Keegan, B Mark

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.

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 Falls in people with multiple sclerosis (pwMS) lead to morbidity and expense. Objective Identify clinical metrics associated with falls. Methods Eighty-six pwMS completed fall surveys, timed 25-foot walk (T25FW), and motion analysis with Clario Opal devices. Logistic regression models were created. Results Median age was 54.5 years (range 21–73), 62% (53) were female. The cohort included 58% with relapsing (50) and 42% with progressive MS (36). Those who reported falling in the last year were older (median age 58 vs 52.5, p = .03) and had a higher Patient Determined Disease Step (PDDS) score (median 3 vs 1, p < .0001). Falls were associated with worse balance metrics including sway area (median 2.3 degrees 2 vs 1.2, p = .01), jerk (median 3.3 m 2 /s 5 vs 1.6, p = .005), and slower T25FW (median 11.5 s vs 8; p < .0001). A multivariable regression model based on gait aid use and T25FW time >10.8 s (c = 0.80) was derived. Having both features portended a probability of falling of 0.97, while having neither, a probability of 0.26. Conclusions Falls in pwMS are more frequent in patients who are older, have higher PDDS, slower walking, and worse balance. Gait aid use and T25FW >10.8 s were strongly associated with falls in the past year.

Abstract Spinal cord disease is important in most people with multiple sclerosis, but assessment remains less emphasized in patient care, basic and clinical research and therapeutic trials. The North American Imaging in Multiple Sclerosis Spinal Cord Interest Group was formed to determine and present the contemporary landscape of multiple sclerosis spinal cord evaluation, further existing and advanced spinal cord imaging techniques, and foster collaborative work. Important themes arose: (i) multiple sclerosis spinal cord lesions (differential diagnosis, association with clinical course); (ii) spinal cord radiological–pathological associations; (iii) ‘critical’ spinal cord lesions; (iv) multiple sclerosis topographical model; (v) spinal cord atrophy; and (vi) automated and special imaging techniques. Distinguishing multiple sclerosis from other myelopathic aetiology is increasingly refined by imaging and serological studies. Post-mortem spinal cord findings and MRI pathological correlative studies demonstrate MRI’s high sensitivity in detecting microstructural demyelination and axonal loss. Spinal leptomeninges include immune inflammatory infiltrates, some in B-cell lymphoid-like structures. ‘Critical’ demyelinating lesions along spinal cord corticospinal tracts are anatomically consistent with and may be disproportionately associated with motor progression. Multiple sclerosis topographical model implicates the spinal cord as an area where threshold impairment associates with multiple sclerosis disability. Progressive spinal cord atrophy and ‘silent’ multiple sclerosis progression may be emerging as an important multiple sclerosis prognostic biomarker. Manual atrophy assessment is complicated by rater bias, while automation (e.g. Spinal Cord Toolbox), and artificial intelligence may reduce this. Collaborative research by the North American Imaging in Multiple Sclerosis and similar groups with experts combining distinct strengths is key to advancing assessment and treatment of people with multiple sclerosis spinal cord disease.

Cerebellar dysfunction is likely to cause severe and treatment-resistant disability in multiple sclerosis (MS). Certain spinocerebellar ataxia (SCA)-related alleles can increase MS susceptibility, and channel polymorphisms can impact disability measures. Following an index patient with the coexistence of MS and SCA Type-8 (SCA8) in the MS clinic, an institutional engine search for MS and hereditary ataxia coexistence was conducted but did not reveal any other cases. This extremely rare coexistence of MS and SCA8 in our index patient may be incidental; however, a yet-to-be-identified contribution of coexistent hereditary ataxia(s) to the susceptibility of a prominent progressive ataxia MS phenotype cannot be ruled out.

Background: Progressive motor impairment anatomically associated with a “critical” lesion has been described in primary demyelinating disease. Most “critical” lesions occur within the spinal cord. Objective: To describe the clinical and radiological features of “critical” lesions of the cervicomedullary junction (CMJ). Methods: Observational study on people presenting with a CMJ lesion associated with primary demyelinating disease-related progressive motor impairment. Clinical data were extracted by chart review. Brain and spinal cord magnetic resonance images were reviewed to characterize the CMJ lesion and determine additional demyelination burden. Results: Forty-one people were included: 29 (71%) had progression from onset and 12 (29%) had a relapse onset (secondary progressive) course. Most had progressive hemiparesis (21 (51%)) or progressive quadriparesis (15 (37%)) with a median Expanded Disability Status Scale (EDSS) of 5.5 (2.0–8.5) at last follow-up. No “critical” CMJ lesion enhanced; most were bilateral (25 (61%)). Brain magnetic resonance images were otherwise normal in 16 (39%) or with a restricted demyelination burden in 15 (37%). Cervical and thoracic cord MRIs were without additional lesions in 25 (61%) and 22/37 (59%), respectively. Conclusion: CMJ “critical” lesions can correlate with progressive motor impairment even with few or no additional magnetic resonance imaging (MRI) lesions. Lesion location is an important determinant of progressive motor impairment in demyelinating disease.

Abstract Among people with multiple sclerosis, cognitive impairment occurs commonly and is a potent predictor of disability. Some multiple sclerosis patients present with severe cognitive impairment, and distinguishing multiple sclerosis-related cognitive impairment from co-existent progressive neurodegenerative diseases such as Alzheimer disease poses a diagnostic challenge. The use of biomarkers such as PET and CSF proteins may facilitate this distinction. The study was a retrospective, descriptive study on convenience samples of separate cohorts, one of cognitively impaired multiple sclerosis patients evaluated on autopsy to demonstrate coincidence of both multiple sclerosis and neurodegenerative cognitive diseases. The second cohort were cognitively impaired multiple sclerosis patients evaluated by biomarker to investigate possible additional neurodegenerative cognitive disorders contributing to the cognitive impairment. We investigated selected biomarkers among 31 severely impaired patients (biomarker cohort) and 12 severely impaired patients assessed at autopsy and selected 24 (23 biomarker cohort, 1 autopsy cohort) had comprehensive neurocognitive testing. Biomarker cohort investigations included 18F-Fluorodeoxyglucose PET and/or CSF amyloid Aβ1-42, phospho-tau and total tau levels. The autopsy cohort was evaluated with comprehensive neuropathological assessment for aetiology of cognitive impairment. The cohorts shared similar sex, age at multiple sclerosis onset and multiple sclerosis clinical course. The autopsy-cohort patients were older at diagnosis (69.5 versus 57 years, P = 0.006), had longer disease duration [median (range) 20 years (3–59) versus 9 (1–32), P = 0.001] and had more impaired bedside mental status scores at last follow-up [Kokmen median (range) 23 (1–38) versus 31 (9–34) P = 0.01]. Autopsy-cohort patients confirmed, or excluded, coexistent neurogenerative disease by neuropathology gold standard. Most biomarker-cohort patients had informative results evaluating coexistent neurogenerative disease. Biomarkers may be useful in indicating a coexistent neurodegenerative disease earlier, and in life, in patients with multiple sclerosis and significant cognitive impairment.