When MS Progression Begins: Early Injury and Relapsing vs Progressive Biology

This episode, "When MS Progression Begins: Early Injury and Relapsing vs Progressive Biology," features Dr. Rosenthal and Dr. Singer examining when damage starts and how the two biologies differ.

Dr. Greenberg reflects that early in his career nearly all of his patients had relapsing-remitting disease and progressive MS was a minority. As highly effective therapies arrived, calls about relapses disappeared and different phenotypes of progression emerged. He asks Dr. Rosenthal when the biology of progression begins.

Dr. Rosenthal explains that eliminating relapse-associated worsening has uncovered processes that were happening in the background. Tissue damage can arise through several mechanisms, whether directly to axons or secondarily from myelin loss. In her view, that damage starts at the very beginning of the disease. It becomes noticeable later as compensatory and reparative capacity declines. She argues clinicians should not wait the number of years once taught before secondary progression sets in, because irreversible damage begins early and drives disability decades later.

Dr. Greenberg then asks Dr. Singer whether relapsing and progressive disease form a continuum. Dr. Singer says he has never liked placing patients in boxes, noting that regulatory requirements drove many of the categories. He recalls asking at Grand Rounds 25 years ago whether secondary and primary progressive MS are the same disease. For relapsing disease, he describes acute, contrast-enhancing inflammatory lesions that monthly MRI studies at the NIH showed coming and going, even in patients who reported no attacks for ten years.

Progressive biology, he continues, brings compartmentalized inflammation, deep gray matter and thalamic damage linked to cognitive impairment, and cortical injury from soluble factors diffusing through the CSF and meninges. Axonal degeneration adds a neurodegenerative component, some of it probably irreversible. Spinal cord lesion burden raises the risk of progression, and data presented at the congress suggest cord volume contributes strongly to ambulation on the EDSS. The two biologies differ but overlap.

In "MS Feedback Loops and Heterogeneity: Why Disease Course Varies," Dr. Krieger and Dr. Rosenthal will explain the feedback loops behind disease variability.