Smoldering Lesions: Red Flags for Severe MS

Researchers find these biomarkers could help in identifying and treating patients at risk for multiple sclerosis faster than before.


“Smoldering” lesions—signaling chronic inflammation—may be a hallmark of more aggressive forms of multiple sclerosis (MS), according to researchers from the National Institute of Neurological Disorders and Stroke (NINDS). New technology that allows long-term in vivo monitoring could make it possible for the first time to predict who is at risk for progressive MS and potential treatments.

MS lesions appear as spots on brain scans. Some lesions heal. Others remain and may have characteristic dark rims, which is inflammatory demyelination at the edges. The dark-rimmed lesions appear to expand, or “smolder” for years. But until recently, researchers did not fully understand what role those chronic active lesions played in MS because it was difficult to find the ones that remain inflamed.

The researchers conducted 3 studies at the NIH Clinical Center. In the first, using a high-powered, 7-tesla MRI scanner and a 3D printer, they scanned the brains of 192 MS patients. Of those, 40% had no rimmed lesions; 32% had 1 to 3 rims; and 20% had ≥ 4 rims. Regardless of the treatment they were receiving, 56% of the patients had at < 1 rimmed lesion.

The researchers compared the brain scans to the patients’ baseline neurologic examinations. Patients with ≥ 4 rimmed lesions were nearly twice as likely to be diagnosed with progressive MS than were those without rimmed lesions. Moreover, the patients with rimmed lesions developed motor and cognitive disabilities at a younger age than did patients without rimmed lesions. Patients with ≥ 4 rimmed lesions also had less white matter and smaller basal ganglia.

When they analyzed a subset of patients whose brains had been scanned once a year for ≥ 10 years, the researchers found that although the rimless lesions generally shrank, the rimmed lesions grew or stayed the same size and were “particularly damaged.”

The team also used a 3D printer to compare the spots they had seen on scans with lesions in brain tissue samples from a patient who died during the trial. All 10 expanding rimmed spots on the scans had the “telltale features” of chronic active lesions when examined under a microscope.

“Figuring out how to spot chronic active lesions was a big step,” said research team member Martina Absinta, MD, PhD. “We could not have done it without the high-powered MRI scanner.” Most MRI scanners used clinically have field strengths of 1.5 or 3 Tesla. The research team had previously published instructions for programming lower powered MRI scanners to detect rimmed chronic active lesions.

Chronic active lesions are common and exert ongoing tissue damage, said Daniel S. Reich, MD, PHD, senior investigator at NINDS, and senior author of the paper. The fact that these lesions are present in patients who are receiving anti-inflammatory drugs, he added, suggests that the field of MS research may want to focus on new treatments that target the brain’s unique immune system—especially a type of brain cell called microglia, which are instrumental in the immune response.


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