Comparing Early vs. Late-Onset MS

By Ulrike W. Kaunzner, MD

Assistant Professor of Clinical Neurology, Weill Cornell Medical College

SYNOPSIS: A recent retrospective study, combining data from a United Kingdom patient registry with a United Kingdom neuropathology tissue bank, showed that late-onset multiple sclerosis (MS), referring to disease onset after age 50 years, is linked with increased disability and quicker progression compared to MS onset at a younger age, and has distinct pathological features.

SOURCE: Knowles S, Middleton R, Cooze B, et al. Comparing the pathology, clinical, and demographic characteristics of younger and older-onset multiple sclerosis. Ann Neurol 2024;95:471-486.

Multiple sclerosis (MS) can be symptomatic at any age but most often is diagnosed between the ages of 20 and 40 years, making it a common neurological condition among young adults. Characteristics of MS in older patients have been described in the past and have been associated with different clinical, radiological, and histopathological features compared to younger patients with MS. Although the female-to-male ratio in the younger MS population appears to be 3:1, with an increasing ratio over time, the male-to-female ratio is 1:1 for patients with primary progressive MS.

In this study, Knowles at al used the United Kingdom (UK) Multiple Sclerosis Register Database and the United Kingdom MS Tissue Bank to retrospectively examine patients with late-onset MS (LOMS; symptom onset older than 50 years of age) and those with early onset MS (EOMS; onset between ages 18 and 49 years). Within the entire cohort of 17,124 patients with MS, 1,608 (9.4%) patients were identified as having LOMS. When compared to EOMS, the LOMS cohort had a lower percentage of female patients, a higher proportion of primary progressive MS, and a lower proportion of relapsing-remitting MS. Ambulation changes, compared to visual symptoms or numbness, were more frequent among the self-reported symptoms in the LOMS population. Also, the degree of disability at the time of diagnosis was worse in patients with LOMS compared to patients with EOMS.

It is consistent with previous research that more male patients, primary progressive disease, and gait-related symptoms were observed in the LOMS group compared to the EOMS cohort. Patients with LOMS received disease-modifying therapy earlier (0.7 years vs. 2.1 years) but were less likely to be prescribed high-efficacy medications (15% vs. 29%). Postmortem histopathology studies from cases with later MS onset often exhibited concomitant findings such as neurodegeneration and vascular disease. Cortical lesions constituted a larger proportion of the total lesion load in LOMS. Neuronal density was decreased in the cingulate and thalamus in the LOMS group when compared to the EOMS group. Also, LOMS patients were less likely to have actively demyelinating lesions and exhibited less leptomeningeal inflammation, while demyelination was more pronounced in EOMS. In conclusion, this is the largest study to date investigating patients with LOMS, showing that LOMS is linked to increased disability and progression compared to EOMS. Also, more neurodegenerative features were seen on pathology as compared to active demyelination.

COMMENTARY

This is an important study, since it investigates a group of MS patients that classically has less acute clinical presentations and less active radiological or pathological features. However, individuals diagnosed with LOMS seem to face an elevated risk of progression, characterized by a higher prevalence of neurodegenerative characteristics and fewer acute inflammatory markers compared to those with younger-onset MS. Moreover, non-MS brain pathologies frequently were detected in the LOMS cohort. Also, administration of highly effective anti-inflammatory medications might be advisable for patients with LOMS. It needs to be mentioned that the majority of histopathologically evaluated brains were from women with MS in the LOMS cohort, and larger studies representing the male-to-female ratio in patients with LOMS will be important.

It also will be important to differentiate patients with LOMS in progressive and relapsing-remitting MS patients and investigate their degree of neurodegeneration. Longitudinal studies will be crucial to see if patients with LOMS with a relapsing-remitting course enter the progressive phase earlier compared to patients with EOMS. Also interesting is the fact that there might be a change of long-standing MS after women enter perimenopause and menopause; women often exhibit more symptoms in their 40s and 50s or even transition into progressive disease. It will be important to look at differences in women with an MS diagnosis before and after age 50 years, and how disease course and radiographic features might behave differently. In summary, this is an informative study, and more clinical, radiological, and histopathological data are needed for patients with LOMS.