Progressive late-onset multiple sclerosis linked to greater disability in Latvian cohort

In a single-center retrospective study of people whose multiple sclerosis symptoms began at age 50 or later, progressive disease was associated with more motor and bladder or bowel symptoms and substantially higher disability than relapsing-remitting multiple sclerosis. The study included 56 patients treated at Riga East University Hospital in Latvia: 38 with relapsing-remitting multiple sclerosis and 18 with a progressive phenotype comprising nine cases of primary progressive and nine of secondary progressive disease. Progressive forms were associated with a median baseline Expanded Disability Status Scale score of 3.75, compared with 2.00 for relapsing-remitting disease, and with a median five-year score of 6.00 rather than 3.00 among patients whose follow-up was available.

The researchers reviewed clinical records collected between 2014 and 2024 from a source database of 518 unique people with multiple sclerosis. Fifty-nine had symptom onset at age 50 or older, the threshold used to define late-onset multiple sclerosis in the study. Three were excluded from the main analysis: two had clinically isolated syndrome and one had an unspecified phenotype, leaving 56 patients with relapsing-remitting, primary progressive or secondary progressive multiple sclerosis. The investigators extracted symptoms, magnetic resonance imaging lesion locations, comorbidities, baseline and five-year disability scores, and initial and current disease-modifying therapies. Because the Expanded Disability Status Scale is ordinal and the sample was small, they used nonparametric and exact statistical tests.

Pyramidal or motor symptoms were the most common early clinical manifestations, reported in 83.9% of the entire cohort. They occurred in every patient with progressive multiple sclerosis and in 76.3% of those with relapsing-remitting disease, a statistically significant difference with a p-value of 0.045. Bowel and bladder dysfunction was also more frequent in the progressive group, affecting 72.2% of progressive cases and 42.1% of relapsing-remitting cases, with a p-value of 0.035 by chi-square testing and 0.047 by Fisher’s exact test. Other frequently recorded symptoms included sensory symptoms and cerebellar or balance problems, each present in 71.4% of patients, as well as brainstem symptoms, reported in 62.5%. Cerebral symptoms appeared only in the relapsing-remitting group, but this result was based on eight patients and was flagged by the researchers as requiring caution.

Magnetic resonance imaging data for the brain, spinal cord and optic nerves were available for all 56 patients, and the cohort had lesion involvement in several central nervous system regions. Periventricular lesions were the most common finding, present in 94.6% of the cohort, followed by juxtacortical lesions in 87.5% and spinal cord lesions in 82.1%. Infratentorial lesions occurred in 75.0% and optic nerve involvement in 50.0%. All 18 patients with progressive disease had periventricular, infratentorial and spinal cord lesions recorded, compared with 92.1%, 63.2% and 73.7%, respectively, among the 38 patients with relapsing-remitting disease. The distributions showed that late-onset multiple sclerosis could involve multiple anatomical pathways, while also illustrating why imaging findings in older adults require caution because vascular, degenerative, metabolic and other inflammatory conditions may produce overlapping clinical or radiological features.

Disability scores documented at baseline and five years showed a pronounced separation between relapsing-remitting and progressive phenotypes. The median baseline Expanded Disability Status Scale score was 2.00, with an interquartile range of 1.50 to 3.00, in the relapsing-remitting group and 3.75, with an interquartile range of 3.12 to 5.88, in the progressive group. The difference was statistically significant, with a p-value below 0.001. Five-year scores were available for 39 of the 56 patients, including 25 of 38 patients with relapsing-remitting disease and 14 of 18 with progressive disease. Their median five-year scores were 3.00 and 6.00, respectively, again a significant difference with a p-value below 0.001. A three-group analysis found an overall difference among relapsing-remitting, primary progressive and secondary progressive disease, with secondary progressive multiple sclerosis showing a higher score than relapsing-remitting disease after Bonferroni adjustment.

Although absolute disability was consistently greater in the progressive group, the amount of change over five years did not differ significantly between the phenotypes. The median change in Expanded Disability Status Scale score was 1.00 point in progressive disease and 0.50 point in relapsing-remitting disease, with a p-value of 0.377. The investigators emphasized that this null comparison must not be interpreted as evidence that the two groups progress at equivalent rates. Progressive patients began with substantially higher scores, and the available follow-up represented only two assessment points rather than a detailed trajectory. Sixteen of the 17 patients lacking a five-year score had an age-derived disease duration shorter than five years, so missing follow-up was strongly associated with shorter observed disease duration.

A sensitivity analysis excluding patients whose age-derived disease duration was under five years did not materially change the pattern. Among the 34 retained patients, the progressive group continued to have higher baseline disability, with a median score of 4.00 versus 2.00 for relapsing-remitting disease, and higher five-year disability, with medians of 6.00 and 3.00. Change in score again did not differ significantly, with medians of 1.00 and 0.50 and a p-value of 0.524. The findings therefore suggest that the greater five-year disability observed in progressive late-onset multiple sclerosis was largely already present at the beginning of observation. They do not establish that progressive and relapsing-remitting phenotypes accumulate disability at the same rate, particularly given the modest sample and incomplete longitudinal data.

Treatment patterns differed sharply by phenotype and changed between the initial and current assessments. Among active disease-modifying therapy users, initial anti-CD20 treatment was recorded in 19.4% of patients with relapsing-remitting disease, 88.9% of those with primary progressive disease and 42.9% of those with secondary progressive disease. At the current assessment, anti-CD20 therapy was used by 38.9% of active-treated relapsing-remitting cases, all nine primary progressive cases and 83.3% of active-treated secondary progressive cases. High-efficacy therapy was also more common in progressive phenotypes, whereas platform or moderate-efficacy treatment predominated in relapsing-remitting disease. Among 33 patients initially receiving platform or moderate therapy, 11 were receiving high-efficacy treatment at the current assessment, while all 19 initially classified in the high-efficacy group remained in that category.

Patients receiving anti-CD20 therapy had higher observed disability than those receiving other active therapies. Those starting with anti-CD20 treatment had a median baseline score of 3.50, compared with 2.00 for other active treatments, while patients currently receiving anti-CD20 therapy also had higher baseline and five-year scores than comparable patients on other active therapies. High-efficacy treatment groups likewise had higher five-year scores than the platform or moderate-efficacy group, with a median of 4.50 versus 2.50 and an adjusted p-value of 0.027. These are treatment associations, not evidence that anti-CD20 or high-efficacy therapy worsened outcomes. In routine care, clinicians may direct more intensive treatment toward patients with progressive disease, greater baseline disability or evidence of inflammatory activity, creating confounding by indication. Treatment exposure was also not fully aligned with the timing of disability assessments, and relapse activity, adherence, switching dates and adverse events were not systematically evaluated.

The study offers a detailed but geographically limited view of contemporary tertiary-care practice, rather than a nationally representative assessment of late-onset multiple sclerosis. Its retrospective design, single center and small progressive subgroups limited statistical power and adjustment for confounders. Diagnostic heterogeneity was possible because the study period spanned revisions of the McDonald criteria, MRI findings came from routine radiology reports rather than centralized image review, and five-year scores were unavailable for some participants. There was also no adult-onset comparison group, meaning the results cannot determine whether the observed features are unique to late-onset disease or mainly reflect the distinction between progressive and relapsing-remitting phenotypes. Multiple exploratory comparisons further argue against treating borderline findings as definitive. The authors positioned the findings as a replication and extension of established observations: late-onset multiple sclerosis, particularly its progressive forms, can carry a substantial motor, sphincter and disability burden, and geographically diverse cohorts are needed to define how that burden and contemporary treatment selection vary across healthcare systems.

Subject of Research: Clinical symptoms, disability outcomes, MRI findings and treatment patterns in late-onset multiple sclerosis

Article Title: Clinical characteristics, disability outcomes, and disease-modifying therapy patterns in late-onset multiple sclerosis: a single-center retrospective cohort study

Article References: Alomar, R., Polunosika, E., Karelis, G., & Pastare, D. (2026). Clinical characteristics, disability outcomes, and disease-modifying therapy patterns in late-onset multiple sclerosis: a single-center retrospective cohort study. Frontiers in Neurology, 17, Article 1966162. https://doi.org/10.3389/fneur.2026.1966162

Image Credits: AI Generated

DOI: 10.3389/fneur.2026.1966162

Keywords: late-onset multiple sclerosis, progressive multiple sclerosis, disability outcomes, Expanded Disability Status Scale, disease-modifying therapy, anti-CD20 therapy, MRI lesions, Latvian cohort, retrospective cohort study, Clinical, characteristics, disability