B. Mark Keegan

Progressive multiple sclerosis (MS) is usually associated with progressive asymmetrical motor impairment. A single critical demyelinating lesion anatomically associated with motor impairment was seen in > 20% of patients with progressive MS. The assessment of critical lesion-associated progressive MS requires understanding their clinical course, how prior inflammatory relapse location and their first MRI appearance relates to progressive motor impairment. To determine: (1) clinical course and prior relapse location and (2) interval between first MRI critical lesion evidence and progressive motor impairment in patients with progressive MS with a single critical lesion. Prospective, consecutively accrued patients with progressive MS were seen at a tertiary MS clinic (July 1, 2021-June 30, 2022). Patients with one critical lesion anatomically associated with progressive motor impairment were included. Patients with two or more tandem critical lesions along the same corticospinal tract or too extensive demyelinating lesion burden to determine the association between motor impairment and one critical lesion were excluded. A location-related relapse (LRR) was defined as a prior acute inflammatory demyelinating event at the same CNS site subsequently identified with critical lesion-associated motor progression. Clinical course was progressive from onset [primary progressive MS (PPMS)] or relapse-onset [secondary progressive MS (SPMS)] with SPMS dichotomized to those with or without LRR. MRIs were reviewed determining the earliest MRI critical lesion appearance and duration between this and the onset of progressive motor impairment. 53 of 266 (20%) patients with progressive MS had a single critical lesion associated with motor progression. Clinical course was SPMS in 36/53 (68%) and PPMS in 17/53 (32%). SPMS critical lesion onset was LRR-associated in 26/36 (72%). Critical lesion was first MRI-evident a median of 2.2 years before the onset of motor progression in SPMS (IQR -1.7 to 4.6) and -4.5 years (IQR -10.6 to -2.5) in PPMS with negative values indicating first MRI evidence came after motor progression onset. In people with a single critical lesion-associated motor progression, this typically presents as SPMS and often follows an LRR. This emphasizes the anatomic association between initial lesion-associated inflammatory presentation and subsequent motor progression.

The spinal cord plays a central role in the pathophysiology and clinical manifestations of multiple sclerosis (MS), yet remains under-studied compared with the brain. This review summarizes key insights from the 2025 North American Imaging in MS Spinal Cord Imaging Workshop, highlighting recent advances, ongoing challenges, and future opportunities in MS spinal cord imaging. We review pathological studies and outline the clinical relevance of spinal cord lesions and atrophy for diagnosis, prognosis, and disease monitoring, highlighting emerging biomarkers of progression independent of relapse activity. Correlations between magnetic resonance imaging, histopathology, and clinical outcomes support the validation and translational potential of advanced spinal cord imaging techniques. Finally, we discuss spinal cord–specific processing pipelines and reproducibility challenges. Collectively, these insights underscore the need to integrate advanced and quantitative spinal cord imaging into clinical trials, research studies, and—when feasible—clinical care, to fully capture the extent of MS pathology, and ultimately improve patient outcomes.

Prior studies examining associations between Epstein Barr Virus (EBV)-positive infectious mononucleosis (IM) and risk of multiple sclerosis (MS) frequently lacked laboratory confirmation of EBV-positive IM or relied on billing codes to identify MS. We assessed whether laboratory-confirmed EBV-positive IM was associated with an increased risk of developing verified cases of MS. We conducted a population-based retrospective cohort study using medical records from the Rochester Epidemiology Project. We identified individuals with serologic evidence of EBV infection and an associated IM diagnosis (EBV-positive IM; exposed cohort) between 1998 and 2022. Age- (± 1 year) and sex-matched individuals without evidence of IM (3:1 match) comprised the unexposed cohort. Incident MS cases were verified through blinded expert chart review. Multivariate Cox proportional hazard models were used to assess associations between EBV-positive IM and risk of MS. 4,721 persons had EBV-positive IM (exposed cohort: 55% female, 70% <20 years). The referent cohort included 14,163 persons without EBV-positive IM (55% female, 70% 3-fold increased risk of MS (adjusted Hazard Ratio: 3.14, 95% Confidence Interval: 1.18-8.34). EBV-positive IM was associated with a substantially higher risk of MS. Findings are consistent with prior studies and underscore the importance of preventive strategies targeting EBV to reduce the long-term burden of MS.

Background/Objectives: Characterizing spinal cord multiple sclerosis (MS) lesions in MRI is critical for diagnosis, monitoring, and treatment evaluation. However, current automated approaches for lesion detection and segmentation are typically designed for specific MRI contrasts or acquisition sites, limiting their generalizability in real-world clinical settings where imaging protocols vary widely. This work proposes a robust multi-site, multi-contrast segmentation framework for spinal cord lesions. Methods: The segmentation model was trained and evaluated on a large-scale dataset comprising 4428 annotated images from 1849 persons with MS across 23 imaging centers, encompassing six MRI contrasts (T1w, T2w, T2*w, PSIR, STIR, and UNIT1) acquired at 1.5 tesla (T), 3 T, and 7 T. Results: Likert-type assessment performed by neuroradiologist ratings demonstrated superior generalization of the model compared to existing contrast-specific pipelines ( p < 0.01). Additional experiments evaluated robustness across spinal levels, acquisition resolutions, binarization thresholds, and quantitative evaluation on external labeled datasets. Conclusions: The proposed model can achieve accurate and reliable spinal cord MS lesion segmentation across heterogeneous MRI data, addressing a key barrier to clinical translation. The model is available in the Spinal Cord Toolbox v7.2 and higher. Code repository: https://github.com/ivadomed/seg-sc-ms-lesion-multicontrast

Background: Tremor in multiple sclerosis (MS) is often refractory to medications. Deep brain stimulation (DBS) may help, but possible side effects and disease exacerbation limit its use. Objectives: Evaluate outcomes of DBS for MS-associated tremor. Methods: Retrospective review of 18 patients with MS-associated tremor who underwent DBS, analyzing Expanded Disability Status Scale (EDSS) and Fahn–Tolosa–Marin (FTM) tremor scores. Results: Median age at surgery was 49.5 years (range, 28–75), with postoperative follow-up 2.5 years (range, 0–22). No relapses (0/18) or new lesions (0/8) occurred postoperatively. All had ventral intermediate nucleus leads; other targets were not used in programming. EDSS remained stable (median 6 to 6.25; p = 0.2). FTM scores improved (median 14.5 to 10, p = 0.008). Patients with EDSS 3.5–6 had variable outcomes ( p = 0.02). Conclusions: DBS is a potential treatment for severe MS tremor and did not provoke relapse. Targeting VIM alone may optimize tremor control and maintain magnetic resonance imaging (MRI) access.

Background and objective Critical demyelinating lesions are individual lesions anatomically associated with progressive motor impairment initially described in highly selected cohorts with demyelinating disease. We aim to determine how frequently individual critical demyelinating lesions were found in an unselected consecutive cohort of people with progressive multiple sclerosis (MS) at a tertiary MS clinic over a one-year duration. Methods Prospective consecutively enrolled observational cohort study of newly evaluated and established people with progressive MS at Mayo Clinic from July 1, 2021 to June 30, 2022. Demographics and clinical information were extracted by chart review following evaluation by an MS subspecialty expert. Participants were evaluated as having predominantly progressive motor or non-motor (ataxic, cognitive, sensory) impairment. All brain and spinal cord MRIs were examined for demyelinating lesions involving the corticospinal motor tracts. Critical lesions were defined as T2 lesions anatomically associated with a progressive upper motor neuron impairment within the lateral columns, brainstem corticospinal tracts, or supra-tentorial corticospinal tracts. Participants were classified as having: A) one critical lesion; B) two “tandem” critical lesions or C) lesion burden too high (i.e., ≥ 3 critical tandem lesions where individual lesions could not reliably associated with motor progression). Results 255 participants were evaluated: 67 (26.3%) with critical lesions, (54 [21.2%] with one critical, and 13 [5.1%] with two tandem critical lesions) and 188 (73.7%) with lesion burden too high. Non-motor progression was found in 15 (5.9%). Critical lesions were identified in most within the spinal cord (cervical in 49 [90.7%] and thoracic in 3 [5.5%]). Those with critical lesions were older at evaluation than those with lesion burden too high (median 62 years IQR 55–68 vs. 58.0 IQR 49–64, p = 0.004), more likely to present with progressive hemiparesis (55.2% vs 14.4%, p < 0.001), and less likely to present with progressive para-paresis (4.5% vs 31.9% p < 0.001) or quadriparesis (1.5% vs 10.1%, p = 0.031). These groups had similar numbers of brain demyelinating lesions. Discussion Critical demyelinating lesions, often within the spinal cord and anatomically associated with progressive motor impairment, are commonly found in people with progressive MS.