Spinal Cord Atrophy Predicts 'Silent Progression' in MS

Nancy A. Melville

February 28, 2022

WEST PALM BEACH, FL ― Spinal cord atrophy, as detected on calibrated brain MRI scans, significantly correlates with silent progression of multiple sclerosis (MS) to progressive MS, new research shows.

The results suggest that this is a potentially important biomarker for disease progression that may otherwise go unrecognized by clinicians and patients, investigators note.

Dr Antje Bischof

"We found that cervical cord atrophy at the C1 level, as obtained from routine brain MRI, is the strongest indicator of silent progression and secondary progressive MS conversion," said lead author Antje Bischof, MD, Department of Neurology and Institute of Translational Neurology, University Hospital, Munster, Germany.

"Silent progression and secondary progressive MS conversion are each predominantly related to spinal cord atrophy," she added.

Bischof presented the findings here at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2022.

Relatively New Concept

Secondary progressive MS (SPMS) generally occurs when relapsing-remitting MS (RRMS) progresses, with relapses ceasing and a more steady accumulation of disability occurring.

However, a relapse-free "silent progression" of MS, described in previous research as occurring in as many as a third or more of patients with relapsing MS, emerges at a much earlier stage prior to secondary progression. This potentially involves widespread neurodegeneration in early disease stages.

Dr Bruce Cree

"Because the concept of silent progression is relatively new and directly challenges the long accepted two-stage hypothesis, many clinicians have yet to actively identify silent progression in clinical practice," co-investigator Bruce A. C. Cree, MD, PhD, professor of clinical neurology at the University of California, San Francisco (UCSF), told Medscape Medical News.

To investigate the underlying structural or pathophysiologic changes that are linked to silent progression, the researchers focused on spinal cord measures, which are known to strongly correlate with disability.

They evaluated 360 patients with RRMS and 47 with SPMS and compared outcomes with 80 participants who acted as the study controls. The groups were matched for age, sex, disease duration, and treatments over a 12-year observation period using data from the UCSF MS Center.

To examine spinal cord changes in areas that could affect MS, the investigators used a novel orientation of MRI brain scans to capture the upper cervical cord area.

Among the patients with RRMS, 54 converted to SPMS over 12 years; 159 had silent progression during the period. Silent progression was defined as the onset of irreversible worsening of scores on the Expanded Disability Status Scale (EDSS). Silent progression was confirmed over 12 months and occurred independently of relapses.

"Strongest Predictor"

The analysis showed spinal cord atrophy at the C1 vertebral level to be the strongest predictor of silent progression, with each 1% increase in spinal cord atrophy associated with a 69% shorter time to silent clinical progression (P < .0001).

Those who converted from RRMS to SPMS showed spinal atrophy rates of -2.19% per year, vs -.88% per year among those who did not convert (P < .001).

"C1A atrophy rates in patients with silent progression were faster even when combining RRMS and SPMS patients," Bischof said.

Of note, the patients who silently progressed showed a lower EDSS score at baseline, she added.

Next to spinal atrophy, ventricular enlargement was the second strongest MRI metric associated with silent progression over the 12 years. Each 1% increase in lateral ventricle size was associated with a 16% reduced time to silent clinical progression (P = .007).

"These findings extend the prognostic value of spinal cord atrophy not only for the conversion to SPMS but also silent progression," Bischof told Medscape Medical News.

"Furthermore, we show that the enlargement of the lateral ventricles is the second strongest indicator of impending silent progression and the strongest of all brain measures," she said.

Standard of Care?

While the unique MRI techniques used in the study may not be easily obtained in standard practice, Cree noted that efforts are underway to facilitate the process.

"Development of a fully automated software package to obtain those measurements for both clinical trials and in some [clinical settings] is underway," he said.

Cree noted that once those technologies are available, the assessment of spinal cord atrophy could become standard in MS care.

"I predict that when upper cervical cord measurements can be readily measured, assessment for decrease in the upper cervical cord area will be an essential component of routine care of relapsing MS patients," he said.

"Because decreases in upper cervical cord areas herald disability worsening, there may well be a window of opportunity to use highly effective treatments to arrest or even reverse this process before irreversible disability accumulates," Cree added.

Treatment Implications

Commenting for Medscape Medical News, ACTRIMS program co-chair Anne Cross, MD, professor of neurology and the Manny and Rosalyn Rosenthal – Dr John Trotter MS Chair in Neuroimmunology, Washington University in St. Louis, Missouri, noted that the study is important for two key reasons.

"We lack a good prognostic marker of future progression, but this could have very important implications for the choice of treatment of patients, particularly if the findings are applicable not only at the group level, as in the study, but also at the level of the individual patient," said Cross, who was not involved with the research.

Secondly, the results suggest benefits in the selection of patients for clinical trials of agents that might stop progression. "Choosing patients who would deliver the most impact in studies of potential new treatments for progressive MS" is important, Cross said.

"We don't want to dilute our trial patient populations with patients who might not be destined to progress in the ensuing years," she added.

Also commenting for Medscape Medical News, Benjamin Segal, MD, director of the University of Michigan's Multiple Sclerosis Center and the Holtom-Garrett Program in Neuroimmunology, Ann Arbor, agreed that the study offers valuable insights.

"These findings are striking in that they underscore the fact that even relapsing-remitting MS patients undergo functional decline in between overt clinical exacerbations, although the decline is more subtle than that experienced by people with progressive forms of MS," Segal said.

He noted that the strong correlation between silent progression and spinal cord atrophy, more so than with brain measures, "is not so surprising, since clinical decline was measured using the EDSS scale ― which emphasizes ambulation over other functions," such as cognition.

"It would be interesting to correlate silent progression with serum neurofilament light chain levels, at baseline as well as change over time," Segal added.

Bischof and Segal have reported no relevant financial relationships. Cree has received personal compensation for consulting from Biogen, EMD Serono, and Novartis.

Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2021: Abstract CE2.2. Presented February 25, 2022.

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