain

Introduction: Dimethyl fumarate (DMF) can cross the blood brain barrier and could be exerting cytoprotective and immunomodulatory properties in neurons and microglia. DMF is metabolized to monomethyl fumarate (MMF), considered as the bioactive compound. Increasing evidence suggests that DMF and MMF produce different effects, highlighting the need to characterize both fumarates and their potential to achieve neuroprotection. Cannabidiol (CBD) is a phytocannabinoid with antioxidant and immunomodulatory properties, which shares common mechanisms of action with DMF. Accordingly, CBD could be relevant as an additional therapy in neuroprotection.

Objectives/Aims: To compare the effects of DMF, MMF and CBD on neuroprotective and anti-inflammatory parameters.

Methods: Primary hippocampal neurons and the BV2 microglial cell line were treated with DMF (1-30 µM), MMF (1-30 µM) or CBD (1-10 μM). Nrf2 and NF-kB p65 activation were determined using confocal microscopy. Nitric oxide (NO) production and apoptosis were measured using the Griess reagent and the TUNEL assay, respectively. RNA-sequencing was used for transcriptome profiling.

Results: DMF activated the Nrf2 antioxidant pathway in both neurons and microglia, in contrast with MMF, which produced no activation. CBD activated Nrf2 to a greater extent than DMF in neurons but produced no activation in microglia. DMF and CBD, but not MMF, inhibited the pro-inflammatory NF-kB pathway in activated microglia. The three drugs reduced NO production in activated microglia. Neuronal apoptosis was reduced when cultured with conditioned media from activated microglia treated with DMF, MMF or CBD compared to media from activated microglia alone. The effect produced on gene expression by DMF, MMF or CBD was compared.

Conclusion: DMF and MMF present different mechanisms of action, suggesting a higher potential of DMF in neuroprotection due to its ability to activate Nrf2 and modulate microglia. MMF exerts anti-inflammatory effects in microglia but through distinct pathways than DMF, which should be further investigated. DMF and CBD share common mechanisms of action, with similar antioxidant properties in neurons and anti-inflammatory effects in microglia, highlighting the potential of exploiting CBD as an additional therapy in neuroprotection.

Disclosure of interest: Sánchez-Sanz: nothing to disclose

Coronado-Albi: nothing to disclose

Sabin-Muñoz: has received funding for research projects and conference fees, mentoring, and assistance for conference attendance from Teva, Merck, Biogen, Roche, Novartis, and Sanofi

Rodríguez-de la Fuente: nothing to disclose

García-Hernández: has received compensation for travel expenses from Novartis, Merck and Sanofi-Genzyme

García-Merino: has received compensation for travel expenses, speaking honoraria and consultation fees from Bayer, Merck, Teva, Biogen Idec, Novartis, Roche, Almirall and Sanofi-Genzyme

Sánchez-López: nothing to disclose

P556/1649

Impaired mitochondrial functionality and increased endoplasmic reticulum-mitochondria contact sites in multiple sclerosis specific induced primary neurons

Celina Böse¹, Zhixiao Wu², Verian Bader², Sanja Augustyniak¹, Anna-Sophia Karl¹, Pia Renk¹, Jessica Rehm¹, Konstanze Winklhofer², Ralf Gold¹, Jeremias Motte¹, Barabra Gisevius¹

¹Ruhr-University Bochum, Department of Neurology, St. Josef-Hospital, Bochum, Germany, ²Ruhr-University Bochum, Department of Molecular Cell Biology, Institute of Biochemistry and Pathochemistry, Bochum, Germany

Introduction: Mitochondria have been implicated as key players in disease pathogenesis of multiple sclerosis (MS), mediating reactive oxygen species and cellular metabolism via respiratory chain dysfunction. However, less is known about dysfunctions of the respiratory chain in neurons and on neuronal degeneration and regeneration. Mitochondria are associated with the endoplasmic reticulum (ER) through membrane contact sites, regulating calcium (Ca²⁺) homeostasis, apoptosis, and mitochondrial biogenesis. To analyze the prevalence of mitochondrial dysfunction in human neurons in the context of MS, we analyzed mitochondrial dysfunction in neuronal precursor cells (NPCs) and induced primary neurons (iPNs) differentiated from people with MS (pwMS)-specific induced pluripotent stem cells (iPSCs) by seahorse analysis compared to healthy controls (HC). We also investigated endoplasmic reticulum – mitochondria contacts (ERMCs), which have been implicated in pathomechanism of neurodegenerative diseases.

Objectives/Aims: NPCs and iPNs, differentiated from pwMS-specific iPSCs display alterations in mitochondrial functionality regarding the respiratory chain and ERMCs compared to HC.

Methods: Analyses of the respiratory chain were performed by seahorse Mito stress Test, measuring mitochondrial parameters such as maximal respiration, spare capacity, and ATP production, expressed as oxygen consumption rate (OCR). Analyses of ERMCs were conducted by transfection with Lipofectamine™ 3000. Afterwards, ERMCs quantification was performed by acquisition of Z-stack images and 3D reconstruction of mitochondria and ER. Images were analyzed by Imaris and Fiji software, contact area was analyzed by using MATLAB.

Results: We observed a significantly lower maximal respiration (p<0.01) and spare capacity (p<0.0001) in differentiated iPNs and neuronal progenitor cells (NPCs) (maximal respiration: p<0.001; spare capacity: p<0.01) of pwMS compared to HC. In addition, we observed a significantly higher amount of ERMCs in pwMS-specific iPNs compared to HC (p<0.05).

Conclusion: The significant decrease in maximal respiration and spare capacity of iPNs and NPCs of pwMS suggests an impaired mitochondrial functionality. Mitochondrial functionality and biogenesis are also affected by ERMCs, particularly by Ca²⁺ transfer between the ER and mitochondria. Increased ERMCs were associated with a Ca²⁺ dyshomeostasis, promoting mitochondrial fragmentation, altering cellular ATP synthesis, leading to apoptosis.

Disclosure of interest: Gold, R: received speaker’s and board honoraria from Baxter, Bayer Schering, Biogen Idec, CSL Behring, Genzyme, Merck Serono, Novartis, Stendhal, Talecris, and Teva. His department received grant support from Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, and Teva.

Gisevius, B: has nothing to disclose.

Motte, J: received speaker honoraria for activities with Alnylam, and Biogen, and research support by Biogen and the Medical Faculty of the University Bochum and Hertie foundation.

Winklhofer, Konstanze F.: has nothing to disclose

Wu, Zhixiao: has nothing to disclose.

Bader, Verian: has nothing to disclose.

Augustyniak, Sanja: has nothing to disclose.

Karl, Anna-Sophia: has nothing to disclose.

Renk, Pia: has nothing to disclose.

Rehm, Adriana: has nothing to disclose.

Böse, Celina: has nothing to disclose.

P557/1304

neuropathological and cerebrospinal fluid correlates of choroid plexus inflammation in progressive multiple sclerosis

Elena Barusolo¹, lauren griffiths², Lewis Watkins², mahshad karimian¹, Antonella Mensi³, Stefano Magon⁴, Marina Mastantuono¹, gian marco berti¹, diana bazan¹, stefania rossi⁵, Simon Hametner⁶, jo anne stratton⁷, Richard Nicholas⁸, Richard Reynolds⁸, Salvatore Monaco¹, Owain Howell², Roberta Magliozzi^1,8

¹Univeristy of Verona, Neuroscience, Biomedicine and Moviment Sciences, Verona, Italy, ²Swansea University, Institute of Life Sciences, Swansea, United Kingdom, ³Univeristy of Verona, Department of computer science, Verona, Italy, ⁴Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Roche Pharma Research and Early Development, Basel, Switzerland, ⁵Istituto Superiore di Sanità, Department of Oncology and Molecular Medicine, Rome, Italy, ⁶Med University of Vienna, Brain Research Center, Wien, Austria, ⁷McGill University, Department of Neurology and Neurosurgery, Montréal, Canada, ⁸Imperial College London, Faculty of Medicine, Department of Brain Sciences, London, United Kingdom

Introduction: In progressive multiple sclerosis (MS), intrathecally compartmentalized inflammation plays a pivotal role in demyelination, neurodegeneration and accumulation of disease activity and progression. The choroid plexus (CP), by virtue of its strategic location at the interface between systemic circulation and cerebrospinal fluid (CSF), in addition to its distinctive structural, immunoregulatory, and neuroprotective properties, has received increased attention in MS pathology. However, it remains to be better characterized whether/how CP inflammation may contribute to intrathecal inflammation in progressive MS.

Objectives/Aims: To better characterize the role of CP in progressive stages of MS and its potential link with intrathecal inflammation involving other brain compartments, such as perivascular spaces, meninges, and CSF.

Methods: By using immunochemistry/immunofluorescence the composition and phenotype of immune cells in the CP within hippocampus from 40 post-mortem pathologically confirmed MS and 10 healthy controls was examined and correlated with clinical outcome, inflammatory features in other cerebral niches and correspondent CSF inflammatory profile.

Results: The degree of CP inflammation does not significantly correlates with clinical/ demographic characteristics of the examined MS population, but instead correlates with several neuropathologic features, such as degree of perivascular inflammation (R: 0.509, p: 7.921x10^-4), meningeal inflammation (R: 0.365, p: 0.021), and the number of early active lesions (R: 0.654, p: 4.659x10^-6).The degree of choroid plexus inflammation was also found mainly correlated with infiltrating macrophages (R: 0.878, p: 1.012x10^-13) and high frequency of innate immune cells expressing the markers CD163, CD209, CD11c, MHCII) and cells expressing TREM2 and TSPO activation markers. From the analysis of 78 inflammatory molecules in paired CSF, 4 of them were correlated significantly with CP inflammation: Fibrinogen (R: 0.640, p: 8.752x10^-6), PDGF-bb (R: 0.470, p: 0.002), CXCL13 (R: 0.428, p: 0.006) and IL15 (R: 0.327, p: 0.040). Correspondently, elevated complement and fibrinogen deposition was found in CP and in subependymal area according to a "surface in" gradient associated with aberrant microglia activation.

Conclusion: Our results suggest a key role of CP inflammation strictly correlated with intrathecal MS inflammation, but is mainly characterized innate immune activity and fibrinogen-complement pattern reactivity.

Disclosure of interest: Barusolo E.: nothing to disclose

Griffiths L.: nothing to disclose

Watkins L.: nothing to disclose

Karimiam M.:nothing to disclose

Mensi A.: nothing to disclose

Magon S. : nothing to disclose

Mastantuono M.: nothing to disclose

Berti G.M: nothing to disclose

Bazan D.:nothing to disclose

Rossi S.: nothing to disclose

Stratton JA: nothing to disclose

Nicholas R.: nothing to disclose

Reynolds R.: nothing to disclose

Hametner S.: nothing to disclose

Monaco S.: nothing to disclose

Howell O.: nothing to disclose

Magliozzi R.: nothing to disclose

P558/2128

mri-based classifier for myelocortical multiple sclerosis identification and periventricular myelinated axonal degeneration

Vikas Singh¹, Yufan Zheng², Kunio Nakamura², Jameson Holloman^2,3, Daniel Ontaneda³, Bruce Trapp¹

¹Lerner Research Institute, Cleveland Clinic, Neurosciences, Cleveland, United States, ²Lerner Research Institute, Cleveland Clinic, Biomedical Engineering, Cleveland, United States, ³Cleveland clinic, Mellen center for Multiple Sclerosis, Cleveland, United States

Introduction: Myelocortical multiple sclerosis (MCMS) is characterized by a paucity of cerebral white matter demyelination (CWMD) and abundant spinal cord and cortical demyelination representing 12% of our autopsy cohort. MCMS cases, however, have abundant T2-weighted (T2W) hyperintensities in cerebral white matter. Identification of MCMS in-vivo has not been studied.

Objectives/Aims: To establish the 3D distribution of T2W hyperintensities in MCMS cerebral white matter and investigate whether T1-weighted (T1W) hypointensities can distinguish myelinated and demyelinated cerebral white matter in postmortem and people living with MS. In addition, we investigated pathological correlates of cerebral myelinated T2W hyperintensities in MCMS.

Methods: Three-dimensional rendering of T1BH and T2W lesions in 10 MCMS and 12 typical multiple sclerosis (TMS) postmortem brains with CWMD were visualized using MRIcroGL. MRIs from 10 MCMS and 12 TMS were analyzed to develop a classifier based on T1BH volume and percentage of T1BHs within T2W hyperintensities. T2W hyperintensities were co-registered on fixed brain slices and examined for myelin and axonal pathology. The classifier was applied to a living progressive MS (PMS) cohort.

Results: T2 hyperintensities in postmortem MCMS cases had a contiguous periventricular distribution that expanded at the posterior pole of the lateral ventricles. Decreased myelinated axon density, myelinated axonal swellings, myelinated axon ovoids and Wallerian degeneration (WD) were observed in posterior periventricular region of MCMS cases. The optimized values for T1BHs and percentage of T1BHs within T2W hyperintensities for MCMS detection is <0.75 ml and <1.9% respectively. A positive linear correlation was found between cerebral white matter demyelinated area and thresholded T1 BH volume (R=0.69; 95% CI 0.51-0.81; P<0.0001) and proportion of T1BH within T2 hyperintensities (R=0.55; 95%CI 0.32-0.72; P<0.0001) in postmortem MS cases confirmed the utility of this classifier. When applied to 255 MS patients from the ibudilast phase 2 trial, this classifier identified 25 potential MCMS cases (10%).

Conclusion: A MRI-based classifier identifies potential MCMS patients having myelinated T2W hyperintensities that are confluent and periventricular. Periventricular myelinated axon loss supports a CSF-associated mechanism of WD in MCMS. Possible MCMS cases were identified in people living with PMS.

Disclosure of interest: BD Trapp: Receives grant support from NINDS/NIH and the National Multiple Sclerosis Society and speaking fees from Sanofi-Genzyme. He is founder of Cashel Neural and member of the scientific advisory board of the NMSS. K Nakamura: Personal compensation for licensing fee from Biogen. DO: Research support from the National Institutes of Health, National Multiple Sclerosis Society, Patient Centered Outcomes Research Institute, Race to Erase MS Foundation, Genentech, Genzyme, and Novartis. Consulting fees from Biogen Idec, Bristol Myers Squibb, Genentech/Roche, Genzyme, Janssen, Novartis, and Merck. V Singh: Nothing to disclose. Y Zheng: Nothing to disclose. J Holloman: Nothing to disclose

P559/863

Oligodendrocyte progenitor cells differentiation induction with MAPK/ERK inhibitor fails to support repair processes in the chronically demyelinated CNS

Tal Ganz¹, Omri Zveik¹, Nina Fainstein¹, Marva Lachish¹, Ariel Rechtman¹, Lihi Sofer¹, Livnat Brill¹, Tamir Ben Hur¹, Adi Vaknin Dembinsky¹

¹Faculty of Medicine, Hebrew University of Jerusalem and The Department of Neurology and Laboratory of Neuroimmunology, The Agnes-Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Introduction: Remyelination failure is considered a major obstacle in treating chronic-progressive Multiple Sclerosis (MS). Studies have shown blockage in the differentiation of resident oligodendrocyte progenitor cells (OPC) into myelin-forming cells, suggesting that pushing OPC into a differentiation program might be sufficient to overcome remyelination failure. Others stressed the need of a permissive environment to allow proper activation, migration, and differentiation of OPC. PD0325901, a MAPK/ERK inhibitor, was previously shown to induce OPC differentiation, non-specific immunosuppression, and a significant therapeutic effect in acute demyelinating MS models.

Objectives/Aims: We aimed to examine whether PD0325901 treatment has a similar therapeutic effect on the chronically-inflamed central nervous system (CNS), and to further characterize its immunosuppressive properties on different cell populations.

Methods: We examined the pathological and clinical effect of PD0325901 in Biozzi mouse Experimental autoimmune encephalomyelitis (EAE) model in vivo, as well as its effect on OPCs differentiation and immune function in vitro.

Results: Treatment with PD0325901 induced OPC differentiation into mature oligodendrocytes with high morphological complexity. However, treatment of Biozzi mice with chronic-progressive EAE with PD0325901 showed no clinical improvement in comparison to control group, no reduction in demyelination, nor induction of OPC migration into foci of demyelination. PD0325901 induced a direct general immunosuppressive effect on various cell populations, leading to a diminished phagocytic capability of microglia and less activation of lymph-node cells. It also significantly impaired the immune-modulatory functions of OPC.

Conclusion: Our findings suggest OPC function depends on a permissive environment, which may include pro-regenerative inflammatory elements. Furthermore, they indicate that maintaining a delicate balance between the regenerative and immune functions of OPC is of importance. Thus, the highly complex mission of creating a pro-regenerative environment depends upon an appropriate immune response controlled in time, place, and intensity. We suggest the need to employ a multi-systematic therapeutic approach, which cannot be achieved through a single molecule-based therapy.

Disclosure of interest: Tal Ganz: nothing to disclose.

Omri Zveik: nothing to disclose.

Nina Fainstein: nothing to disclose.

Marva Lachish: nothing to disclose.

Ariel Rechtman: nothing to disclose.

Lihi Sofer: nothing to disclose.

Livnat Brill: nothing to disclose.

Tamir Ben-Hur: nothing to disclose.

Adi Vaknin-Dembinsky: nothing to disclose.

P560/115

Predicting multiple sclerosis slowly expanding lesions using cross-sectional radiomics and machine learning

Refaat Gabr¹, Bastien Caba¹, Colm Elliott², Phoebe Jiang¹, Willem Huijbers¹, Ian Tagge¹, Douglas L. Arnold^2,3, Arie Gafson¹, Shibeshih Belachew¹

¹Biogen, Cambridge, United States, ²NeuroRx Research, Montreal, Canada, ³McGill University, Montreal, Canada

Introduction: Slowly expanding lesions (SELs) are a promising in vivo biomarker of chronic lesion activity that correlates with disability progression in multiple sclerosis (MS). However, SELs are identified retrospectively from changes in longitudinal magnetic resonance imaging (MRI). This limits their potential as a prognostic marker. Identifying SELs from cross-sectional MRI could inform clinical trials through novel pharmacodynamic biomarkers and support clinical decision-making through improved individualized prognostication.

Objectives/Aims: To assess the feasibility of using machine learning (ML) to predict SEL status of MS lesions based on cross-sectional brain MRI radiomics.

Methods: We analyzed MRI scans from 1036 subjects in the ADVANCE clinical trial of relapsing-remitting MS (NCT00906399) to identify non-enhancing T2 lesions at baseline that are likely to exhibit post-baseline SEL phenotype. SEL labels were identified over the study period of 96 weeks as contiguous areas of expansion on T1-weighted and T2-weighted MRI showing constant concentric expansion. A total of 223 shape, location, and intensity radiomic features were extracted from lesions and perilesional tissues from baseline MRI. Data were split into training and test sets of equal size. A random forest ML model was developed to predict the post-baseline SEL status from the baseline radiomic features. The accuracy of the prediction was assessed using the area under the receiver operating characteristics curve (AUC).

Results: Out of 28,686 non-enhancing T2 lesions at baseline, 2,260 (7.9%) were associated with SELs, observed in 67.7% of the subjects. The ML model predicted SELs from baseline radiomic features with an AUC of 0.79. The sensitivity/specificity/balanced accuracy were 0.72/0.73/0.72, respectively. The most predictive features of SELs were lesion size and radiomic measures of lesion heterogeneity.

Conclusion: Using cross-sectional MRI radiomics, we were able to predict post-baseline SEL status with an AUC of 0.79. Further research will investigate whether the predicted SEL status can be modified by treatment or whether it can identify patients with more severe progressive disease.

Disclosure of interest: RG, BC, XJ, WH, IT, AG, and SB are all employees of and hold stock/stock options in Biogen.

CE has received speaker honoraria from Merck and is an employee of NeuroRx Research.

DLA has received personal compensation for serving as a Consultant for Alexion, Biogen, Celgene, Eli Lilly, EMD Serono, Frequency Therapeutics, Genentech, Merck, Novartis, Roche, Sanofi, and Shionogi, and holds an equity interest in NeuroRx.

P561/766

Longitudinal changes of MS lesions on chi-separation MRI: association of iron deposition to remyelination in early stage MS lesion

Jeonghyun Park¹, Hyeong-Geol Shin^2,3, Woojun Kim⁴, Jongho Lee⁵, Jinhee Jang⁶

¹St. Vincent Hospital, Suwon, South Korea, ²Johns Hopkins University, Baltimore, United States, ³Kennedy Krieger Institute, Baltimore, United States, ⁴Seoul St. Mary's Hospital, Neurology, Seoul, South Korea, ⁵Seoul National University, Seoul, South Korea, ⁶Seoul St. Mary's Hospital, Radiology, Seoul, South Korea

Introduction: In multiple sclerosis (MS), monitoring the dynamics of lesion pathology is important for understanding the clinical outcomes of patients and their treatment responses. While histopathology offers precise measure of tissue changes, it is invasive and cross-sectional; it cannot be repeated to the same lesions for the longitudinal observation. Instead, MRI can provide longitudinal information but demands a specific contrast to evaluate the histopathological changes of MS lesions. The chi-separation is a recently proposed method that enables for the separate assessment of myelin and iron distribution in the brain.

Objectives/Aims: This study aimed to evaluate the longitudinal changes of early-stage MS lesions using chi-separation.

Methods: Forty MS patients underwent 3T brain MRI scans, including chi-separation. Two types of MS lesions were selected as early-stage lesions: (1) new T2 FLAIR hyperintense lesions during follow-up and (2) contrast-enhancing lesions in the initial MRI. The clinical and radiologic characteristics of the lesions were assessed, and the association between the initial MRI findings and their changes during follow-up were evaluated.

Results: Of the 66 early-stage MS lesions assessed from 18 MS patients (13 women, 30.1 ± 8.3 years old, disease duration 28.4 ± 32.4 months, EDSS 1.5 ±1.1), 92.4% exhibited demyelination, with 49% displayed iron deposition. 24.2% had paramagnetic rims. Among the 48 lesions with follow-up chi-separation imaging (mean follow-up 25.8 months, range 8-62 months), 33 showed regression on T2 FLAIR images, 11 were stable, and 4 progressed. Remyelination was significantly associated to younger age (25.2 yo vs. 30.0 yo), no iron deposition (16/18, 88.9%), but not the presence of a paramagnetic rim (P = 0.359). Clinically stable disease status at the lesion onset was related to iron deposition (14/20, 70% of clinically stable disease vs 7/28, 25% of clinically active lesions), younger age, and shorter disease duration. Lesions with demyelination only were associated with active disease at the lesion onset, while lesions with demyelination and iron deposition were related to the onset of lesions without clinical worsening. Additionally, lesions with a clinical attack had a higher proportion of remyelination.

Conclusion: Chi-separation is a useful tool for evaluating the dynamic changes of early MS lesions. Iron deposition at the lesion onset was related to the failure of remyelination, and the chi-separation findings were associated with clinical features at the lesion onset.

Disclosure of interest: None

P562/1002

Susceptibility-based imaging aids accurate diagnosis of pediatric MS and myelin oligodendrocyte glycoprotein antibody-associated disease

Simone Sacco¹, Akash Virupakshaiah¹, Nico Papinutto¹, Amit Akula¹, Haojun Zhao¹, William Stern¹, Janet Chong¹, Janace Hart¹, Pascal Sati¹, Roland Henry¹, Emmanuelle Waubant¹

¹Weill Institute for Neurosciences, University of California, San Francisco, UCSF, Department of Neurology, San Francisco, United States

Introduction: Myelin oligodendrocyte glycoprotein antibody disease (MOGAD) can mimic pediatric-onset multiple sclerosis (POMS) on MRI. The two conditions however differ significantly for their prognosis and treatment and an early and accurate diagnosis of POMS is essential to provide optimal management. Central vein sign (CVS), paramagnetic rim lesions (PRLs) and central core lesions (CCL) are 3 Susceptibility-based imaging related signs that help discerning adult-onset MS from MOGAD. Systematic assessments of CVS and PRLs and their ability to discern POMS from MOGAD are however still lacking. CCL have never been systematically assessed in pediatric MOGAD.

Objectives/Aims: To assess the power of Susceptibility-based imaging in differentiating POMS from MOGAD.

Methods: Fluid attenuated inversion recovery (FLAIR) and different susceptibility techniques (T2*/phase 3D-EPI, SWI/phase) were used based on their availability of the 1.5T and 3T scanners included in this study. An experienced neuroradiologist, blinded to clinical information, evaluated the phase-sensitive images to identify the presence of PRLs and CCL. The CVS+ rate was calculated using North American Imaging in MS (NAIMS) consensus criteria through visual assessment of FLAIR and susceptibility images linear registrations. Finally, a logistic regression analysis was conducted to assess the ability of CVS+ rate and PRLs to predict disease type.

Results: The study included 27 POMS (mean age 13 years, 63% females, mean EDSS 1.5) and 14 MOGAD (8.2years, 35%, 1.0) participants. There was no overlap between POMS and MOGAD for the CVS+ rate (area under the ROC=1; p<0.0001) with a cutoff of 46% separating POMS and MOGAD. The average CVS+ rate was 64+/-10% for POMS and 22+/-12% for MOGAD participants. In contrast, the presence of PRLs showed a more modest power of differentiation, with 80% of POMS participants showing at least one PRL (mean 2.28, range 0-10) and none of the MOGAD participants showing any PRLs (ROC=0.9, p<0.0001). CCL were more frequently observed in POMS participants (mean 3.4+/-3) compared to MOGAD participants (mean 0.64+/-1).

Conclusion: Susceptibility-based imaging represents an essential imaging tool for the work-up of pediatric inflammatory diseases at onset and should be routinely performed in clinical practice. Early differentiation between POMS and MOGAD is crucial to initiate appropriate treatment and prevent disability accumulation in POMS. Our results also suggest major pathology differences between the 2 disorders.

Disclosure of interest: SS, AV, AA, HZ, JC, JH and WS have no conflicts of interest to report.

NP reports research support from the Race to Erase MS Foundation and from the National Center for Advancing Translational Sciences, National Institutes of Health, through a UCSF-CTSI grant.

PS receives research support from the National Institutes of Health and the National Multiple Sclerosis Society.

RGH discloses consulting for Boston Pharma, Novartis, QIA Consulting, Roche/Genentech and research support from Atara and Roche/Genentech.

EW has participated in multicenter clinical trials funded by Genentech, Alexion and Biogen. She has current support from the NIH, NMSS, DoD, PCORI, CMSC and Race to Erase MS. She does not receive honorarium from companies.

P563/989

Recent glucocorticoid treatment decrease the rate of spinal cord pseudoatrophy in the first year after DMT start

Simone Sacco¹, Nico Papinutto¹, Shuiting Cheng¹, Amit Akula¹, Haojun Zhao¹, Jeremy Juwono¹, William Stern¹, Refujia Cuquita Gomez¹, Adam Santaniello¹, Riley Bove¹, Jeffrey Gelfand¹, Ari Green¹, Jorge R Oksenberg¹, Emmanuelle Waubant¹, Michael Wilson¹, Scott Zamvil¹, Bruce Cree¹, Stephen Hauser¹, Roland Henry¹

Study Group: MS-EPIC Team

¹Weill Institute for Neurosciences, University of California, San Francisco, UCSF, Department of Neurology, San Francisco, United States

Introduction: An increased rate of volume loss during the first year of treatment with disease modifying therapies (DMT) is observed in MS for both brain and spinal cord (SC), suggesting a pseudoatrophy phenomenon. The influence of glucocorticoid (GC) administration on pseudoatrophy -ie resolution of lesion and non-lesion inflammation- is unknown. Whereas in the brain this GC-associated pseudoatrophy might have a negligible effect on volumetric parameters, the same is not true for the smaller SC, where the ratio between lesions and normal appearing tissue is generally higher.

Objectives/Aims: To assess influence of GC administration on SC pseudoatrophy development.

Methods: SC and brain MRI were performed on 88 newly diagnosed, treatment naïve, RRMS participants (age 35+/-8, EDSS 2+/-1, 70%Female) at baseline and at 1 and 2 years after DMT initiation. Fifty participants received high-dose GC before baseline (GC-Rx), whereas 38 did not (non-GC). Total cord area (TCA) was segmented at C2-C3 level on phase sensitive inversion recovery images. Brain volumetric data were obtained through Freesurfer. Annualized TCA, thalamus and brain white matter changes were computed and compared using linear mixed models and pairwise t-test.

Results: At the baseline scan, the GC-RX and non-GC groups did not differ in age, %female, EDSS, scan enhancement and cervical cord lesion number; over the observed period new SC lesions and type of DMTs administered were also similar. During the first year, TCA loss was greater for non-GC compared to GC-Rx (respectively, -2.2% and -0.8%; difference -1.4% p=0.0054). In the second year, the non-GC and GC-Rx TCA atrophy rates were similar (respectively, -0.76% and -0.82%, p=0.9049). This difference in first year rate of change between GC-RX and non-GC groups was particularly pronounced when considering only participants with SC lesions. For brain white matter and thalamus, the atrophy rates were faster for those participants with brain enhancing lesions at baseline, suggesting treatment-related pseudoatrophy, but this was not related to pre-baseline GC administration.

Conclusion: Recent treatment with high-dose GC is associated with less SC pseudoatrophy in the first year after DMT start, possibly because of resolution of perilesional vasogenic edema and overall inflammation before the baseline assessment. This observation implies that homogenizing or accounting for pre-baseline GC administration may be important for clinical trials in which SC areas are assessed for therapeutic efficacy.

Disclosure of interest: SS, SC, AA, HZ, JJ, WS, RCG, AS and JRO have no conflicts of interest to report.

NP reports research support from the Race to Erase MS Foundation and from the National Center for Advancing Translational Sciences, National Institutes of Health, through a UCSF-CTSI grant.

RMB is the recipient of a National Multiple Sclerosis Harry Weaver Award. She has received research support from the National Multiple Sclerosis Society, the National Institutes of Health and the Department of Defense. She has also received research support from Biogen, Novartis and Roche Genentech. She has received personal compensation for consulting from Alexion, EMD Serono, Horizon, Jansen and TG Therapeutics.

JMG has received Research support to UCSF from Roche and Vigil Neurosciences and discloses Consulting for Arialys.

AJG reports other from Bionure, grants, personal fees, and other from Inception Sciences, grants from Sherak Foundation, personal fees and other from Pipeline Pharmaceuticals, grants from Hilton Foundation, grants from Adelson Foundation, grants from National MS Society, personal fees from JAMA Neurology, personal fees and other from Mediimmune/Viela; In addition, AJG has a patent small molecule drug for remyelination pending and has worked on testing off-label compounds for remyelination.

EW has participated in multicenter clinical trials funded by Genentech, Alexion and Biogen. She has current support from the NIH, NMSS, DoD, PCORI, CMSC and Race to Erase MS. She does not receive honorarium from companies.

MRW got research funding from Genentech and Novartis. He also received speaking honoraria from Genentech, Novartis, Takeda and WebMD.

SSZ is Deputy Editor of Neurology, Neuroimmunology and Neuroinflammation and is an Associate Editor for Frontiers in Immunology and Frontiers in Neurology. He serves on the Advisory Committee for the American Congress on Treatment and Research in Multiple Sclerosis (ACTRIMS) and is a standing member of the research grant review committee for the National Multiple Sclerosis Society (NMSS). He has served on the Editorial Board of the Journal of Clinical Investigation, The Journal of Immunology and The Journal of Neurological Sciences, and has been a charter member of the grant review committee for the National Institutes of Health (NIH) Clinical Neuroimmunology and Brain Tumors (CNBT). He has served, or serves, as a consultant and received honoraria from Alexion, Biogen-Idec, EMD-Serono, Genzyme, Novartis, Roche/Genentech, and Teva Pharmaceuticals, Inc., and has served on Data Safety Monitoring Boards for Lilly, BioMS, Teva and Opexa Therapeutics. Currently, Dr. Zamvil receives research grant support from the NIH, NMSS and Weill Institute.

BACC received personal compensation for consulting from Alexion, Atara, Autobahn, Avotres, Biogen, Boston Pharma, EMD Serono, Gossamer Bio, Hexal/Sandoz, Horizon, Immunic AG, Neuron23, Novartis, Sanofi, Siemens, TG Therapeutics and Therini and received research support from Genentech.

S.L. Hauser serves on the Board of Directors for Neurona and on scientific advisory boards for Accure, Alector, and Annexon; has previously consulted for BD, Moderna, and NGM Bio; and has received travel reimbursement and writing assistance from F. Hoffmann-La Roche Ltd and Novartis AG for CD20-related meetings and presentations.

RGH discloses consulting for Boston Pharma, Novartis, QIA Consulting, Roche/Genentech and research support from Atara and Roche/Genentech.

P564/2241

Exploring the Role of Meningeal Lymphatic Vessels in Multiple Sclerosis: Implications for Disease Progression and Clinical Outcomes

Dinesh Sivakolundu¹, Mark Zuppichini², Kathryn West³, Shruthi Venkataraman⁴, Erin Longbrake¹, David Hafler¹, Thanh Nguyen⁵, Amit Mahajan⁶, Bart Rypma⁷

¹Yale University, School of Medicine, Neurology, New Haven, United States, ²University of Michigan, Ann Arbor, United States, ³Abbott Industries, Dallas, United States, ⁴McGill University, School of Medicine, Montreal, Canada, ⁵Weill Cornell Medicine, Radiology, New York, United States, ⁶Yale University, School of Medicine, Radiology, New Haven, United States, ⁷University of Texas at Dallas, Dallas, United States

Introduction: Meningeal lymphatic vessels (mLV) drain interstitial fluid with waste products from the brain and play a role in immune surveillance. Their role in Multiple Sclerosis (MS) pathophysiology remains unknown. This study investigates how changes in mLV may be linked to MS disease progression.

Objectives/Aims: To compare changes in mLV between MS patients and healthy controls (HCs) and assess how changes in mLV throughout the course of MS impacts clinical outcomes.

Methods: We conducted a prospective study with 42 MS patients and 22 age- and sex-matched HCs. All participants underwent high-resolution 3D T2-FLAIR and T1-MPRAGE sequences on a Philips 3T MRI scanner. The mLV and choroid plexus (CP) were identified and segmented using in-house code. The morphology of the mLV were studied by assessing the average volume, thickness, and surface area to volume ratio. The contents of mLV were evaluated by calculating their signal intensity (rSI) relative to that of the temporalis muscle on the FLAIR scan. A lower rSI indicated that the mLV contained fewer macromolecules, as compared to a higher rSI.

Results: MS patients had higher mLV volumes (mean difference; MD=5.57cm³, p<.005) and surface area to volume ratios (MD=.26mm^-1, p<.005), and lower thicknesses (MD=-.05mm, p<0.005), compared to HCs. There were no group differences in rSI. Additionally, MS patients had higher CP volumes compared to HCs (MD=.32cm³, p=.01), and the CP volume increased with increases in mLV volume across all participants (r=.39, p<.005). Among MS patients, mLV volume increased with increases in disease duration (r=.37, p=.01), total lesion volume (r=.31, p=.04), and brain atrophy (r=.48, p<.005), while no such changes were observed with changes in rSI. The mLV rSI/volume ratio decreased with worsening processing speed scores (r=.55, p=.008), visuospatial scores (r=0.45, p=.03) and 9-hole peg test scores (r=.45, p=.03) for HCs but no such relationships were observed in MS patients.

Conclusion: Our study suggests that changes in mLV drainage and immune surveillance may be linked to MS disease progression. Specifically, we found that as MS progresses, mLV possibly drain fewer macromolecules and hypertrophy. This process could explain the increased brain atrophy, cognitive decline, and motor disability seen in the MS disease course. Further research is needed to uncover the underlying mechanisms of these changes and their clinical implications.

Disclosure of interest: Dinesh Sivakolundu: Has a patent pending related to the work presented here

Mark Zuppichini: nothing to disclose

Kathryn West: nothing to disclose

Shruthi Venkataraman: nothing to disclose

Erin Longbrake: Consultant & Research: Genentech Consultant: Bristol Myers Squibb, Biogen, Janssen, NGM Bio, TG Therapeutics

David Hafler: nothing to disclose

Thanh Nguyen: nothing to disclose

Amit Mahajan: Has a patent pending related to the work presented here

Bart Rypma: nothing to disclose

P565/1540

Baseline paramagnetic rim lesions presence does not predict greater disability progression over 10 years

Jack Reeves¹, Taylor Wicks¹, Maryam Mohebbi¹, Dejan Jakimovski¹, Niels Bergsland¹, Fahad Salman¹, Ferdinand Schweser^1,2, Bianca Weinstock-Guttman³, Michael Dwyer^1,2, Robert Zivadinov^1,2

¹Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, United States, ²Center for Biomedical Imaging at Clinical and Translational Science Institute, University of Buffalo, State University of New York, Buffalo, United States, ³Jacobs Multiple Sclerosis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, United States

Introduction: Previous studies have shown that paramagnetic rim lesions (PRLs) are associated with greater cross-sectional and mid-term disability. However, it is unclear whether PRLs predict future disability progression over longer timeframes (e.g. 10 years).

Objectives/Aims: To assess whether baseline PRL presence and number are associated with disability progression over 10 years.

Methods: 123 people with MS received a 3T MRI scan and clinical assessment at baseline and received at least 3 additional clinical assessments over the subsequent 10 years. Quantitative Susceptibility Mapping (QSM) was used to identify PRLs based on the proposed North American Imaging in MS (NAIMS) PRL classification guidelines. Confirmed disability progression (CDP) was determined by identifying patients who had an (Expanded Disability Severity Scale (EDSS) increase of either 1 (for starting EDSS < 5.5) or 0.5 (for starting EDSS > 5.5) sustained over at least 3 clinical visits. Progression independent of clinical relapse (PIRA) was assigned to patients who had CDP but no relapses within 6 months of any of the relevant clinical visits. CDP was compared between patents with PRLs (PRL+) and without PRLs (PRL-) using Kaplan-Meier survival analysis and a log-rank test. Presence of at least 1 PIRA episode was compared between the PRL+ and PRL- groups using a chi-squared test. Finally, rate of log-transformed EDSS change was compared between PRL+ and PRL- groups using a time by group interaction effect in a mixed-effects model, controlling for baseline age, sex, disease duration, disease modifying therapy efficacy (none, low/moderate, or high), T2 lesion volume (T2-LV), and disease course.

Results: 64 pwMS (50.6%) had at least one PRL. The PRL+ and PRL- groups had similar baseline age, sex, disease duration, overall follow-up time, EDSS, DMT usage, and disease course (p > 0.2). The PRL+ group had a greater baseline T2-LV than the PRL- group (p < 0.001). CDP was not different between the PRL+ and PRL- groups (p = 0.925), and proportion of patients with at least one PIRA episode was similar between PRL+ and PRL- groups (41.1% for PRL- and 45.3% for PRL+; p = 0.401). The time by group interaction effect was not significantly associated with EDSS (beta = 0.031, p = 0.163).

Conclusion: The present results show baseline presence of PRLs is not associated with CDP, PIRA, or longitudinal EDSS change. Further studies are needed to evaluate whether PRLs are clinically relevant in predicting future disease progression.

Disclosure of interest: Jack A. Reeves, Taylor Wicks, Maryam Mohebbi, Dejan Jakimovski, Niels Bergsland, Fahad Salman and Ferdinand Schweser have nothing to disclose.

Bianca Weinstock-Guttman has participated in speaker’s bureaus and/or served as a consultant for Biogen, EMD Serono, Novartis, Genentech, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, Bayer, Janssen, Labcorp and Horizon. Dr. Weinstock-Guttman also has received grant/research support from the agencies listed in the previous sentence. She serves in the editorial board for BMJ Neurology, Children, CNS Drugs, MS International and Frontiers Epidemiology.

Michael G. Dwyer has received personal compensation from Mapi Pharma for consultant fees. He received financial support for research activities from Bristol Myers Squibb, Mapi Pharma, Protembis and V-WAVE Medical.

Robert Zivadinov has received personal compensation from Bristol Myers Squibb, EMD Serono, Sanofi, Janssen, Sanofi, 415 Capital, Filterlex and Mapi Pharma for speaking and consultant fees. He received financial support for research activities from Novartis, Bristol Myers Squibb, EMD Serono, Octave, Mapi Pharma, CorEvitas, Protembis and V-WAVE Medical.

P566/2299

Associations between paramagnetic rim lesions and proteomic levels

Jack Reeves¹, Dejan Jakimovski¹, Maryam Mohebbi¹, Niels Bergsland¹, Fahad Salman¹, Ferdinand Schweser^1,2, Bianca Weinstock-Guttman³, Michael Dwyer^1,2, Robert Zivadinov^1,2

¹Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, United States, ²Center for Biomedical Imaging at the Clinical Translational Science Institute, University at Buffalo, State University of New York, Buffalo, United States, ³Department of Neurology, Jacobs Comprehensive MS Treatment and Research Center, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, United States

Introduction: Previous studies have shown that paramagnetic rim lesions (PRLs) are cross-sectionally associated with greater serum neurofilament light (sNFL) levels. However, it is unclear whether PRLs are associated with longitudinal changes in sNFL, or are associated with other proteomic serum markers.

Objectives/Aims: To assess whether PRLs are associated with cross-sectional levels or longitudinal changes in proteomic serum markers.

Methods: 149 people with clinically-definite MS (pwMS) received a 3T MRI scan, clinical assessment, and serum proteomic assessment at baseline (97 relapsing-remitting MS (RRMS), 52 progressive MS (PMS)) and 103 pwMS underwent an additional proteomic assessment 5 years later. Quantitative Susceptibility Mapping (QSM) was used to identify PRLs based on the proposed North American Imaging in MS PRL classification guidelines. Blood-based proteomic values were obtained for GFAP, serum neurofilament light (sNFL), APLP1, CCL20, CD6, CDCP1, CNTN2, COL4A1, CXCL13, CXCL9, FLRT2, growth hormone (GH), IL12b, MOG, OPG, OPN, PRTG, Serpina 9, TNFRS10a, TNFSf13b, and VCAN. Proteomic values were log-transformed, and baseline levels and change in proteomic levels were assessed for their relationship to baseline PRL number or PRL category (0, 1-3, or 4+ PRLs) using linear models, controlling for baseline age, sex, disease duration, disease modifying therapy efficacy (none, low/moderate, or high), T2 lesion volume (T2 LV), gadolinium-enhancing lesion volume, disease course (RRMS or PMS), body mass index, follow-up time and baseline log-proteomic levels (for longitudinal assessment).

Results: At baseline, the cohort contained 109 females and 40 males with mean age of 47.7 ± 11.6 years, disease duration 15.3 ± 10.2 years, BMI 27.3 ± 5.5, T2 LV 16.1 ± 20.2 mL, and median EDSS 3.0 (range: 0 – 8.0). 51.7% of pwMS had at least 1 PRL at baseline, with a mean of 1.9 ± 3.4 PRLs. The mean time to follow-up was 6.0 years. At baseline, none of the log-transformed proteomic values were associated with PRL number (p > 0.05) or category (p > 0.15). Longitudinally, higher PRL number was associated with a decrease in Serpina 9 (beta = -0.059, p = 0.046), with no other associations reaching statistical significance (p > 0.05).

Conclusion: We found that the only PRL-proteomic association was between baseline PRL number and 5-year decreases in Serpina 9 levels. These differ from previously-published results, which may be due to cohort differences between the studies such as higher disease duration in our cohort.

Disclosure of interest: Jack A. Reeves, Maryam Mohebbi, Dejan Jakimovski, Niels Bergsland, Fahad Salman and Ferdinand Schweser have nothing to disclose.

Bianca Weinstock-Guttman has participated in speaker’s bureaus and/or served as a consultant for Biogen, EMD Serono, Novartis, Genentech, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, Bayer, Janssen, Labcorp and Horizon. Dr. Weinstock-Guttman also has received grant/research support from the agencies listed in the previous sentence. She serves in the editorial board for BMJ Neurology, Children, CNS Drugs, MS International and Frontiers Epidemiology.

Michael G. Dwyer has received personal compensation from Mapi Pharma for consultant fees. He received financial support for research activities from Bristol Myers Squibb, Mapi Pharma, Protembis and V-WAVE Medical.

Robert Zivadinov has received personal compensation from Bristol Myers Squibb, EMD Serono, Sanofi, Janssen, Sanofi, 415 Capital, Filterlex and Mapi Pharma for speaking and consultant fees. He received financial support for research activities from Novartis, Bristol Myers Squibb, EMD Serono, Octave, Mapi Pharma, CorEvitas, Protembis and V-WAVE Medical.

P567/1909

Cortical lesion load at diagnosis predicts progression independent of relapse activity and long-term disability accumulation in multiple sclerosis

Gianmarco Schiavi¹, Damiano Marastoni¹, Tommaso Becchi², Stefano Ziccardi¹, Agnese Tamanti¹, Maddalena Guandalini¹, Anna Isabella Pisani¹, Annalisa Colombi¹, Roberta Magliozzi¹, Antonio Scalfari³, Chiara Romualdi², Nicola De Stefano⁴, Massimiliano Calabrese¹

¹University of Verona, Verona, Italy, ²University of Padua, Padua, Italy, ³Imperial College of London, Centre for Neuroscience, Department of Medicine, London, United Kingdom, ⁴University of Siena, Siena, Italy

Introduction: Cortical lesions (CLs) are frequently observed in MS and are one of the major drivers of disability accumulation since the early stage

Objectives/Aims: The impact of CLs on the progression independent of relapse activity (PIRA) and the long-term disability accumulation remains to be fully elucidated.

Methods: We retrospectively evaluated 199 RRMS patients (F=135), who underwent brain and spinal cord (SC) MRI at diagnosis and after two years, to assess CL number (CLn, with Double Inversion Recovery sequences), CL volume (CLv), WM lesions number and volume, presence of SC lesions and Gd enhancing lesions. Confirmed disability worsening (CDW) was assessed, based on EDSS increase by ⩾1.5, 1 or 0.5 points according to baseline EDSS (0,<5.5 or ⩾5.5, respectively). PIRA was defined as a 6-month CDW in which the EDSS-worsening occurred at least 90 days from previous relapse and was sustained in all following assessments Random survival forest (RSF) and Cox multivariate regression models were adopted to predict sustained PIRA and time to EDSS ⩾4 and ⩾6.

Results: The mean follow-up was 18.0±3.2 yrs. Eighty-three patients (41.7%) had a PIRA event after a mean of 7.6±3.6 yrs. Patients with PIRA had at diagnosis higher CLn (mean 4.7±3.7 vs 0.3±0.9, p<0.001) and volume (mean 482.2±406.2 mm³ vs 34.4±77.6 mm³, p<0.001), compared to those free of PIRA. After RSF, higher CLn, CLv, and EDSS at the diagnosis were factors best associated with the risk of PIRA. Multivariate regression (with MRI, demographics, clinical variables including therapies) confirmed a higher number of CLs (HR 1.15 [CI 1.41-2.31], p<0.001), a larger CLv (HR 1.00 [CI 1.00- 1.00],p=0.003) and higher EDSS (HR 1.15 [CI 1.41-2.31], p<0.001) at diagnosis as predictive of PIRA.

During the follow-up, 54 (27%) patients reached an EDSS ⩾4 (mean time 9.6±4.6 yrs) and 28 (14%) an EDSS ⩾6 (mean time 11.5±3.5yrs): higher CLv, CLn, baseline EDSS and presence of SC lesions were best predictors of both outcomes with the models mentioned above.

ROC analysis estimated ⩾3 CLs as the optimal cut-off to identify patients more likely to develop PIRA (⩾3,HR 12.2 [CI 3.55-41.8],p< 0.001).

Finally, 2-year accumulation of new CLs predicted the risk of PIRA (HR 1.3 [CI 1.1-1.5],p<0.001), and to attain EDSS⩾4 and ⩾6 (HR 1.28[CI 1.09-1.51],p=0.002, and HR 1.39 [CI 1.12-1.73],p=0.003, respectively).

Conclusion: Early accumulation of focal cortical damage is an independent predictor of PIRA and long-term disability, suggesting a role of focal cortical pathology in driving disease progression unrelated to relapses.

Disclosure of interest: D Marastoni received honoraria for research or speaking and funds for travel from Roche, Biogen Idec, Sanofi-Genzyme, Novartis, BMS and grant research from Italian Health Minister. M. Calabrese received honoraria for research or speaking and funds for travel from Roche, Sanofi-Genzyme, Merck-Serono, Biogen Idec, Teva and Novartis Pharma.

P568/1421

Phenotyping of chronic inflammation in vivo in multiple sclerosis by combined 11CPBR28 Translocator Protein targeting and 7T susceptibility-weighted imaging

Constantina Treaba^1,2, Elena Herranz^1,2, Valeria Barletta^1,2, Ambica Mehndiratta¹, Jacob Sloane³, Tobias Granberg^4,5, Marco Loggia^1,2, Caterina Mainero^1,2

¹Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Radiology, Boston, United States, ²Harvard Medical School, Boston, United States, ³Beth Israel Deaconess Medical Center, Boston, United States, ⁴Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden, ⁵Karolinska University Hospital, Department of Neuroradiology, Stockholm, Sweden

Introduction: Positron emission tomography (PET) targeting of the Translocator Protein (TSPO), which is overexpressed in activated glia, and assessment of paramagnetic rim lesions (PRL) on susceptibility-weighted images have recently emerged as in vivo imaging tools for evaluating chronic inflammation in multiple sclerosis (MS). However, a univocal consensus on the optimal biomarker for MS chronic inflammation still needs to be reached. Both approaches detect different aspects, and studies directly comparing these methods are limited.

Objectives/Aims: To compare ¹¹CPBR28 TSPO targeting to PRL assessment on 7T susceptibility imaging in their ability to identify chronic inflammation and its correlates in a heterogeneous MS population.

Methods: Thirty MS patients underwent 90-min ¹¹CPBR28 imaging on an integrated 3T MR-PET system and susceptibility-weighted imaging at 7T two weeks apart. ¹¹CPBR28 binding was measured using normalized 60-90 min standardized uptake values (SUVR). T1/T2-weighted myelin-sensitive images were simultaneously acquired to PET data. Phase reconstructions at 7T were used to identify PRL. The relative difference in white matter (WM) SUVR between patients and 21 healthy controls (HC), matched for age, and ¹¹CPBR28 affinity was used to classify WM lesions as active or inactive. PET active lesions were further classified as PET rim lesions (PET-RL) if the mean SUVR at the lesion periphery were above 0.5 SD from the mean SUVR in the core.

Results: We identified 42 PRL. Mean PRL SUVR did not significantly differ from mean rimless lesion SUVR. In fact, 451/1040 (43.4%) 7T rimless lesions resulted as active on PET: 75 PET-RL and 376 PET active throughout the entire lesion (PET-WL). Relative to HC and MS normal-appearing white matter (NAWM), PET-RL, PRL, and PET-WL had significantly lower T1/T2 values (p<0.002) but were no differences between active lesion types. There was a trend of significance for lower T1/T2 in PRL relative to PET inactive lesions. Out of all WM imaging metrics, only mean NAWM SUVR (ρ=0.41, p=0.02), rimless WM lesion volume (ρ=0.63, p<0.001), and PET active lesion volume (PET-WL+PET-RL, ρ=0.70, p<0.001) positively correlated with Expanded Disability Status Scale scores.

Conclusion: TSPO PET imaging reveals more active WM lesions, including peripherally active lesions, than PRL assessment at 7T. Although PRL and PET active lesions show similar levels of tissue destruction, PET detection of diffuse and focal WM inflammation has the strongest association with neurological disability.

Disclosure of interest: This study was funded by Genentech.

Dr. Treaba has nothing to disclose.

Dr. Herranz has nothing to disclose.

Dr. Barletta has nothing to disclose.

Ms. Mehndiratta has nothing to disclose.

Dr. Sloane has consulted for Novartis, Biogen, Cellgene, Genentech.

Dr. Granberg is a recipient of the Grant for Multiple Sclerosis Innovation, funded by Merck.

Dr. Loggia has nothing to disclose.

Dr. Mainero has received research support from Genentech.

P569/1399

Ocrelizumab treatment reduces glia activation in the brain of MS patients: a 11C-PBR28 imaging study

Constantina Treaba^1,2, Valeria Barletta^2,3, Elena Herranz^2,3, Eric Klawiter^2,4, Jacob Sloane⁵, CAROLINA IONETE⁶, Rebecca Gillani^2,7, Roberto Bomprezzi⁶, Caterina Mainero^1,2

¹Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Radiology, Boston, United States, ²Harvard Medical School, Boston, United States, ³Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Radiology, Boston, United States, ⁴Massachusetts General Hospital, Neurology, Boston, United States, ⁵Beth Israel Deaconess Medical Center, Neurology, Boston, United States, ⁶UMass Chan Medical School, Neurology, Worcester, United States, ⁴Massachusetts General Hospital, Neurology, Boston, United States

Introduction: Ocrelizumab, a humanized monoclonal antibody targeting the B cell CD20 marker, improves clinical and MRI measures of disease activity and progression in phase III multiple sclerosis (MS) clinical trials. Compartmentalized chronic inflammation sustained by activated glia has been demonstrated at all MS stages associated with disease progression. Molecular imaging of the translocator protein (TSPO), overexpressed in activated glia/macrophages, can be used to study chronic inflammation in vivo. Positron emission tomography (PET) studies consistently demonstrate abnormal TSPO expression in people with MS.

Objectives/Aims: To evaluate, using ¹¹C-PBR28, a second-generation TSPO radiotracer, whether 1-year Ocrelizumab treatment reduces brain glial activation in MS.

Methods: Seventeen MS patients (13 relapsing-remitting, 4 progressive MS; RRMS, PMS) with mixed or high-affinity for ¹¹C-PBR28 were prospectively enrolled in the study. Subjects underwent 90-min simultaneous 3T MR-PET after ¹¹C-PBR28 injection at baseline within a mean of 23±19 days before starting Ocrelizumab. The same protocol was repeated following 1-year treatment in 7 patients (6 RRMS,1 PMS). ¹¹C-PBR28 standardized uptake values normalized by a pseudo-reference region (SUVR) were reconstructed from 60-90 min acquisitions in different brain tissue compartments, segmented from FreeSurfer, at both time points. Univariate correlations between SUVR and clinical metrics were investigated. Longitudinal SUVR changes were assessed using paired t-tests.

Results: At baseline, SUVR inversely correlated with information processing speed as measured by the Symbol Digit Modalities Test in the hippocampus (ρ=-0.7, p=0.003), thalamus (ρ=-0.6, p=0.02), and normal-appearing white matter (NAWM, ρ=-0.5, p=0.04). We did not find any association with neurological disability. At 1-year follow-up, a significant decrease in the mean ¹¹C-PBR28 SUVR was observed in several regions, including the hippocampus (1.18vs1.09, p=0.05), thalamus (1.37vs1.26, p=0.05), NAWM (1.03vs0.95, p=0.05). There was a trend for SUVR decrease in white matter lesions (0.92vs0.85, p=0.06) and cortical sulci (1.13vs1.04, p=0.06).

Conclusion: Our initial data suggest that Ocrelizumab treatment reduces the diffuse compartmentalized CNS inflammation related to brain resident innate immune cells. Enrollment and collection of additional follow-up data are ongoing. ¹¹C-PBR28 MR-PET can be used to assess longitudinal changes in neuroinflammation across the brain in MS patients.

Disclosure of interest: This study was funded by Genentech.

Dr. Treaba has nothing to disclose.

Dr. Barletta has nothing to disclose.

Dr. Herranz has nothing to disclose.

Dr. Klawiter received personal compensation as a Consultant for Galen/Atlantica; for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech, Banner Life Sciences, Greenwich Biosciences, OM1, TG Therapeutics. Dr. Klawiter also received research support from Biogen, Abbvie, Genzyme and Genentech.

Dr. Sloane has consulted for Novartis, Biogen, Cellgene, Genentech.

Dr. Ionete has received personal compensation for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi and received research support from Genentech and Biogen.

Dr. Gillani has nothing to disclose.

Dr. Bomprezzi has nothing to disclose.

Dr. Mainero has received research support from Genentech.

P570/1907

A periventricular gradient of paramagnetic rim lesion distribution and its correlates in multiple sclerosis: a 7-Tesla imaging study

Alessandro Miscioscia^1,2, Constantina Treaba^1,3, Valeria Barletta^1,3, Elena Herranz^1,3, Jacob Sloane^1,4, Elena Barbuti^1,5, Caterina Mainero^1,3

¹Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Department of Radiology, Boston, United States, ²University of Padua, Deparment of Neuroscience, Padua, Italy, ³Harvard Medical School, Boston, United States, ⁴Beth Israel Deaconess Medical Center, Department of Neurology, Boston, United States, ⁵Sapienza University of Rome, Sant'Andrea Hospital, Department of Neurology, Roma, Italy

Introduction: In multiple sclerosis (MS) MRI studies have demonstrated a ‘surface-in’ gradient of pathological changes as a function of distance from cerebrospinal fluid (CSF), possibly triggered by CSF inflammatory soluble factors. Paramagnetic rim lesions (PRL) are an important manifestation of chronic white matter (WM) MS inflammation and have implications for non-relapsing biological progression. These lesions are characterized by a paramagnetic rim, which is easily detectable on 7T susceptibility-weighted images and colocalizes with iron-laden microglia. Whether PRL development and distribution is influenced by CSF inflammatory factors is unknown.

Objectives/Aims: To investigate i) PRL distribution as a function of distance from ventricular CSF; ii) and its the relationship with clinical and imaging measures including cortical lesions, as CSF driven inflammation with microglia activation is thought to be involved in the pathogenesis of cortical demyelination in MS.

Methods: Ultra-high resolution brain T2*-weighted gradient-echo sequences, yielding magnitude and phase images, were acquired at 7T from 27 MS patients (15 relapsing-remitting MS, RRMS, 12 progressive MS, PMS) to obtain PRL, leukocortical, intracortical and total cortical lesion (LCL, ICL, TCL) volumes. The WM was divided into 1-mm-thick concentric bands radiating from the ventricular surface toward the cortex, and the PRL volume was extracted from each band. Correlations between PRL and clinical and structural measures were evaluated using linear mixed-effects models and Spearman correlations.

Results: PRL volume was higher in the periventricular WM and declined with increasing distance from ventricular surface (intercept= 93 mm3, slope = -3.04, P<0.001). The higher the PRL volume in the bands at the closest proximity to the ventricles, the longest disease duration (ρ= 0.40, P= 0.037), the greater WM non-rim lesion volume (ρ= 0.58, P= 0.001), and the lower NAWM volume (ρ= -0.41, P= 0.033) and thalamic volume (ρ= -0.48, P= 0.011). PMS also showed a significant correlation between PRL volume in ventricle-closest bands and LCL volume (ρ= 0.58, P= 0.048).

Conclusion: PRL, an imaging marker of MS chronic inflammation, show a periventricular gradient of distribution, which correlates with measures of neurodegeneration and, in PMS, with cortical lesion load. Our data suggest that, in common with cortical lesion pathogenesis, PRL development could be influenced by CSF-derived immune soluble factors.

Disclosure of interest: This study was funded by Genentech.

Dr. Miscioscia has nothing to disclose.

Dr. Treaba has nothing to disclose.

Dr. Barletta has nothing to disclose.

Dr. Herranz has nothing to disclose.

Dr. Sloane has consulted for Novartis, Biogen, Cellgene, Genentech.

Dr. Barbuti has nothing to disclose.

Dr. Mainero has received research support from Genentech.

P571/140

Increased white matter disconnectivity and inflammation in multiple sclerosis patients with paramagnetic rim lesions

Ceren Tozlu¹, Keith Jamison¹, Yeona Kang², Ulrike W Kaunzner³, Elizabeth Sweeney⁴, Amy Kuceyeski¹, Susan Gauthier³

¹Weill Cornell Medicine, Department of Radiology, NYC, United States, ²Howard University, Department of Mathematics, Washington DC, United States, ³Weill Cornell Medicine, Department of Neurology, NYC, United States, ⁴University of Pennsylvania, Department of Biostatistics, Epidemiology, and Informatics, Philadelphia, United States

Introduction: Paramagnetic rim lesions (PRL) that occur in people with multiple sclerosis (MS) are characterized by iron-laden active microglia and macrophages. PRL lesions were shown to have more inflammation measured on ¹¹C-PK11195-PET (Kaunzner et al., 2019) and to be associated with more disability (Marcille et. al, 2022; Hemond et al., 2022). However, how PRLs impact connected white matter (WM) beyond the lesion in terms of their dysconnectivity patterns and association with diffuse inflammation, have not yet been studied.

Objectives/Aims: Our study aims to investigate (1) the association between change in connectivity (ChaCo) due to PRL and PK11195-PET binding metrics on the WM in MS patients with at least one PRL compared to those without a PRL and (2) the association of disability with global ChaCo and inflammatory activity on the white matter streamlines.

Methods: Forty subjects (age 45.25±13.91, 60% female) were included in our study; Expanded Disability Status Scale (EDSS) was used to measure disability. Global inflammation was computed by averaging voxel-wise ¹¹C-PK11195 PET binding metrics. Quantitative susceptibility mapping (QSM) was used to distinguish PRL vs non-PRL status of all T2 FLAIR lesions. Then, the Network Modification tool (Kuceyeski et al., 2013) was used to estimate voxel-wise WM disconnectivity due to all MS lesions; global disconnectivity was the average of these values over all WM voxels. Pearson’s correlation (r) was used to assess the association between voxel-wise inflammatory activity and WM ChaCo.

Results: Twenty-four MS patients with at least one PRL had greater global WM disconnection and inflammation compared to those without PRL (p<0.05 for both comparisons). In PRL subjects, worse disability was associated with increased WM disconnection (r=0.39, p=0.05) and increased inflammation (r=0.43, p=0.03), relationships that were not significant in non-PRL subjects. The voxel-wise correlation between the inflammatory activity and WM disconnection in patients with PRL was positive (mean r = 0.48 across subjects with PRL) and greater (p<0.05) compared to patients without PRL (mean r = 0.40 across subjects without PRL).

Conclusion: Our study shows that, in people with MS having PRLs, WM voxels that are more disconnected because of a lesion also have increased inflammatory activity measured with ¹¹C-PK11195 PET, and, importantly, both WM disconnection and inflammation markers were associated with disability in MS patients with PRL.

Disclosure of interest: No conflict of interest

P572/373

Incorporation of the central vein sign into the International Panel criteria increases specificity and accuracy for a diagnosis of multiple sclerosis

Moein Amin¹, Kunio Nakamura², Lynn Daboul^3,4, Carly O'Donnell⁵, Quy Cao⁵, Paulo Rodrigues⁶, John Derbyshire⁷, Christina Azevedo⁸, Amit Bar-Or⁹, Eduardo Caverzasi^10,11, Peter Calabresi¹², Bruce Cree¹¹, Leorah Freeman¹³, Roland Henry¹¹, Erin Longbrake¹⁴, Jiwon Oh¹⁵, Nico Papinutto¹¹, Daniel Pelletier⁸, Vesna Prchkovska⁶, Praneeta Raza⁴, Marc Ramos⁶, Rohini Samudralwar^9,16, Matthew Schindler⁹, Elias Sotirchos¹², Nancy Sicotte¹⁷, Andrew Solomon¹⁸, Russell Shinohara⁵, Daniel Reich³, Pascal Sati^3,17, Daniel Ontaneda¹

¹Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, United States, ²Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, United States, ³Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States, ⁴Cleveland Clinic Lerner College of Medicine, Cleveland, United States, ⁵Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States, ⁶QMENTA Inc., Boston, United States, ⁷Functional MRI Facility, NIMH, National Institutes of Health, Bethesda, United States, ⁸Department of Neurology, University of Southern California, Los Angeles, United States, ⁹Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States, ¹⁰Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy, ¹¹UCSF Weill Institute for Neurosciences, Department of Neurology, University of California at San Francisco, San Francisco, United States, ¹²Department of Neurology, Johns Hopkins University, Baltimore, United States, ¹³Department of Neurology, Dell Medical School, The University of Texas, Austin, United States, ¹⁴Department of Neurology, Yale University, New Haven, United States, ¹⁵Division of Neurology, St. Michael’s Hospital, University of Toronto, Toronto, Canada, ¹⁶Department of Neurology, University of Texas Health Science Center, Houston, United States, ¹⁷Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, United States, ¹⁸Department of Neurological Sciences, Larner College of Medicine, The University of Vermont, Burlington, United States

Introduction: The diagnosis of multiple sclerosis (MS) relies on establishing dissemination in time (DIT) and dissemination in space (DIS) as codified in the 2017 International Panel criteria (IP2017). Although sensitive, the IP2017 has a misdiagnosis rate of 20%, primarily attributed to incorrect application of MRI criteria. The central vein sign (CVS) is a putative diagnostic biomarker for MS that may increase specificity and diagnostic accuracy, but how to optimally incorporate CVS with the IP2017 criteria is not established.

Objectives/Aims: To evaluate the diagnostic performance of different CVS criteria incorporated into IP2017.

Methods: This analysis used data from the Central Vein in Multiple Sclerosis Pilot, a cross-sectional, international multi-center study conducted by North American Imaging in MS Cooperative at 10 sites from April 2018 - February 2020. The study collected data on 97 adults referred to an academic MS center for a clinical or radiological suspicion of MS. Participants with unclear final diagnosis and incomplete MRI were excluded. IP2017 was based on clinical documentation and adjudicated by 3 experts. Independent blinded MRI assessments for IP2017 DIS and DIT were evaluated using T2-weighted, FLAIR, pre and post contrast T1-weighted MPRAGE sequences on the QMENTA platform. CVS was assessed on post-contrast T2*-weighted segmented echoplanar imaging, merged with FLAIR images (FLAIR*). DIS was defined per IP2017 on the study MRI, and DIT was defined as presence of enhancing and non-enhancing lesions. Incorporation of CVS into IP2017 was examined by requiring one of the following criteria in addition to DIS: (a) only CVS+ lesions can be used to meet DIS CVS; (b) ⩾1 of the lesions used to meet DIS is CVS+; (c) ⩾1 brain lesion with CVS irrespective of location.

Results: 89 participants were included in the analysis, 36 with MS and 53 with other diagnoses. Sensitivity, specificity, and accuracy were, respectively: 92%, 70%, and 79% for DIS alone; 25%, 100%, and 70% for DIT alone; and 25%, 100%, and 70% for DIS plus DIT. Optimal diagnostic performance was seen with requirement of at least one lesion with CVS in any location in addition to DIS with sensitivity, specificity, and accuracy of 92%, 79%, and 84%, respectively. All other combinations of DIS, DIT, and CVS had worse diagnostic performance.

Conclusion: Addition of CVS to IP2017 increases the specificity for DIS without an impact on sensitivity. Requiring one CVS in addition to DIS could be easily implemented in clinical practice and can be evaluated in future prospective studies.

Disclosure of interest: MA: Received Novartis fellowship award NGC4474.

KN: Received licensing fee from Biogen; received Research Support from Department of Defense, National Institutes of Health, Patient Centered Outcomes Research Institute, and Biogen.

LD: None

CMO: None

QC: None

PR: Employed by and holds stocks in QMENTA

JD: None

CA: Has received grant support from the National Multiple Sclerosis Society and the NIH. Has received consulting fees from Horizon Therapeutics, Genentech, Sanofi Genzyme, TG Therapeutics, and EMD Serono. Has received honoraria for serving on grant review committees for the Department of Defense and the NIH and for participation in unbranded CME activities from the American Academy of Neurology, Efficient LLC, Spire Learning, and Catamount Medical Education

AB: Consulting and/or advisory board fees from Accure, Atara Biotherapeutics, Biogen, BMS/Celgene/Receptos, GlaxoSmithKline, Gossamer, Janssen/Actelion, Medimmune, Merck/EMD Serono, Novartis, Roche/Genentech, Sanofi-Genzyme. Grant support to the University of Pennsylvania from Biogen Idec, Roche/Genentech, Merck/EMD Serono and Novartis. Research funding from the National Institutes of Health (NIH), The National MS Society (NMSS), the Juvenile Diabetes Research Foundation (JDRF), the Canadian Institutes of Health Research, Multiple Sclerosis Society of Canada.

EC: None

PAC: PI on grants to JHU from Genentech. Serves on scientific advisory boards for Lilly and Idorsia.

BACC: Compensation for consulting from: Alexion, Atara, Biogen, EMD Serono, Novartis, Sanofi, and TG Therapeutics

LF: Received fees for consultancy and/or advisory board participation from Genentech, Novartis, Celgene/Bristol Myers Squibb, EMD Serono, and TG Therapeutics; Received fees for educational activities from Medscape, LLC, and the MS Association of America; program sponsorship to UT from EMD Serono; and grant support to UT from NIH/NINDS, PCORI, Genentech, and EMD Serono.

RGH: Research support from Roche, Genentech, Atara, Medday. Consulting for Novartis, Sanofi/Genzyme, Roche/Genentech, QIA, and Neurona.

EEL: Grants: Genentech, Biogen. Consulting: EMD Serono, BMS, Genentech, Genzyme, Bristol Myers Squibb, TG Therapeutics, Janssen, NGM Bio

JO: Research support from Biogen-Idec, Roche, and EMD-Serono; consulting compensation from EMD-Serono, Sanofi-Genzyme, Biogen-Idec, Roche, Celgene, and Novartis

NP: Reports research support from the Race to Erase MS Foundation and from the National Center for Advancing Translational Sciences, National Institutes of Health, through a UCSF-CTSI grant

DP: Consulting compensation from EMD-Serono, Sanofi Genzyme, Roche, and Novartis

VP: Employed by and holds stocks in QMENTA

PR: None

MR: Employed by and holds stock options in QMENTA

RDS: Advisory board participation (Biogen, EMD Serono, Sanofi Genzyme); Consulting (EMD Serono, Biogen)

MKS: None

ESS: Consulting for scientific advisory boards from Viela Bio and Genentech, Speaker honoraria from Viela Bio

NLS: Research support from the National Institutes of Health, National Multiple Sclerosis Society, Patient Centered Outcomes Research Institute, Race to Erase MS Foundation and Biogen-Idec

AJS: Consulting: EMD Serono, Biogen, Alexion, Celgene, Greenwich Biosciences, Octave Bioscience, TG Therapeutics, Sanofi; Non-promotional speaking: EMD Serono; Research Funding: Biogen, Bristol Myers Squibb; Contracted Research: Biogen, Novartis, Actelion, Genentech/Roche

RTS: Supported NIH R01NS112274, R01MH112847, R01MH123550. Consulting income from Octave Bioscience.

DSR: Supported by the Intramural Research Program of NINDS; additional research support from Vertex Pharmaceuticals, Sanofi-Genzyme, and Abata Therapeutics.

PS: Research support from the National Institutes of Health and the National Multiple Sclerosis Society.

DO: Received research support from the National Institutes of Health, National Multiple Sclerosis Society, Patient Centered Outcomes Research Institute, Race to Erase MS Foundation, Genentech, Genzyme, and Novartis. Consulting fees from Biogen Idec, Genentech/Roche, Genzyme, Novartis, and Merck.)

P573/1033

Imaging multiple sclerosis with demyelination tracer [18F]3F4AP

Eric Klawiter¹, Andrew Russo¹, Nicolas Guehl¹, Karla Ramos-Torres¹, Amal Tiss¹, Nicole Dasilva¹, Fang Liu¹, Brian Popko², Marc Normandin¹, Kuang Gong¹, Georges El Fakhri¹, Pedro Brugarolas¹

¹Massachusetts General Hospital, Boston, United States, ²Northwestern University, Evanston, United States

Introduction: The PET tracer [¹⁸F]3F4AP is a radiolabeled analog of the MS drug 4-aminopyridine (4AP, dalfampridine) that binds to K⁺ channels in demyelinated axons. Previous studies in rodents and monkeys demonstrate high sensitivity of [¹⁸F]3F4AP for demyelinated lesions.

Objectives/Aims: To further investigate the ability of [¹⁸F]3F4AP to detect brain demyelination in vivo with a first-in-human study.

Methods: Three healthy controls and three people with MS underwent a dynamic PET scan after injection of ~10 mCi of [¹⁸F]3F4AP and a 3T MRI. MR sequences included MEMPRAGE, T2FLAIR, myelin water imaging (MWI) and post-gadolinium T1. Summed PET images corresponding to 60-120 minute frames were generated after applying partial volume correction and motion correction. PET and MR images were co-registered. Lesions were manually segmented on T2FLAIR. Grey matter (GM) and normally appearing white matter (NAWM) masks were made for each subject. For comparison to lesions, NAWM regions of similar size and location were segmented for each subject. Mean PET standardized uptake value (SUV) and myelin water fraction (MWF) were extracted for GM, NAWM and for each lesion.

Results: Across all subjects, the PET signal in GM was 8.8 ± 2.4% higher than NAWM (SUV_60-120min 0.52 ± 0.13 vs. 0.48 ± 0.13), consistent with the distribution of K⁺ channels. Each participant with MS showed multiple lesions on T2FLAIR (range 10-34), all non-enhancing on post-gadolinium T1. The PET signal in MS lesions was 10.2 ± 5.8% higher than NAWM regions (p < 0.05) with 1-3 lesions in each subject showing particularly high signal (>25% higher than NAWM mean). There was a modest inverse correlation between PET signal and MWF (R² = 0.224, p=0.047) in one participant but not the other two.

Conclusion: [¹⁸F]3F4AP showed higher uptake in lesions compared to NAWM with a few lesions showing particularly high uptake. The weak correlation between PET and MWF suggests that [¹⁸F]3F4AP may only bind to demyelinated lesions with spared axons whereas MWI may show a decreased value in lesions with or without spared axons. These findings provide initial evidence that [¹⁸F]3F4AP is a potential quantitative marker of demyelinated axons with application for remyelinating therapies.

Disclosure of interest: Eric C. Klawiter: ECK has received consulting fees from Banner Life Sciences, EMD Serono, Galen/Atlantica, Genentech, Greenwich Biosciences, INmune Bio, and OM1. ECK has received research funds from Abbvie, Biogen, and Genentech.

Andrew W. Russo: nothing to disclose

Nicolas J. Guehl: nothing to disclose

Karla M. Ramos-Torres: nothing to disclose

Amal Tiss: nothing to disclose

Nicole E. Dasilva: nothing to disclose

Fang Liu: nothing to disclose

Brian J. Popko: BJP is a named inventor in patents related to [18F]3F4AP owned by the University of Chicago and licensed to Fuzionaire Diagnostics.

Marc D. Normandin: nothing to disclose

Kuang Gong: nothing to disclose

Georges El Fakhri: nothing to disclose

Pedro Brugarolas: PB is a named inventor in patents related to [18F]3F4AP owned by the University of Chicago and licensed to Fuzionaire Diagnostics. PB is a consultant for Fuzionaire Diagnostics.

P574/1058

Choroid plexus volume and slowly expanding lesions as inflammatory markers in relapsing multiple sclerosis

Muhammad Raghib¹, Fen Bao¹, Mahmoud Elkhooly¹, Emily Lazar¹, Adam Lazar¹, Zaima Liaquat¹, Zahid Latif¹, Xiufang Jia¹, Carla Martinez¹, Jacob Rube¹, Evanthia Bernitsas¹

¹Wayne State University, Detroit, United States

Introduction: Slowly expanding lesions (SELs) are markers of chronic inflammation, seen in all phenotypes of multiple sclerosis (MS), and are identified through longitudinal deformation analysis using routinely acquired volumetric magnetic resonance imaging (MRI). Studies have suggested that the expansion of MS lesions and enlargement of choroid plexus (CP) may be linked to chronic inflammation.

Objectives/Aims: We investigated the potential association between total CP volume (tChPV) and SELs in MS patients.

Methods: One hundred seven MS patients were included in this cross-sectional study. Each patient underwent a whole brain MRI scan on a SIEMENS 3T Verio system. FreeSurfer software package (v7) performed automated segmentation of the CP within the lateral ventricles on 3D T1-weighted images. tChPV was calculated by adding the CP volumes measured in the left and right lateral ventricles. SELs were identified when they presented with a hypointense paramagnetic rim signal on filtered phase images from susceptibility-weighted imaging (SWI) sequences and were not presented as gadolinium-enhancing lesions on post-contrast T1-weighted images. The number of SELs was estimated on each scan. tChPV was adjusted for age, gender, and total intracranial volume. Linear regression analysis was performed using SPSS v29 to check for an association between tChPV and the number of SELs. A p-value of <0.05 was considered significant.

Results: The mean age of patients was 41.03 years±10.71 (females=73, males=34) with a median expanded disability status scale (EDSS) of 1.5 (2.5-4.9), and a disease duration of 7.87 years±7.49. The mean tChPV was 1.32 mL ± 0.47 and the mean number of SELs was 6.47 ± 5.29. There was a significant positive correlation observed between tChPV and the number of SELs (β=0.378, p<0.001).

Conclusion: Our results demonstrate a significant positive correlation between tChPV and the number of SELs indicating the possible role of both entities being used as inflammatory biomarkers in MS.

Disclosure of interest: Muhammad Faraz Raghib: Nothing to disclose

Fen Bao: Nothing to disclose

Mahmoud Elkhooly: Nothing to disclose

Emily Lazar: Nothing to disclose

Adam Lazar: Nothing to disclose

Zaima Liaquat: Nothing to disclose

Zahid Latif: Nothing to disclose

Xiufang Jia: Nothing to disclose

Carla Santiago Martinez: Nothing to disclose

Jacob Rube: Nothing to disclose

Evanthia Bernitsas: Received research grants from Roche/Genentech, Sanofi-Genzyme, Bristol-Meyers-Squibb. Received consulting fees from Biogen, Roche/Genentech, Alexion, Horizon. and royalties from the Brain Sciences Journal as Editor-in Chief.

P575/1051

Choroid plexus volume correlates with advanced MRI metrics in relapsing multiple sclerosis

Fen Bao¹, Muhammad Raghib¹, Adam Lazar¹, Mahmoud Elkhooly¹, Zaima Liaquat¹, Xiufang Jia¹, Zahid Latif¹, Carla Martinez¹, Jacob Rube¹, Evanthia Bernitsas¹

¹Wayne State University, Detroit, United States

Disclosure of Introduction: Evidence supports the use of advanced magnetic resonance imaging metrics (AMRIM) to evaluate the severity of multiple sclerosis (MS). These AMRIM include magnetization transfer ratio (MTR), fractional anisotropy (FA), mean diffusivity (MD), and the ratio of total N-acetyl-aspartate concentration/total creatine concentration (tNAA/tCr) using proton magnetic resonance spectroscopy (¹H-MRS).

Objectives/Aims: We investigated the relationship between total choroid plexus (CP) volume (tChPV) and AMRIM in normal-appearing white and gray matter (NAWM and NAGM) in MS.

Methods: One hundred seven MS patients were included in this cross-sectional study. Each patient underwent a whole brain MRI scan on SIEMENS 3T Verio system. FreeSurfer software package (v7) performed automated segmentation of CP within the lateral ventricles on 3D T1-weighted images. tChPV was calculated by adding CP volumes measured in the left and right lateral ventricles. tChPV was adjusted for age, gender, and total intracranial volume. Linear regression analysis was performed using SPSS v29 to check for an association between tChPV and AMRIM. p-value of <0.05 was considered significant.

Results: The mean age of patients was 41.03 years ±10.71 (females=73, males=34) with a disease duration of 7.87 years±7.49. The mean tChPV was 1.32 mL±0.47. We reported the mean MTR in NAGM (48.66% ±1.44) and NAWM (56.36% ±1.33), FA in NAGM (0.24±0.01) and NAWM (0.43±0.03), MD in NAGM (1.00 x10^-3 mm²/s ±0.08) and NAWM (0.78 x10^-3 mm²/s ±0.05), and tNAA/tCr in central white matter (2.03±0.24). There was a significant correlation between tChPV and MTR in NAGM (β=-0.524, p<0.001) and NAWM (β=-0.388, p=0.003), FA in NAGM (β=-0.420, p<0.001) and NAWM (β=-0.490, p<0.001), MD in NAGM (β=0.579, p<0.001) and NAWM (β=0.584, p<0.001), and tNAA/tCr (β=0.388, p<0.001).

Conclusion: Our results demonstrate a significant correlation between tChPV and AMRIM. As the diagnosis of MS is complex, the use of tChPV may provide a more distinct multidimensional approach to quantify the pathological process and treatment response in MS.

Disclosure of interest: Fen Bao: Nothing to disclose

Muhammad Faraz Raghib: Nothing to disclose

Adam Lazar: Nothing to disclose

Mahmoud Elkhooly: Nothing to disclose

Zaima Liaquat: Nothing to disclose

Xiufang Jia: Nothing to disclose

Zahid Latif: Nothing to disclose

Carla Santiago Martinez: Nothing to disclose

Jacob Rube: Nothing to disclose

Evanthia Bernitsas: Received research grants from Roche/Genentech, Sanofi-Genzyme, Bristol-Meyers-Squibb. Received consulting fees from Biogen, Roche/Genentech, Alexion, Horizon. and royalties from the Brain Sciences Journal as Editor-in Chief.

P576/1396

A novel model for performing lesion-adjusted structural connectivity in multiple sclerosis patients

Sara Bosticardo^1,2,3,4, Matteo Battocchio¹, Po-Jui Lu^2,3,4, Xinjie Chen^2,3,4, Sabine Schädelin², Matthias Weigel^2,3,4, Alessandro Cagol^2,3,4,5, Mario Ocampo-Pineda^2,3,4, Lester Melie-Garcia^2,3,4, Alessandro Daducci¹, Cristina Granziera^2,3,4

¹University of Verona, Diffusion Imaging and Connectivity Estimation (DICE) Lab, Department of Computer Science, Verona, Italy, ²Faculty of Medicine, University Hospital Basel and University of Basel, Translational Imaging in Neurology (ThINK) Basel, Department of Biomedical Engineering, Faculty of Medicine, Basel, Switzerland, ³University Hospital Basel, Department of Neurology, Basel, Switzerland, ⁴University Hospital Basel and University of Basel, Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), Basel, Switzerland, ⁵University of Genova, Department of Health Sciences, Genova, Italy

Introduction: Quantitative tractography models assume constant microstructural values along fibre trajectories. However, in multiple sclerosis (MS), the presence of focal lesions could bias structural connectivity (SC) estimations and reduce the sensitivity to pathology.

Objectives/Aims: In this work, we apply a novel multi-compartment model to accurately describe the impact of focal lesions on connectomes of MS patients.

Methods: We reconstructed connectomes of 85 healthy controls (HC) (47f, 37.4±12.9y.o.) and 111 MS patients (63f, 44.9±14.7y.o., median EDSS 2.5, range:0-8) by combining tractography with myelin volume fraction (MVF) maps to quantify the myelin content of each fibre bundle. Traditional methods do not consider the lesions in the estimation; in contrast, our novel method includes a dedicated compartment to explicitly account for lesions and, thus, provides more accurate estimates of the myelination of each bundle as well as of the axonal damage within lesions.

We examined four global network metrics: mean strength S (connection strength), efficiency E (information exchange), modularity M (network segregation), and clustering coefficient CC (number of nodes clustered together). We report only bundles that are significant: cingulum CB, cortico-spinal CS, and inferior-occipital frontal IOF. We used a robust linear model corrected for age, sex, WM volume, and network density to compare SC between patients and HC. We used a gamma regression model adjusted for age and sex to test the impact of pathology on the bundles.

Results: The impact of focal lesions on the SC of MS patients was well captured by our multi-compartment approach (p<=0.001; S R²=0.78; E R²=0.64; M R²=0.57; CC R²=0.7), whereas traditional methods that ignore the lesions appeared to be insensitive to pathology (p>0.3). In addition, our multi-compartment method showed that pathology significantly affected the analysed bundles, equally in both the left (L) and right (R) hemispheres: p<0.001, CB-L χ²=5836, CB-R χ²= 6833; CS-L χ²=238, CS-R χ²= 238; IOF-L χ²=29, IOF-R χ²=29. Conversely, traditional methods were only sensitive to damage in the IOF bundle: p<0.001, IOF-L χ²=13, IOF-R χ²=16.

Conclusion: We applied for the first time a method that allowed us to accurately estimate microstructural characteristics of fibre bundles also in presence of focal lesions. The application of this novel method to a cohort of MS patients made it possible to reliably characterize SC and to assess changes in the brain networks that traditional approaches were not sensitive to.

Disclosure of interest: S. Bosticardo: No conflicts of interest related to this work.

M. Battocchio: No conflicts of interest related to this work.

P.-J. Lu: No conflicts of interest related to this work.

X. Chen: is supported by the China Scholar Council (CSC).

S. Schaedelin: No conflicts of interest related to this work.

M. Weigel: has received research funding from Biogen for developing spinal cord MRI.

A. Cagol: is supported by EUROSTAR E!113682 HORIZON2020, and received speaker honoraria from Novartis.

M. Ocampo-Pineda No conflicts of interest related to this work.

L. Melie-Garcia: No conflicts of interest related to this work.

A. Daducci: No conflicts of interest related to this work.

C. Granziera: The University Hospital Basel (USB), as the employer of C.G., has received the following fees which were used exclusively for research support: (i) advisory boards and consultancy fees from Actelion, Novartis, Genzyme-Sanofi, GeNeuro, Hoffmann La Roche and Siemens; (ii) speaker fees from Biogen, Hoffmann La Roche, Teva, Novartis, Merck, Jannsen Pharmaceuticals and Genzyme-Sanofi; (iii) research grants: Biogen, Genzyme Sanofi, Hoffmann La Roche, GeNeuro.

P577/1635

Inclusion of attention gates in a 3D CNN model improves the performance in new T2 lesion quantification

Marc Guirao¹, Nerses N. Kocharyan², Sergi Valverde¹, Roger Bramon¹, Albert Clèrigues³, Liliana Valencia³, GARY CICERON ALVAREZ BRAVO², Marc Puig Casadevall², Ariadna Gifreu⁴, ARNAU OLIVER³, Xavier Llado³, Alex Rovira Cañellas⁵, Lluís Ramió-Torrentà²

¹Tensormedical, Girona, Spain, ²Neurodegeneration and Neuroinflammation Research Group, Girona Biomedical Research Institute (IDIBGI). Girona Multiple Sclerosis and Neuroimmunology Unit. Neurology Department. Dr. Josep Trueta University Hospital and Santa Caterina Hospital., Department of Medical Sciences. University of Girona, Girona, Spain, ³Research institute of Computer Vision and Robotics, University of Girona, Girona, Spain, ⁴Neurodegeneration and Neuroinflammation Research Group, Girona Biomedical Research Institute (IDIBGI). Girona Multiple Sclerosis and Neuroimmunology Unit. Neurology Department. Dr. Josep Trueta University Hospital and Santa Caterina Hospital., Girona, Spain, ⁵Section of Neuroradiology and MR Unit Department of Radiology, Vall d’Hebron Hospital Universitari, Barcelona, Spain

Introduction: New T2 lesions on brain MRI are considered a good biomarker for monitoring and predicting treatment response. However, quantification of new T2 lesions using automated software is usually challenging due to the requirement for strict standardization of image acquisition.

Objectives/Aims: To assess the capability of attention gates mechanisms on CNN based automated decision-systems to detect the presence of new T2 lesions.

Methods: The study was composed of 100 treated MS patients with two MRI exams (mean interval of 14 months [range 6–36 months]). MRI data were acquired on two 1.5T Philips scanners following the same protocol (3D-FLAIR, 3D-T1-w, 2D T2-w, and 2D PD-w sequences). Two automated systems based on convolutional neural network (CNN) approaches trained with data from a 3.0T Siemens scanner were used to directly detect the presence of new T2 lesions in the follow-up images. The first system was trained using four input sequences (M1), while the second one was trained using only 3D-FLAIR images but with the addition of attention gates mechanisms within the CNN model (M2). Both CNN approaches were then applied to automatically compute the new lesion masks of the 100 MS patients acquired with the Philips scanners. The outcome of the visual standard radiological report used during clinical routine (O1) was compared with the outcome of the M1 and M2 systems. An experienced radiologist evaluated the output of the combined automated decision-systems during the visual analysis and combined it with the radiological report to create a ground-truth (GT).

Results: The visual standard report (O1) detected 26 lesions in 14 patients (33% sensitivity, 100% specificity). The automated (M1) method using 4 sequences detected 56 lesions in 19 patients (71% sensitivity, 76% specificity). In contrast, the automated method (M2) using only 3D-FLAIR and including attention gates detected 69 lesions in 24 patients (87% sensitivity, 90% specificity). In terms of the capability to detect patients with at least one new T2 lesion, (O1) scored 54%, while (M1) and (M2) detected the 73% and 92%, respectively.

Conclusion: The application of the supervised CNN system incorporating attention gates and using only 3D-FLAIR images increased from 33% to 87% the capability of the radiologist detecting new T2 lesions, outperforming a current state-of-the-art CNN method based on using four image sequences. These results are encouraging and show the potential of automated systems to increase the sensitivity and to reduce acquisitions times during the clinical practice.

Disclosure of interest: M. Guirao: nothing to disclose.

N. Nerseyan: nothing to disclose.

S. Valverde: He is the CEO of Tensormedical.

R. Bramon: nothing to disclose.

A. Clérigues: nothing to disclose.

L. Valencia: nothing to disclose.

G. Álvarez: nothing to disclose.

M. Puig: nothing to disclose.

A. Gifreu: nothing to disclose.

A. Oliver: He has received support from the DPI2020-114769RBI00 project funded by the Ministerio de Ciencia, Innovación y Universidades, and is co-founder of Tensormedical.

X. Lladó: is currently being supported by the ICREA Academia Program. He has also received support from the DPI2020-114769RBI00 project funded by the Ministerio de Ciencia, Innovación y Universidades, and is co-founder of Tensormedical.

A. Rovira: serves/ed on scientific advisory boards for Novartis, Sanofi-Genzyme, Synthetic MR, TensorMedical, Roche, and Biogen, and has received speaker honoraria from Bayer, Sanofi-Genzyme, Merck-Serono, Teva Pharmaceutical Industries Ltd, Novartis, Roche, Bristol-Myers and Biogen, is CMO and co-founder of TensorMedical, and receives research support from Fondo de Investigación en Salud (PI19/00950) from Instituto de Salud Carlos III, Spain.

Ll. Ramió-Torrentà: has received compensation for consulting services and speaking fees from Biogen, Novartis, Bayer, Merck, Sanofi, Genzyme, Roche, Bristol-Myers-Squibb, TEVA, Almirall, Janssen.

P578/1706

Neurite orientation dispersion and density imaging and multiparameter mapping in aquaporin-4 antibody positive neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein antibody-associated disease

Qianlan Chen¹, Henri Trang¹, Darius Mewes^1,2,3, Claudia Chien^1,2,4, Patrick Schindler^1,5, Rebekka Rust^1,2, Tim Hartung⁵, Carsten Finke^5,6, Tanja Schmitz-Hübsch^1,2, Stefan Hetzer⁶, Alexander U. Brandt¹, Friedemann Paul^1,2,5

¹Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany, ²Neuroscience Clinical Research Center, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany, ³Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Biomedical Innovation Academy, Berlin, Germany, ⁴Department of Psychiatry and Neurosciences, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany, ⁵Department of Neurology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany, ⁶Berlin Center for Advanced Neuroimaging, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

Introduction: Aquaporin-4 immunoglobulin G seropositive (AQP4-IgG+) neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are distinct autoantibody mediated neuroinflammatory diseases. Neurite orientation dispersion and density imaging (NODDI) is an advanced diffusion MRI, which provides orientation dispersion index (ODI), intracellular volume fraction (ICVF), and isotropic volume fraction (ISOVF). Multi-parameter mapping (MPM) provides quantitative maps of magnetization transfer saturation (MT), proton density (PD), and longitudinal relaxation rate (R1).

Objectives/Aims: This study aims to explore white matter lesion (WML) differences between AQP4-IgG+ NMOSD and MOGAD, and compared to WM of healthy controls based on NODDI and MPM-derived biomarkers.

Methods: Thirty-one AQP4-IgG+ NMOSD (29 female/2 male), 21 MOGAD (14F/7M) patients, and 45 age- and sex-matched healthy controls (HC) (36F/9M) were prospectively included in an ongoing observational study applying standardized multi-modal assessment. All participants underwent 3 Tesla MRI, including multi-shell diffusion weighted imaging, 3D MPM, T2 fluid-attenuated inversion recovery (FLAIR) and T1 magnetization prepared–rapid acquisition gradient echo (MPRAGE) sequences. WML were manually segmented on FLAIR. Normal-appearing WM (NAWM) was segmented using FastSurfer based on MPRAGE. Mean metrics of each tissue were extracted from reconstructed NODDI and MPM maps. WML differences were analyzed using linear regression model (adjusted with age and sex), analysis of variance followed by Tukey's post hoc analysis for multiple comparisons.

Results: Compared to NAWM of HC, WML in NMOSD and MOGAD patients showed decreased MT (R-squared=0.72 [95%CI: 0.61-0.83], F=54.8, p<.001), R1 (R²=0.63 [95%CI:0.51-0.76], F=37.2, p<.001) in addition to an increase in PD (R²=0.41 [95%CI: 0.25-0.58], F=15.2, p<.001). In both diseases, WML were characterized by higher ISOVF (R²=0.22 [95%CI: 0.03-0.40], F=6.0, p<.001), lower ICVF (R²=0.52 [95%CI: 0.38-0.67], F=23.7, p<.001) and ODI (R²=0.36 [95%CI: 0.18-0.53], F=11.8, p<.001) compared to NAWM of HC. WML ICVF was lower in MOGAD (Cohen’s d: 0.9(95%CI: 0.3-159.4), p<.01) compared to NMOSD WML.

Conclusion: MPM and NODDI metrics are promising biomarkers to characterize WML in NMOSD and MOGAD relating to myelin loss and fiber coherence. Differences in axonal damage as determined by ICVF between diseases may reflect distinct pathomechanisms.

Disclosure of interest: Q.Chen: is supported by the Chinese Scholarship Council (CSC);

H.Trang: was supported by iNAMES - MDC - Weizmann - Helmholtz International Research School for Imaging and Data Science from NAno to MESo;

D.Mewes: has received a research scholarship form the Berlin Institute of Health at Charité, Berlin, Germany;

C.Chien: has received speaking honoraria from Bayer and research support from Novartis and Alexion, unrelated to this study. She also serves as a member of the Standing Committee on Science for the Canadian Institutes of Health Research (CIHR);

P.Schindler: received travel support by UCB;

R.Rust: nothing to disclose;

T.Hartung: nothing to disclose;

C.Finke: nothing to disclose;

T.S.Hübsch: has received research funding form Celgene/bms and speaker honoraria from Bayer, both unrelated to this work;

S.Hetzer: nothing to disclose;

A.U. Brandt: is cofounder and holds shares of medical technology companies Motognosis GmbH and Nocturne GmbH. He is named as inventor on several patents and patent applications describing methods for retinal image analyses, motor function analysis, multiple sclerosis serum biomarkers and myelination therapies utilizing N-glycosylation modification. He is cofounder of IMSVISUAL. AUB is now full-time employee and holds stocks and stock options of Eli Lilly and Company. His contribution to this work is his own and does not represent a contribution from Eli Lilly.

F.Paul: nothing to disclose;

P579/1741

Accumulation of iron-rim lesions correlates with change in cognition in early Multiple Sclerosis

Eunice Koroma¹, Amjad Altokhis¹, Nikos Evangelou^2,3, Radu Tanasescu^2,3

¹School of Medicine, University of Nottingham, Nottingham, United Kingdom, ²Academic Clinical Neurology, School of Medicine, University of Nottingham, Nottingham, United Kingdom, ³Nottingham University Hospitals, Department of Neurology, Nottingham, United Kingdom

Introduction: Iron rim lesions (IRLs) detected on susceptibility-weighted imaging (SWI) are associated with higher disability scores in established MS and represent indicators of clinical worsening and progression of MS over the long term. It is not clear if the presence of IRL at diagnosis and detection of IRL early accumulation are clinically meaningful in early MS.

Objectives/Aims: To assess whether the presence and number of IRLs detected in the first two years in newly diagnosed patients with relapsing remitting MS (RRMS) are associated with short-term cognitive change.

Methods: 90 newly diagnosed RRMS patients (first symptoms <5y from recruitment) were assessed prospectively between 2019 and 2022 with 6-monthly 3T MRI and Symbol Digit Modalities Test (SDMT) (66 women; 50 patients followed up for 2y; 22 patients followed up for 1y). All patients were commenced on disease-modifying treatments (DMT; 53% on injectables and tablet forms; 48% on monoclonal antibodies). IRLs were identified using SWI-filtered phase images at diagnosis and on subsequent scans. We assessed the relationship between the IRL count at diagnosis and the SDMT score; and between IRLs accumulation and the change in SDMT score with prospective follow-up. Impact of DMT (high efficacy vs moderate efficacy) was considered.

Results: At MS diagnosis 31% of patients had at least one IRL; 27% had 1-3 IRLs and 4% had ⩾4 IRLs. IRL prevalence was higher greater in males (p=0.01). 36% pf people with MS with IRL at diagnosis developed at least an additional IRL over a mean follow up of 21 months. Of the 69% of patients who had no IRLs at diagnosis, 16 (28%) developed at least one IRL over a median follow up of 17.25 months. No significant correlation was found between IRL count at diagnosis and baseline SDMT scores, or between the IRL count at baseline and the change in SDMT scores at follow-up. In contrast, the accumulation of additional IRLs correlated with SDMT change at both the 1 year (p 0.006) and 2-year follow-up (p 0.004). Type of DMT did not influence this. .

Conclusion: The accumulation of IRLs in early MS in the first two years after diagnosis already correlates with changes in cognitive measures. IRL accumulation may hold prognostic value for long-term cognitive impairment in MS.

Disclosure of interest: Radu Tanasescu received support from UK MRC (CARP MR/T024402/1).

The authors have nothing to disclose related to the current work.

P580/669

Effects of Actual and Imagined Music-Cued Gait Training on Motor Functioning and Brain Activation In People with Multiple Sclerosis: A Randomised Multicentre Study - Part 2: Outcomes from task-fMRI

Birgit Helmlinger¹, Barbara Seebacher^2,3,4, Stefan Ropele¹, Stefanie Hechenberger¹, Peter Opriessnig¹, Gernot Reishofer⁵, Paola Valsasina⁶, Maria Assunta Rocca^6,7,8, Massimo Filippi^6,7,8,9,10, Bettina Heschl¹, Rainer Ehling^4,11, Markus Reindl², Michael Khalil¹, Christian Enzinger¹, Florian Deisenhammer², Christian Brenneis^4,11, Daniela Pinter¹

¹Medical University of Graz, Department of Neurology, Graz, Austria, ²Medical University of Innsbruck, Clinical Department of Neurology, Innsbruck, Austria, ³Clinic for Rehabilitation Münster, Department of Rehabilitation Science, Münster, Austria, ⁴Karl Landsteiner Institute of Interdisciplinary Rehabilitation Research, Münster, ⁵Medical University of Graz, Department of Radiology, Graz, Austria, ⁶IRCCS San Raffaele Scientific Institute, Neuroimaging Research Unit, Division of Neuroscience, Milan, Italy, ⁷IRCCS San Raffaele Scientific Institute, Neurology Unit, Milan, Italy, ⁸Vita-Salute San Raffaele University, Milan, Italy, ⁹IRCCS San Raffaele Scientific Institute, Neurorehabilitation Unit, Milan, Italy, ¹⁰IRCCS San Raffaele Scientific Institute, Neurophysiology Service, Milan, Italy, ¹¹Clinic for Rehabilitation, Department of Neurology, Münster, Austria

Introduction: This imaging sub-study is part of a larger multi-center randomized-controlled trial (n=132) on the effects of different music-cued gait trainings (including actual gait and/or motor imagery) on gait function and neuronal reorganization in people with multiple sclerosis (pwMS). So far, functional MRI (fMRI) studies on lower-limb rehabilitation in pwMS are scarce, but generally suggested training-induced alterations of brain activation in motor areas.

Objectives/Aims: We aimed to investigate differences in task-related brain activation between pwMS with and without training-related improvements in gait-function (responders vs. non-responders).

Methods: The 31 pwMS (15 females; age: M=44.2, SD=1.5; EDSS: Median=2.5; IQR=1.5) enrolled in the Graz-center completed MRI-examinations at baseline (BL) and post-intervention (PI, interval: 4 weeks). To investigate training-induced neuronal reorganization, we developed an fMRI-paradigm, comprising music-cued gait-like bipedal ankle movements on a treadmill and corresponding motor imagery. Motor- and motor-imagery-related brain activation was assessed using FSL FEAT (cluster-threshold: z>2.3; p<0.05). For region-of-interest (ROI) analyses, activation within the leg area was extracted. PwMS displaying an increase in walking distance of >5% in the 2-Minute Walk Test (2MWT) from BL to PI were defined as responders (n=11). Responders were compared to non-responders in terms of movement-related brain activation at BL, PI, and activation-changes from BL to PI.

Results: At BL, responders did not differ from non-responders regarding sex, age, EDSS, training-group, disease-modifying treatment, and walking-distance. Although non-responders constantly displayed more widespread activation than responders in all investigated contrasts, whole-brain group-comparisons did not reach significance. Exploratory ROI-analyses revealed similar movement-related brain activations in the leg area between groups at BL, but responders showed a significant reduction of activation from BL to PI compared to non-responders (t(29)=-3.5; p=0.002). Reduced activation in the leg area correlated with an increase in walking distance (r=0.497, p=0.004).

Conclusion: Responders of the gait training showed a significant reduction of movement-related brain activation in the leg area. Stronger reductions of activation in this area were associated with higher increases in walking distance from BL to PI. This pattern suggests more efficient primary motor cortex activation.

Disclosure of interest: Birgit Helmlinge:r has received speaker honoraria from Roche and travel funding from Janssen.

Barbara Seebacher: has received speaker honoraria from Sanofi-Aventis.

Stefan Ropele: nothing to disclose

Peter Opriessnig: nothing to disclose

Gernot Reishofer: nothing to disclose

Paola Valsasina: received speaker honoraria from Biogen Idec.

Maria Assunta Rocca: received consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, Roche; and speaker honoraria from Bayer, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Merck Healthcare Germany, Merck Serono SpA, Novartis, Roche, and Teva. She receives research support from the MS Society of Canada and Fondazione Italiana Sclerosi Multipla. She is Associate Editor for Multiple Sclerosis and Related Disorders.

Massimo Filippi: is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Neurological Sciences, and Radiology; received compensation for consulting services from Alexion, Almirall, Biogen, Merck, Novartis, Roche, Sanofi; speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA; participation in Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, Takeda; scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis, Sanofi-Genzyme; he receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Italian Ministry of Health, and Fondazione Italiana Sclerosi Multipla.

Bettina Heschl: has received funding for travel or speaker honoraria from Bayer, Biogen, Bristol-Myers Squibb, Janssen, Merck, Novartis, Roche, Sanofi-Genzyme and Teva.

Rainer Ehling: has participated in meetings sponsored by, received speaker honoraria or travel funding from Almirall, Biogen, Bristol-Myers Squibb, Novartis, Roche and Sanofi.

Stefanie Hechenberger: has received speaking honoraria from Roche and Bristol-Myers Squibb.

Markus Reindl: is supported by research grants from the Austrian Science Fund (FWF project P32699), the Austrian Research Promotion Agency, Euroimmun, and Roche, and consulting fees and advisory board from Roche (to institution). Markus Reindl works at the Clinical Department of the Medical University of Innsbruck (Innsbruck, Austria), which offers diagnostic testing for MOG-IgG and other autoantibodies.

Michael Khalil: has received funding for travel and speaker honoraria from Bayer Schering Pharma, Novartis Genzyme, Merck Serono, Biogen Idec and Teva Pharmaceutical Industries Ltd. And a research grant from Teva Pharmaceutical Industries Ltd.

Christian Enzinger: has received travel funding and speaker honoraria from Biogen Idec, Bayer Schering Pharma, Merck Serono, Novartis, Genzyme and Teva Pharmaceutical Industries Ltd./Sanofi-Aventis, Shire; has received research support from Merck Serono, Biogen Idec, and Teva Pharmaceutical Industries Ltd./Sanofi-Aventis; and serves on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, Genzyme, Roche, and Teva Pharmaceutical Industries Ltd./Sanofi- Aventis.

Florian Deisenhammer: Dr. Deisenhammer has participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Alexion, Almirall, Biogen, Celgene-BMS, Genzyme-Sanofi, Horizon, Janssen, Merck, Novartis Pharma, and Roche. His institution has received research grants from Biogen and Genzyme Sanofi. He is section editor of the MSARD Journal (Multiple Sclerosis and Related Disorders) and review editor of Frontiers Neurology.

Christian Brenneis: His institution has received research grants from Sanofi Genzyme, Biogen, Novartis, Celgene – Bristol Meyers Squibb, Roche, Teva, Merck and Almirall.

Daniela Pinter: has received travel funding from Merck, Genzyme/Sanofi-Aventis and Biogen and speaker honoraria from Biogen, Novartis and Merck.

P581/1720

Microstructural assessment of multiple sclerosis lesions and peri-plaques using advanced multishell diffusion MRI

Colin Vanden Bulcke^1,2, Anna Stolting¹, Martina Absinta^3,4, Pietro Maggi¹

¹Institute of NeuroSciences, Bruxelles, Belgium, ²Institute of Information and Communication Technologies, Electronics and Applied Mathematics, Louvain-la-Neuve, Belgium, ³Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Hospital and Vita-Salute San Raffaele University, Milan, Italy, ⁴Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Introduction: Chronic active multiple sclerosis (MS) lesions, seen on susceptibility-based MRI as Paramagnetic Rim Lesions (PRL), are associated with increased clinical disability and axonal damage. Diffusion MRI (dMRI) can characterize in vivo tissue damage, however, the tissue microstructure specificity of established dMRI models is limited.

Objectives/Aims: Here, we characterized PRL vs non-PRL microstructure and their surrounding peri-plaque white matter (PPWM) using Track Density Imaging (TDI) and 4 different dMRI models, including two novel ones; Microstructure Fingerprinting (MF) and DIstribution of Anisotropic MicrOstructural eNvironments in DWI (DIAMOND). To our knowledge, MF, DIAMOND, and TDI have never been used to depict the microstructure of MS lesions.

Methods: In 75 MS patients (47 relapsing-remitting, 19 secondary progressive, 9 primary progressive) 582 lesions (330 PRL and 252 non-PRL) were detected on 3T high-resolution unwrapped-phase images. Their surrounding PPWM was automatically computed by extending their lesion mask by 4 mm in every direction. Each patient as well as 7 Healthy Controls (HC) underwent multishell diffusion-weighted imaging. For each lesion, we computed quantitative T1 values and extracted diffusion parameters using 4 dMRI models: Diffusion Tensor Imaging (DTI), Neurite Orientation Dispersion and Density Imaging (NODDI), DIAMOND and MF. TDI was derived from a probabilistically generated and filtered tractogram of 1 million tracts for a subset of 24 patients and 7 HC. Patient TDI images were spatially z-score normalized according to the average HC TDI.

Results: PRL and PRL PPWM featured higher T1-values vs non-PRL and non-PRL PPWM, respectively (p<0.001). The DTI and DIAMOND models showed lower fractional anisotropy, higher mean diffusivity, and radial diffusivity in PRL and PRL PPWM vs non-PRL and non-PRL PPWM (p<0.001); NODDI and MF models showed respectively lower neurite density index and lower fibre volume fraction (p<0.001), suggesting impaired axonal integrity/density in PRL and PRL PPWM vs non-PRL and non-PRL PPWM. The TDI analysis showed reduced track density in PRL vs non-PRL lesions (p<0.005).

Conclusion: Consistent with previous data, we show that PRL and their surrounding PPWM are characterized by higher axonal damage when compared to non-PRL. Results derived from the TDI, MF and DIAMOND models are in line with those obtained with DTI and NODDI, suggesting that these advanced diffusion imaging methods can be used to study MS lesion pathology.

Disclosure of interest: Colin Vanden Bulcke has the financial support of the Fédération Wallonie Bruxelles - Fonds Spéciaux de Recherche (F.S.R.).

Anna Stölting has nothing to disclose.

Martina Absinta: consultancy honoraria from Abata Therapeutics, Biogen, Sanofi-Genzyme and GSK.

Pietro Maggi research activity is supported by the Fund for Scientific Research (F.R.S, FNRS; grant #40008331), the Belgian Charcot Fundation, Cliniques universitaires Saint-Luc “Fonds de Recherche Clinique” and Biogen. PM received consultancy honoraria from Sanofi-Genzyme, Biogen and Merck, and research funding from Biogen.

P582/476

Ocurrence of new asymptomatic MRI lesions during follow-up of patients with NMOSD in a real-world Argentinean cohort

Edgar German Carnero Contentti^1,1, Pablo A. Lopez¹, VERONICA ANALIA TKACHUK², Carlos Vrech³, Agustina Zarate³, Jorge Correale⁴, Norma Deri⁵, GERALDINE GABRIELA LUETIC⁶, Mariano Marrodan⁴, Fatima Pagani Cassara⁷, Dario Tavolini⁸, Celica Ysrraelit⁴, Maria Balbuena², Javier Hryb⁹, Edson Chiganer⁹, Felisa Leguizamon¹⁰, Eduardo Knoree¹⁰, Gisela Zanga¹¹, Claudia Pestchanker¹², Andres Guillermo Barboza¹³, Débora Nadur², Edgardo Cristiano¹⁴, Liliana Patrucco¹⁴, Ricardo Nicolas Alonso¹⁵, Marina Alonso¹⁶, Friedemann Paul¹⁷, Juan Ignacio Rojas¹⁴

¹Hospital Aleman, Buenos Aires, Argentina, ²Hospital de Clinicas, Buenos Aires, Argentina, ³Sanatorio Allende, Cordoba, Argentina, ⁴FLENI, Buenos Aires, Argentina, ⁵Centro de Investigaciones Diabaid, Buenos Aires, Argentina, ⁶Instituto de Neurociencias de Rosario, Rosario, Argentina, ⁷Fundacion Favaloro, Buenos Aires, Argentina, ⁸INECO Neurociencias Oroño, Rosario, Argentina, ⁹Hospital Durand, Buenos Aires, Argentina, ¹⁰Hospital Alvarez, Buenos Aires, Argentina, ¹¹Hospital Milstein, Buenos Aires, Argentina, ¹²Hospital Ramon Carrillo, San Luis, Argentina, ¹³Hospital Central de Mendoza, Mendoza, Argentina, ¹⁴CEMBA, Buenos Aires, Argentina, ¹⁵Hospital Ramos Mejia, Buenos Aires, Argentina, ¹⁶Hospital Italiano, Buenos Aires, Argentina, ¹⁷Charité — Universitätsmedizin Berlin, Berlin, Germany

Introduction: We aimed to assess the occurrence of new asymptomatic lesions on brain and spinal imaging (MRIs) and their association with subsequent relapses in a large cohort of neuromyelitis optica spectrum disorder (NMOSD) patients in Argentina.

Objectives/Aims: Methods: We retrospectively reviewed 675 MRIs (225 performed during an attack and 450 during the relapse-free period [performed at least 3 months from the last attack]) of NMOSD patients who had at least 2 years of clinical and MRI follow-up since disease onset. Kaplan-Meier curves were used for depicting time from remission MRIs to subsequent relapse.

Results: We included 135 NMOSD patients (64.4% were AQP4-IgG-positive). We found that 26 (19.26%) and 66 (48.88%) of patients experienced at least one new asymptomatic MRI lesion during both the relapse-free period and attacks, respectively. The most frequent asymptomatic MRI lesions were optic nerves followed by short-segment myelitis during the relapse-free period and attacks. Kaplan-Meier curves did not show differences in the time taken to develop a new relapse.

Conclusion: Our findings showed that new asymptomatic lesions can be observed in a real-world setting. However, the presence of new asymptomatic MRI lesions during the relapse-free period as well as at relapses were not associated with a shorter time to developing subsequent relapses.

Disclosure of interest: No potential conflict of interest relating to this poster was reported by the authors

P583/562

Evaluate amide proton transfer weighted signal intensity of multiple sclerosis lesions and contralateral normal-appearing white matter

IBRAHIM KHORMI^1,2,3, Oun Al-iedani^2,4, Stefano Casagranda⁵, Christos Papageorgakis⁵, Abdulaziz Alshehri^1,2,6, Rodney Lea², Patrick Liebig⁷, Saadallah Ramadan^1,2, Jeannette Lechner-Scott^2,8,9

¹University of Newcastle, School of Health Sciences, Callaghan, Australia, ²Hunter Medical Research Institute, New Lambton Heights, Australia, ³University of Jeddah, College of Applied Medical Sciences, Jeddah, Saudi Arabia, ⁴University of Newcastle, School of Biomedical Sciences and Pharmacy, Callaghan, Australia, ⁵OLEA MEDICAL, Department of R&D Advanced Applications, La Ciotat, France, ⁶King Fahd Hospital of the University, Imam Abdulrahman Bin Faisal University, Department of Radiology, Al Khobar, Saudi Arabia, ⁷Siemens Healthineers, Erlangen, Germany, ⁸John Hunter Hospital, Department of Neurology, New Lambton Heights, Australia, ⁹University of Newcastle, School of Medicine and Public Health, Challaghan, Australia

Introduction: Autoimmune attacks in Multiple Sclerosis (MS) disease cause inflammatory demyelination, leading to axonal loss and destruction of myelin. Amide proton transfer weighted (APTw) imaging is a novel type of magnetic resonance imaging (MRI) that can detect the interaction between mobile protons, found in the intra/extra-cellular myelin debris proteins and surrounding tissue water.

Objectives/Aims: To evaluate APTw signal differences between MS lesions and contralateral normal-appearing white matter (cNAWM). Cellular changes during the demyelination process were assessed by comparing APTw signal intensity in T1-weighted isointense (ISO) and hypointense (black hole-BH) lesions in relation to cNAWM.

Methods: Twenty-four people with relapsing-remitting MS on stable therapy were recruited (19 females and 5 males with mean age:48.11 years; mean disease duration:11.25 years; median EDSS:2). MRI/APTw acquisitions were undertaken on 3T MRI. For assessment of MS lesions, 3D T1-MPRAGE and T2-FLAIR were used. Pre/post-processing APTw analysis, co-registration with structural MRI maps, and identifying regions of interest were all performed with Olea Sphere 3.0 software. Generalized linear model univariate ANOVA was undertaken to test the hypotheses that differences in mean APTw signal intensity. Receiver operating characteristic curve analyses were performed to evaluate the diagnostic performance of these comparisons.

Results: Mean APTw signal intensity values of MS lesions were higher than cNAWM (lesion=0.44,cNAWM=0.13,F=44.12,p<0.001). The mean APTw values of ISO lesions were higher than cNAWM (ISOlesions=0.42,cNAWM=0.21,F=12.12,p<0.001). The mean APTw signal intensity values of BH were higher than cNAWM (BH lesions=0.47,cNAWM=0.033,F=40.3,p<0.001). The effect size (difference between lesion and cNAWM) for BH was found to be higher than for ISO (14 vs.2). Diagnostic performance showed that APTw was able to discriminate between all lesions and cNAWM with an accuracy of greater than 75% (AUC=0.79,SE=0.014). Discrimination between ISO lesions and cNAWM was accomplished with an accuracy greater than 69% (AUC=0.74,SE=0.018), while discrimination between BH lesions and cNAWM was achieved at an accuracy of greater than 80% (AUC=0.87,SE=0.021).

Conclusion: Our results highlight the potential of APTw imaging as a non-invasive technique that can provide essential molecular information to clinicians and researchers so that the stages of inflammation and degeneration in MS lesions can be better characterized.

Disclosure of interest: Ibrahim Khormi: nothing to disclose.

Oun Al-iedani: nothing to disclose.

Stefano Casagranda: is an employee at Olea Medical, La Ciotat, France.

Christos Papageorgakis: is an employee at Olea Medical, La Ciotat, France

Abdulaziz Alshehri: nothing to disclose.

Rodney Lea: nothing to disclose.

Patrick Liebig: is an employer with Siemens Healthcare GmbH, Erlangen, Germany.

Saadallah Ramadan: nothing to disclose.

Jeannette Lechner-Scott: has accepted travel compensation from Novartis, Biogen, and Merck. Her institution received honoraria for talks, advisory board commitment, and research grants from Biogen Idec, Merck, Roche, and Novartis. She is on the board of directors for MS Plus.

P584/718

Thalamus-derived Radiomic Features to Predict Symbol Digit Modalities Test Results in MS

Korhan Buyukturkoglu¹, Lin Lu², Renan Orellana¹, Alexander Ratzan¹, Hao Yang², Jennie Mata¹, Vicky Leavitt¹, Binsheng Zhao², Claire Riley¹, Philip De Jager¹

¹Columbia University, Neurology, New York, United States, ²Columbia University, Radiology, New York, United States

Introduction: Thalamic atrophy is correlated with cognitive impairment in Multiple Sclerosis (MS). However, other thalamic features derived from magnetic resonance imaging (MRI) data may also be associated and could help to predict cognitive dysfunction. Radiomics is a rapidly emerging quantitative approach which aims to enhance information extraction from medical images to capture disease-specific processes that are imperceptible to the human eye.

Objectives/Aims: Herein, we aimed to predict Symbol Digit Modalities Test (SDMT) performance using high-dimensional radiomic features of the thalamus extracted from clinical MRI data.

Methods: One hundred thirty-eight (138) individuals (110 Female, Mean Age=49 ± 12) with remitting-relapsing MS who had both an SDMT measure and a clinical MRI participated in this study. The participants were divided into three datasets, the training (49), testing (23) and validation (66) sets. The training set was used for model building, the testing set was used for model optimization, and the validation set was used for robustness validation on new data.

In each participant, both thalami were segmented using normalized 3D-T1 weighted images acquired in a 3T MRI scanner and the FreeSurfer 6.0 thalamic subnuclei segmentation tool. For each of the three datasets, a total of 1158 radiomics features were extracted using the Columbia Image Feature Extractor. Least Absolute Shrinkage and Selection Operator (LASSO) algorithm was used to identify optimal features, i.e., informative, and non-redundant features, for creating the linear regression model.

Results: Nine radiomics features (i.e., features with estimated importance ⩾ 10-³), were identified by the LASSO and selected to build the prediction model. The Root Mean Squared Error (RMSE) on the training, testing and validation sets were 10.0, 13.4 and 15.7 respectively, showing a reliable regression fitness. Among these 9 features, the LoG_Median_Gray_Intensity (LoG_MGI), which is a feature to characterize regional homogeneity in the MR image, showed the highest importance. LoG_MGI was significantly correlated with the SDMT in the test (r=0.56, p<0.001) and validation sets (r=0.41 p<0.001).

Conclusion: Despite our modest sample size, we demonstrated that a radiomics approach has the potential to leverage conventional clinical MRI data and uncover thalamus-cognition relationships in MS.

Disclosure of interest: Korhan Buyukturkoglu: nothing to disclose

Lin Lu: nothing to disclose

Hao Yang: nothing to disclose

Alexander Ratzan: nothing to disclose

Jennie Mata: nothing to disclose

Victoria Leavitt: nothing to disclose

Binsheng Zhao: nothing to disclose

Claire Riley: nothing to disclose

Phil De Jager: nothing to disclose