‘Silent Progression’ in Relapsing MS Linked to Significant Brain Atrophy

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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People with relapsing multiple sclerosis who have disability progression, but no clinical relapses, show significantly faster brain shrinkage, or atrophy, than those with a stable disease, a study shows.

There were no significant differences in the brain atrophy rate between patients with progression independent of relapse activity (PIRA) and those having clinical relapses only. In both groups, the cerebral cortex — the brain’s outer layer — was mostly affected.

The findings add to previous studies that support the clinical importance of “silent progression” in relapsing forms of MS, and underscore the need to identify the best therapeutic options to prevent further brain atrophy in relapsing MS patients with PIRA, the researchers noted.

The study, “Association of Brain Atrophy With Disease Progression Independent of Relapse Activity in Patients With Relapsing Multiple Sclerosis,” was published in JAMA Neurology.

“While the insidious accumulation of disability is characteristic of the progressive MS disease courses, PIRA has recently emerged as a crucial clinical feature also in relapsing MS,” the researchers wrote, adding that the finding has challenged “the traditional distinction between an early exclusively relapsing phase and a late secondary progressive MS (SPMS).”

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In relapsing forms of MS, disability accumulation is thought to result from “neuroinflammatory events occurring in clinical relapses (relapse-associated worsening),” but “it is much less clear why some patients experience [PIRA],” the researchers wrote.

Brain atrophy, particularly the loss of gray matter  — which mainly contains nerve cell bodies — is an established way of monitoring MS progression. Accelerated brain volume loss is associated with disease disability, but whether different atrophy patterns and rates characterize distinct MS courses remains poorly understood.

A team of researchers in Switzerland and Italy evaluated whether PIRA is associated with accelerated brain atrophy, as assessed with an MRI, in adults with relapsing forms of MS. They also investigated whether the pace and pattern of brain volume loss in patients with PIRA are distinct from those in patients with relapse-associated worsening.

The researchers retrospectively analyzed demographic, clinical, and brain MRI data of 516 RMS patients (348 women and 168 men) who were participating in the multi-center, observational Swiss Multiple Sclerosis Cohort study. The data were collected between January 2012 and September 2019.

The selected patients had regular clinical follow-up and at least two brain MRI scans suitable for brain volume analysis. Their mean age was 41.4 years and they had mild disability, as assessed with the Expanded Disability Status Scale score (EDSS).

Patients were followed for a median of 3.2 years and each had a median of four suitable brain scans. They were divided based on the occurrence of either PIRA, clinical relapses, both, or none.

PIRA was defined as an episode of six-month confirmed disability progression, measured as a sustained increase in EDSS scores, with no relapse during the 90 days before the EDSS increase and during the subsequent six-month confirmation period.

During follow-up, most patients (64.7%) remained clinically stable, 122 patients (23.6%) experienced at least one relapse (irrespective of whether it was linked to confirmed disability progression) but no PIRA, 46 patients (8.9%) experienced PIRA alone, and 14 patients (2.7%) both PIRA and relapse activity.

Results, based on 1,904 brain MRI scans, showed that patients exclusively having PIRA had a significantly increased rate of brain volume loss, compared with a group of patients with stable disease that had been matched to those with PIRA based on several features at the study’s start.

This accelerated atrophy rate was also experienced by the 26 PIRA-exclusive patients who did not show inflammatory activity on an MRI during the entire follow-up, when compared with a matched group of stable patients.

The observed PIRA-associated faster brain atrophy was found to be mainly driven by gray matter loss in the cerebral cortex, the brain’s outer surface that’s involved in higher level processes such as thought, consciousness, emotion, language, and memory.

Patients with clinical relapses, but no PIRA, also showed significantly faster brain atrophy — particularly of gray matter in both the cerebral cortex and deeper brain regions — compared with its corresponding matched group of patients with stable disease.

Atrophy rates did not differ between patients with and without confirmed disability progression after a relapse in any of the evaluated brain regions.

Researchers found no significant differences in brain atrophy rates between the 46 patients with PIRA alone and 46 matched patients with relapse activity alone, suggesting that these patient subgroups experience similarly accelerated brain volume loss.

This is consistent with the results of a previous study that showed that brain atrophy rates were similar between patients with “silent” disease progression and those with obvious brain inflammatory activity.

The results also revealed that “accelerated brain atrophy in patients with PIRA and in patients with relapse activity is mainly driven by GM [gray matter] atrophy, with involvement of the cerebral cortex in both patient groups and involvement of deep GM in relapsing patients only,” the researchers wrote.

The findings highlight that “events of insidious PIRA are associated with increased atrophy rates, likely reflecting ongoing diffuse neurodegenerative processes, especially in cortical GM,” the researchers wrote.

This association “points at the need to identify insidious disease progression in patients with relapsing multiple sclerosis and to further investigate therapeutic approaches to prevent irreversible brain tissue loss in these patients,” they said.

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