Severe MS: Researchers report findings from some of the first studies conducted on patients with this rare form of the disease

BUFFALO, N.Y. — A University at Buffalo research program that is investigating what causes some people with multiple sclerosis to experience severe and aggressive disease is beginning to shed light on how their disease differs from those with mild to moderate MS.

Initial findings from UB’s Comprehensive Assessment of Severely Affected MS (CASA-MS), reveal that some of the so-called “gold standards” of MS monitoring are inadequate for patients with severe disease and that novel methods of assessing these people can be more effective.

Findings from papers published online during the past few months will be presented Oct. 23 in person and virtually to the news media, patients and their families at The Boston Home, UB’s partner on the research. The Boston Home is a long-term care facility in Boston, Massachusetts, that specializes in caring for people with advanced-stage MS.

Principal investigator on the study is Robert Zivadinov, MD, PhD, SUNY Distinguished Professor in the Department of Neurology in the Jacobs School of Medicine and Biomedical Sciences at UB. He is director of UB’s Buffalo Neuroimaging Analysis Center (BNAC), a world leader in performing quantitative MRI analysis in neurodegenerative disorders, and director of the Center for Biomedical Imaging at UB’s Clinical and Translational Research Center.

“Little research has been done to characterize severe progressive MS, in part because there is no consensus on the exact definition and classification of this disease phenotype, no specific management and treatment guidelines have been defined, and there are significant practical difficulties in studying this population,” Zivadinov says.

A population left behind

For that reason, people with severe, progressive MS and their families have often felt like a population left behind. Comprising 5-10% of the 2.8 million MS patients worldwide, these people require significant nursing care either provided at home by a patchwork of caregivers or in a skilled nursing facility. Such extensive disability can prove financially and emotionally devastating. Partly because of the challenges of studying this underserved population, many of whom are bedridden, they have long been neglected by the research community.

BNAC’s strongly patient-driven Advisory Council convinced Zivadinov and colleagues to consider studying this rare form of MS. The council’s chair, Larry Montani, had watched two of his siblings experience advanced MS and finally succumb to complications of the disease. One of them lived at The Boston Home. It didn’t make sense to Montani that there had been almost no research on people living with such severe disability.

UB researchers visited The Boston Home in 2019 and the collaboration began. Phase 1 of CASA-MS compared 53 patients from The Boston Home with severe MS with a control group of 53 people matched by age, sex and disease duration living in the greater Buffalo area with mild to moderate MS. Buffalo, like many cities in northern latitudes, has a high incidence of people with MS.

The researchers aimed to determine the most useful ways to study the disability of these patients, their cognitive functioning and neuroimaging endpoints.

Unique trajectories

“Our pilot data suggest that people with severe progressive MS have unique disability and cognitive trajectories compared to those with less severe disease,” Zivadinov says.

In a paper published in April, the team investigated five methods for assessing MS disability; they reported that current methods of assessing MRI outcomes and correlating them with disability measures fall short for evaluating severely disabled MS patients. When looking at the combined analysis of all the participants in both groups, worse scores on the Scripps Neurological Rating Scale were correlated with worse MRI pathology in eight of nine outcomes, whereas with the gold standard Expanded Disability Status Scale (EDSS), only three measures correlated with worse MRI scores.

The researchers conclude that additional, more precise methods of assessing advanced neurological disability are more useful in assessing people with severe MS and that the focus of the EDSS on mobility restriction ignores impairments these patients experience in vision, manual dexterity, sexual dysfunction, fatigue, depression and cognition. They also found that neurodegenerative measures of the brain and spinal cord, such as whole brain volume, were best correlated with greater disability.

White matter lesions in the brain are the biomarker most commonly monitored in patients with MS to assess progression, but the UB researchers reported in a paper published in May that it was grey matter atrophy that correlates more closely with severe physical and cognitive disability. “This study showed significantly more grey matter atrophy in severe compared to less severe progressive MS,” Zivadinov says. He notes, however that because different MRI facilities were used, these findings need to be corroborated in future studies.

Assessing cognition

One challenge is how to assess cognition with some patients who have lost the ability to speak or move to indicate a response. In July, the researchers reported that a greater percentage of people with severe MS were able to complete the Auditory Test of Processing Speed (ATOPS), a smartphone-based auditory test of mental speed, than were able to complete the current gold standard, the Symbol Digit Modalities Test.

“Novel technologies must be considered that can accommodate the complexities of studying severe progressive people with MS within their living environments,” says Zivadinov, “ensuring that these patients are not left behind in the quest for improved quality of life.”

The researchers note that the advent of new therapies that target the chronic inflammation that characterizes severe progressive MS could potentially be a turning point in the care of people with severe MS.

While researching these patients is more challenging for investigators, patients didn’t hesitate to participate in CASA-MS, says Christine Reilly, chief executive officer at The Boston Home.

“Our community at The Boston Home is active and engaged,” she says. “Whether it’s participating in writing group, painting watercolors, or getting out to events in the neighborhood, our residents want to live life to the fullest, despite the challenges of advanced disabilities due to MS and other progressive neurological disorders.

“The CASA-MS study gives participants the chance to bring that same spirit to MS research,” she continues. “Our residents want to play a part in changing the future for people with progressive MS. Their own experience can help inform and shape the emerging research, and that’s both incredibly meaningful and exciting.”

CASA-MS is funded by private foundations and individuals; applications to federal funders are pending. Donations may be made at this link.

The UB researchers anticipate starting Phase 2 in 2025. It will focus on examining longitudinal trajectories of progression in this patient population over three years.

In addition to Zivadinov, UB co-investigators from the Jacobs School are Bianca Weinstock-Guttman, MD; Ralph H. Benedict, PhD; Dejan Jakimovski, MD, PhD; Niels Bergsland, PhD; Michael G. Dwyer III, PhD; Ferdinand Schweser, PhD. Murali Ramanathan, PhD, from the UB School of Pharmacy and Pharmaceutical Sciences, is also a co-investigator.

The Boston Home collaborators are Alex Burnham, director, TBH Institute and rehabilitation services, and Mark Ostrem, MD, medical director.