MRI plays an increasingly important role in the diagnosis of multiple sclerosis. We discuss the expanded role of MRI in the 2024 McDonald diagnostic criteria for multiple sclerosis, which include the optic nerve as a fifth anatomical location, in addition to the periventricular, juxtacortical or cortical, infratentorial, and spinal cord regions. The diagnosis of multiple sclerosis can now be confirmed when the criteria of dissemination in space are fulfilled with the detection of typical lesions in at least four locations without additional evidence. We recommend appropriate imaging strategies and MRI acquisition protocols for all aspects of multiple sclerosis diagnosis, including fat-saturated sequences for detection of symptomatic optic nerve lesions. Diagnostic imaging should always cover the brain and spinal cord and include susceptibility-sensitive sequences for the assessment of the central vein sign and paramagnetic rim lesions, which can be especially helpful in cases when conventional imaging findings are insufficient to establish a diagnosis. We discuss how to handle the diagnosis of radiologically isolated presentations of multiple sclerosis, which are included in the 2024 criteria. We present recommendations for image interpretation and avoidance of misdiagnosis, and extend the recommendations to the use of MRI in the diagnosis of multiple sclerosis in older people, children, people with vascular comorbidities or migraine, and people living outside Europe and North America. Finally, we provide recommendations for standardisation of MRI acquisition and communication of results to enable an earlier diagnosis while maintaining high diagnostic specificity.

BACKGROUND AND OBJECTIVES:Invasive procedures may delay the diagnostic process in multiple sclerosis (MS). We investigated the added value of serum neurofilament light chain (sNfL), glial fibrillary acidic protein (sGFAP), chitinase-3-like 1 (sCHI3L1), and the immune responses to the Epstein-Barr virus-encoded nuclear antigen 1 to current MS diagnostic criteria. METHODS:In this multicentric study, we selected patients from 2 prospective cohorts presenting a clinically isolated syndrome (CIS). Patients were classified as (1) not presenting dissemination in space (DIS) nor dissemination in time (DIT) (noDIS and noDIT); (2) presenting DIS without DIT (DIS and noDIT); and (3) presenting both (DIS and DIT), which were used as a reference. sNfL, sGFAP, and sCHI3L1 levels were measured with single-molecule array immunoassays and EBNA1-specific IgG levels with ELISA. Biomarker levels were compared between groups using linear regression models. Receiver operating characteristic curve analyses and Youden Index were used to determine cutoff values associated with MS diagnosis during follow-up. RESULTS:We included 181 patients (66.3% females, mean [SD] age of 35.0 [9.7] years). At baseline, 25 (13.8%) were classified as noDIS and noDIT, 62 (34.3%) as DIS and noDIT, and 94 (51.9%) as DIS and DIT. Only sNfL Z-scores discriminated between groups (DIS and DIT vs DIS and noDIT [p = 0.002], DIS and DIT vs noDIS and noDIT [p < 0.001], and DIS and noDIT vs noDIS and noDIT [p = 0.026]). In noDIS and noDIT patients (median interquartile range [IQR] follow-up of 8.1 [5.0-11.7] years), high sNfL Z-scores best predicted MS diagnosis (specificity [SP] and 95% CI of 93.3% [68.1-99.8] and positive predictive value [PPV] of 87.5% [47.3-99.7]). Among DIS and noDIT patients (median [IQR] follow-up of 6.8 [4.0-9.1] years), high sNfL Z-scores best predicted MS diagnosis (SP of 80% [28.4-99.5] and PPV of 97.3% [85.8-99.9]) without considering oligoclonal band (OB) status. In the subset of patients of this group with negative OBs, a combination of high sNfL Z-scores and sGFAP levels predicted MS diagnosis (SP of 100% [39.8-100] and PPV of 100% [54.1-100]). DISCUSSION:These results suggest that sNfL and sGFAP may be incorporated in particular scenarios to diagnose MS in patients with CIS not fulfilling current diagnostic criteria.

BACKGROUND:Radiologically isolated syndrome (RIS) represents a subclinical period of multiple sclerosis (MS). OBJECTIVES:We aimed to characterize and identify risk factors for developing MS in an RIS cohort and to assess various proposed RIS definitions for their predictive value in MS development. METHODS:This cohort study included all patients with at least one typical inflammatory-demyelinating lesion suggestive of MS on brain and/or spinal cord magnetic resonance imaging (MRI). The development of MS symptoms and new T2 lesions were the primary and secondary outcomes, respectively. Cox regression was used to identify risk factors, and diagnostic performance was assessed. RESULTS:Eighty-eight patients were included, with 25.0% developing MS symptoms over a mean 55.1-month follow-up. Younger age and spinal cord and cortico-/juxtacortical lesions were associated with worse outcomes. The 2017 McDonald dissemination in space (DIS) criteria and 2023 Lebrun RIS definition, which correspond to either the 2005 McDonald DIS criteria or one brain inflammatory-demyelinating lesion associated with two among oligoclonal bands, a spinal cord lesion and dissemination in time during radiological follow-up, showed high sensitivity (0.82 and 0.94, respectively). However, the sensitivity decreased (0.79) when only the baseline characteristics of the 2023 Lebrun RIS definition were considered. Combining the 2017 McDonald DIS criteria with positivity for oligoclonal bands or contrast-enhancing lesions on baseline MRI, which are the current McDonald MS criteria, improved the specificity (to 0.64 and 0.90, respectively). CONCLUSIONS:Our findings support the utility of the current DIS component of the 2017 McDonald MS criteria for RIS patients.

Multiple sclerosis is a chronic immune-mediated disorder of the central nervous system characterized by demyelination, axonal loss, and neuroinflammation, culminating in progressive neurological disability. Despite significant advances in understanding its immunopathogenesis, current immunotherapies remain limited in their ability to halt disease progression, making multiple sclerosis incurable and highlighting the critical need for novel therapeutic strategies. Antigen-specific immunotherapy represents a groundbreaking approach that aims to restore immune tolerance to myelin-derived antigens while preserving the protective functions of the immune system. Unlike broad immunosuppressive strategies, antigen-specific immunotherapy offers the potential for highly targeted modulation of pathogenic immune responses, reducing off-target effects and enhancing safety profiles. Over the last two decades, preclinical studies and clinical trials have explored diverse antigen-specific immunotherapy modalities, ranging from peptide-based vaccines to nanoparticle platforms, each aimed at achieving durable tolerance in multiple sclerosis. This review provides a comprehensive overview of multiple sclerosis, covering its etiology, clinical features, pathogenesis, pathology, and current therapeutic approaches. Thus, it delves into the current state of antigen-specific immunotherapy research, critically examining its successes and limitations while addressing the translational challenges that must be overcome to realize its therapeutic potential. By integrating insights from immunology, biotechnology, and translational medicine, we propose directions for advancing antigen-specific approaches in the quest for transformative multiple sclerosis therapies.

The combined use of serum and CSF biomarkers for prognostic stratification in multiple sclerosis (MS) remains underexplored. This multicenter observational study investigated associations between serum neurofilament light chain (sNfL), glial fibrillary acidic protein (sGFAP), and CSF lipid-specific IgM oligoclonal bands (LS-OCMB) with different forms of disability worsening, such as relapse-associated worsening (RAW), active progression independent of relapse activity (aPIRA), and non-active PIRA (naPIRA). A total of 535 patients with MS were included, all sampled within one year of disease onset. Biomarkers were quantified using single-molecule array and immunoblotting techniques, and CSF cell subsets were analyzed by flow cytometry. High sNfL z-scores and LS-OCMB positivity were independently associated with increased risk of RAW and aPIRA, collectively termed inflammatory-associated worsening (IAW), while elevated sGFAP levels predicted naPIRA. Patients with both high sNfL and LS-OCMB positivity had the highest risk of IAW. Among LS-OCMB-positive patients, higher regulatory T cell percentages were associated with lower sNfL levels, suggesting a protective role. Conversely, in LS-OCMB-negative patients, sNfL levels correlated with CSF C3 concentrations. These findings support the complementary role of sNfL, sGFAP, and LS-OCMB in identifying distinct mechanisms of disease worsening and may inform early personalized management strategies in MS.

BackgroundSerum biomarkers as neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) enabled early identification of multiple sclerosis (MS) patients at risk of relapse-associated worsening (RAW) or progression independent of relapses (PIRA). However, the immunological mechanisms underlying these clinical phenotypes remain unclear.MethodsWe conducted a cross-sectional study including 117 MS patients and 84 healthy controls (HC). Patients were stratified as NLGL (low sNfL and sGFAP), NH (high sNfL at different levels of sGFAP), and NLGH (low sNfL and high sGFAP). Percentages of blood and cerebrospinal fluid (CSF) mononuclear cells, and intracellular production of cytokines by T and B cells after “in vitro” stimulation were analyzed by flow cytometry.ResultsWe identified a common inflammatory profile present in the blood of all MS groups comprising significant increases of effector CD4+ and CD8+ T cells, of memory and antigen-presenting B cells, of CD4+ and CD8+ T cells producing interferon-gamma, interleukin-17 and tumor necrosis factor-alpha (TNF-α) and of B cells producing TNF-α. Additionally, the highly inflammatory NH group showed lower frequencies of different regulatory subsets (transitional B cells, PDL1+ monocytes and Treg cells) compared to HC and increased percentages of CD4+ and CD8+ T cells producing granulocyte-macrophage colony-stimulating factor and of effector CD56dim NK cells. They also showed lower percentages of Treg in blood and CSF compared to the low inflammatory NLGL group, which also displayed higher frequencies of regulatory CD56dim, NKG2A+ cells.ConclusionAll MS patients share increased inflammatory B and T cells, but differ in regulatory or NK subsets, which identify highly inflammatory or benign disease courses.

Background and ObjectivesThe role of the complement system in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is not completely understood, and studies exploring its potential utility for diagnosis and prognosis are lacking. We aimed to investigate the value of complement factors (CFs) as diagnostic and prognostic biomarkers in patients with MOGAD.MethodsMulticentric retrospective cohort study including patients with MOGAD, multiple sclerosis (MS) and aquaporin-4 seropositive neuromyelitis optica spectrum disorder (AQP4-NMOSD) with available paired serum and CSF samples. A panel of CFs were measured by multiplex ELISA, and the levels were compared between the 3 conditions. Univariable and multivariable analyses were performed to evaluate the association between levels of CFs and relapse and disability outcomes in MOGAD patients.ResultsNinety-four patients (MOGAD, n = 60; MS, n = 18; AQP4-NMOSD, n = 16) were included. Mean (SD) age at sampling was 39.4 (16.7), 40.7 (7.0), and 43.3 (21.0), respectively. Female were predominant, especially in AQP4-NMOSD (88%). Combination of the serum levels of C3a, C4a, and C3a/C3 ratio showed excellent potential to discriminate MOGAD from patients with MS (area under the curve [AUC] [95% CI] 0.95 [0.90-0.99]) and from AQP4-NMOSD (AUC 0.88 [0.76-1.00]). In patients with MOGAD, CSF levels of CFs of the classical/lectin pathway influenced relapse-related outcomes, and lower C4 levels were associated with higher number of relapses during follow-up (incidence rate ratio [95% CI] 0.88 [0.78-0.99]; p = 0.04 in multivariable analysis), and a high C4a/C4 ratio was associated with increased risk of second relapse during the first year (hazard ratio [95% CI] 3.68 [1.26-10.78]; p = 0.02 in multivariable analysis). Time to second relapse was shorter in patients with MOGAD with a high CSF C4a/C4 ratio (log-rank p = 0.01). CSF levels of the membrane attack complex SC5b9 influenced disability-related outcomes, and baseline CSF SC5b9 levels were higher in patients who reached the final Expanded Disability Status Scale (EDSS) >= 3.0 (p = 0.002), and elevated SC5b9 levels were associated with increased risk of reaching EDSS >= 3.0 (odds ratio [95% CI] 1.79 [1.16-3.67]; p = 0.04 in multivariable analyses).DiscussionOur results suggest that serum and CSF levels of CFs have diagnostic and prognostic value respectively in patients with MOGAD. These findings support the use of complement inhibitors as a therapeutic approach in these patients.

The 2024 McDonald diagnostic criteria for Multiple Sclerosis (MS) introduce kappa free light chains (κ-FLC) detection in cerebrospinal fluid (CSF) which can be used interchangeably with oligoclonal IgG bands (OCB) to demonstrate intrathecal immunoglobulin synthesis. Diagnostic sensitivity and specificity of κ-FLC is equal to OCB on a 95% confidence level. In rare cases determination of both, κ-FLC and OCB should be considered as the concordance rate is around 90%. We recommend calculating the κ-FLC index with values of ≥6.1 performing best for diagnosing MS. Validated turbidimetric or nephelometric assays should be applied for which proficiency testing programs are available. There is some prognostic use of the κ-FLC index with higher values predicting higher disease activity. Neurofilament light (NfL) should not be used for diagnostic purposes although it might be useful for prognosis and disease monitoring. All recommendations apply to paediatric and adult relapsing as well as progressive onset MS.

Background This study evaluated the feasibility and the impact of implementing the Expert Patient Programme of Catalonia™ (EPPC) for people with multiple sclerosis (MS) to improve disease-related knowledge and key health indicators. Methods This feasibility pre–post interventional study was conducted in two MS units in Catalonia (Spain) between June 2020 and September 2022. Participants were included in two parallel groups with relapsing and two with progressive MS. An expert patient (EP), remotely trained and supported by a nurse, led nine virtual sessions of 90min. After a theoretical 30-min presentation by the EP to introduce the session topic, the EP encouraged interaction between participants to share knowledge and express doubts, questions, and experiences. Questionnaires assessing disease-related knowledge, quality of life (QoL), anxiety and depression, lifestyle habits, and disability were delivered after certain sessions and at 6 and 12 months using an online platform; healthcare services utilization was also assessed. Results Thirty-nine patients (20 with relapsing and 19 with progressive multiple sclerosis) received the intervention, and most attended all sessions. Answers to six of 18 knowledge questions changed significantly. Health indicators did not change significantly, except for exercise and diet, with a general trend towards stability in the relapsing group and towards worsening in the progressive group. Conclusion This nurse-led study demonstrated the feasibility of a remotely delivered expert patient programme for people with MS. The intervention was safe, and disease-related knowledge improved, supporting this programme's implementation throughout Catalonia to analyze its impact on QoL, empowerment, and other key health indicators.

OBJECTIVE:An alteration in the composition of the intestinal microbiota has been observed in patients with multiple sclerosis (pwMS) with respect to healthy controls (HC). Microorganism-derived metabolites such as short-chain fatty acids (SCFA) have been suggested to play a role in the disease. Thus, to analyze the association of SCFA with clinical and radiological parameters of the disease and with those related to the inflammatory response of the immune system. METHODS:Multicentric observational retrospective cross-sectional study. In addition 161 pwMS and 130 HC were included. The following plasma SCFA were analyzed using liquid chromatography coupled to mass spectrometry: acetate (AA), propionate (PA) and butyrate (BA). Blood cell subpopulations and cytokine expression were analyzed by flow cytometry. RESULTS:Plasma PA and PA/AA ratio was lower in pwMS than in HC (P = 0.0001, and P = 0.00005, respectively). PA/AA and BA/AA ratios were lower in pwMS with higher disability (P = 0.001, and P = 0.001, respectively). T2 lesion load inversely correlated with PA/AA (r = -0.353; P = 0.002) and BA/AA (r = -0.322; P = 0.005) ratios. Plasma PA/AA and/or BA/AA ratios negatively correlated with the following pro-inflammatory cytokines producing cells: GM-CSF+CD4+T, GM-CSF+CD8+T, TNF-alpha+CD4+T, TNF-alpha+CD8+T, IFN-gamma+CD4+T, IFN-gamma+CD8+T, and TNF-alpha+B cells. INTERPRETATION:In MS, plasma PA/AA and BA/AA ratios are unbalanced, promoting an environment that could be boosting the mechanisms underlying the pathogenesis of the disease. Since we have found statistical significant associations with the EDSS and the number of T2 lesions, but not with the number of relapses or gadolinium enhancing lesions, PA/AA and BA/AA ratios could be more associated with those mechanisms of the disease related to the neurodegenerative processes than those related with the activity of the disease.

BACKGROUND AND OBJECTIVES:Immune effector cell-associated neurotoxicity syndrome (ICANS) is a potential complication following Chimeric Antigen Receptor (CAR) T-cell infusion. Biomarkers to aid in early diagnosis and severity assessment are lacking. We aim to describe and compare serum neurofilament light chain (sNfL) dynamics in non-Hodgkin lymphoma (NHL) patients undergoing anti-CD19 CAR T-cell therapy, based on ICANS presence and severity. METHODS:This is a case-control study nested within a cohort of NHL patients treated with anti-CD19 CAR T-cells at a tertiary care center. From this cohort, we selected those who developed ICANS and had available blood samples. These patients were compared to matched NHL patients without ICANS from the same cohort. sNfL concentrations were measured immediately pre-infusion and on days 7 and 14 post-infusion, with z-scores calculated against a normative database. Mixed linear and ROC analysis assessed sNfL dynamics by ICANS presence and severity. RESULTS:Of 159 patients treated, 54 (34%) developed ICANS. We included 32 patients with ICANS and 22 matched controls. Baseline sNfL concentrations were similarly elevated in both ICANS and non-ICANS patients. However, on day 7, patients with moderate-severe ICANS (grade ≥ 2) had higher sNfL levels (median z-score 2.33) than those with mild or no ICANS (median z-score 1.72;p = 0.022). The optimal cutoff to discriminate moderate-severe ICANS from other patients based on sNfL was a z-score of 2.14 on day 7 (p = 0.004). DISCUSSION:Moderate-severe ICANS is associated with elevated sNfL levels by day 7 post-infusion, indicating early neuroaxonal damage and underscoring sNfL as a valuable biomarker for assessing ICANS severity.

BACKGROUND AND OBJECTIVES:To investigate whether CSF 14-3-3 protein levels discriminate aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) from myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and multiple sclerosis (MS) and the association of CSF 14-3-3 protein levels with clinical features in patients with AQP4-NMOSD. METHODS:This was a multicentric retrospective cohort study of patients with AQP4-NMOSD, MOGAD, and MS, with available CSF samples. 14-3-3 protein levels were quantified using ELISA and compared between the 3 conditions. In patients with AQP4-NMOSD, the association between CSF 14-3-3 protein levels and disability outcomes was explored. RESULTS:A total of 134 patients were included (AQP4-NMOSD, n = 29; MOGAD, n = 43; MS, n = 62). Patients with AQP4-NMOSD had higher 14-3-3 protein levels (median [interquartile range] 4,441.37 [3,240.05-11526.41] arbitrary units (AU)/mL) compared with those with MS (3,169.86 [2,522.65-3,748.57], p = 0.001) and MOGAD (3,112.95 [2,367.37-3,889.43], p = 0.004). Patients with AQP4-NMOSD presenting with optic neuritis had lower 14-3-3 levels compared with those with other phenotypes (p < 0.001). In AQP4-NMOSD, 14-3-3 levels associated with Expanded Disability Status Scale (EDSS) at attack (β [95%CI] 0.33 [0.15-0.52], p = 0.003) and predicted final EDSS ≥ 6.0 (odds ratio 9.48 [1.69; 194.34]; p = 0.041) in patients with myelitis. DISCUSSION:The study suggests a potential role of CSF 14-3-3 protein levels as a biomarker of neuroaxonal damage in AQP4-NMOSD, because of its ability to correlate with disease severity and predict poor clinical recovery. CLASSIFICATION OF EVIDENCE:This study provides Class IV evidence that in individuals presenting with acute myelitis, CSF 14-3-3 differentiates AQP4-NMOSD from MS or MOGAD with a sensitivity of 0.60 (0.30-0.80) and specificity of 0.95 (0.84-1.00).

Serious symptomatic SARS-CoV-2 infection and COVID-19 complications are particular concerns for people with multiple sclerosis, especially those receiving immunosuppressants or immunomodulators. Studies have aimed to identify individuals with multiple sclerosis who are at high risk for SARS-CoV-2 infection, to analyse the interplay between SARS-CoV-2 and multiple sclerosis and to evaluate immunological responses to SARS-CoV-2 infection and vaccines. The emergence of evolving dominant SARS-CoV-2 variants, a range of available vaccines, and novel therapeutic approaches requires that clinical neurologists be regularly updated with the latest information. Unresolved issues include optimisation of vaccination strategies to enhance vaccine efficacy and the management of patients who do not show seroconversion post vaccination. Tailored vaccination has the potential to improve patient care, and future studies should focus on evaluating novel therapies and preventive measures while constantly updating our knowledge of potential SARS-CoV-2 variants, in preparation for future outbreaks or pandemics.

BACKGROUND:Neurofilament light chain (NfL) is a promising marker for predicting disease activity in relapsing multiple sclerosis (RMS). To date, however, there has been no commercially available NfL assay validated in MS and intended for routine clinical use. OBJECTIVE:To identify and validate a single threshold for NfL in blood that differentiates RMS patients, aged 18-55 years, at a higher versus lower risk of disease activity over 2 years, using the Atellica® IM NfL assay. METHODS:The optimal NfL threshold for this assay/use case was identified and independently validated using ASCLEPIOS I and II data, respectively. The primary endpoint (annualized number of new/enlarging T2 (neT2) lesions) was analyzed using negative binomial models. Threshold optimization used maximum likelihood methodology. Generalizability analyses used data from ASCLEPIOS II, FREEDOMS, and TRANSFORMS. RESULTS:NfL concentration of 12.9 pg/mL was validated as the optimal cutoff for prognosticating disease activity as measured by neT2 lesion over 2 years. This threshold prognosticated individual patient risk for persistent disease activity (>3 neT2 lesions/year over 2 years) and showed prognostic value across relevant subgroups and clinical scenarios. Findings for relapses were similar. CONCLUSION:The CE-marked Atellica® IM NfL assay is now validated for prognostic use in RMS patients.

BACKGROUND AND OBJECTIVES:The optimal immunosuppressive treatment for autoimmune chronic intestinal pseudo-obstruction (CIPO) is unknown due to lack of clinical trials. Even less data exist on treatment recommendations for patients who do not respond to first-line immunotherapy. METHODS:We describe 4 patients with autoimmune CIPO treated with vedolizumab (3/4), a monoclonal antibody that interferes the lymphocyte trafficking to the gastrointestinal tract, or rituximab (1/4) who did not respond to steroids or IV immunoglobulins. We made a systematic review of previously published cases of CIPO treated with these biological agents. RESULTS:Vedolizumab was effective in 2 of 3 patients but failed in a child with nonparaneoplastic anti-Hu-associated CIPO, who had generalized dysautonomia. The 2 patients who responded to vedolizumab had an isolated CIPO, and they did not present neuronal antibodies. Rituximab was prescribed in a case of anti-Hu-associated, nonparaneoplastic CIPO, who showed a complete clinical response after this treatment. Our review of the literature retrieved 4 previous cases of autoimmune CIPO treated with rituximab but none treated with vedolizumab. All patients treated with rituximab had Hu antibodies. Two patients showed a clinical response to the treatment with rituximab. DISCUSSION:Our findings underscore the potential efficacy of rituximab and vedolizumab in the management of autoimmune CIPO refractory to first-line treatments.

The 2024 revisions of the McDonald diagnostic criteria include the optic nerve as a fifth anatomical location within the CNS for the diagnosis of multiple sclerosis, in addition to periventricular, juxtacortical or cortical, infratentorial, and spinal cord lesions. Demonstration of dissemination in space can now be achieved with the detection of typical lesions in at least two of these five locations. We review the evidence supporting the use of optical coherence tomography (OCT) and visual evoked potentials (VEPs) to show optic nerve involvement in the diagnosis of multiple sclerosis. We also report consensus recommendations for their use. Provided there is no better explanation for optic nerve involvement and that rigorous quality control is applied, OCT-derived peripapillary retinal nerve fibre layer inter-eye differences of 6 μm or greater or composite macular ganglion cell and inner plexiform layer inter-eye differences of 4 μm or greater support optic nerve injury. Delayed VEP latency, which depends on technical and methodological factors, and is centre and device dependent, supports demyelinating optic nerve injury when done with appropriate technical knowledge and interpretation.

BACKGROUND:This study aimed to test the association between cervical canal area (CCaA), a proxy for spinal cord reserve, measured at the first demyelinating event and disability accumulation in people with multiple sclerosis (pwMS). METHODS:Subjects with a clinically isolated syndrome (CIS) enrolled at Cemcat between January 2009 and December 2014 were included if they had a baseline brain three-dimensional T1-weighted image (3DT1WI), at least a 10-year clinical follow-up, and diagnosis of MS during follow-up. Clinical data were collected at the onset of CIS, and at 6 months, 1 year, 5 years, 10 years, and at the last follow-up visit. CCaA was measured on 3DT1WI using a validated segmentation pipeline at the C2/C3 and C3/C4 disc levels. RESULTS:Of the initial 121 pwMS, the final cohort comprised 81 pwMS with CCaA measures at C2/C3 and 76 pwMS at C3/C4. Linear mixed-effects models showed that while CCaA was not predictive of Expanded Disability Status Scale (EDSS) at disease onset, its influence on disability accumulation increased over time (C3/C4: CCaA-Time interaction, β = -0.023, p = 0.034). CONCLUSION:Larger spinal cord reserve at disease onset appeared to be associated with a slower rate of disability accumulation, supporting the concept of spinal cord reserve.