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  • Writer's pictureGary Birnbaum, MD

Changing Insights Demand Change

Multiple sclerosis progression: time for a new

mechanism-driven framework

Tanja Kuhlmann, Marcello Moccia, Timothy Coetzee et al

Lancet Neurol 2023; 22: 78–88

Bottom Line:

MS is a heterogeneous disease and identifying persons with similar patterns of MS is critical both for the design of clinical trials and for recommending treatments. For the past 25 years persons with MS have been grouped according to their clinical course (relapsing forms of multiple sclerosis, primary progressive multiple sclerosis, secondary progressive MS) and on central nervous system MRI changes. Important new insights into the pathobiology of MS require a change in this schema. To truly “personalize” care for persons with MS it is essential to measure parameters that inform about the underlying disease processes. For example, while slow progressive disability worsening was felt for years to be a late feature of the illness, it is now known that there are changes in the central nervous system showing tissue degeneration characteristic of progressive disease at the very onset of the illness. In addition there are changes on central nervous system MRIs that vary from individual to individual, and relate to patterns of tissue destruction, to the ability to heal and remyelinate, and to regional changes in the central nervous system that relate to cognitive dysfunction and motor disability. Thirdly, there are proteins in blood and spinal fluid levels of proteins that correlate with the extent of tissue damage that can be measured and used a markers of disease activity and response to treatment. Finally, non-neurological changes must be considered when designing clinical trials or making treatment recommendations. These include an individual’s age, sex, habits (e.g., smoking, alcohol intake), and comorbid health issues (e.g., diabetes, heart disease, obesity, high blood pressure).

The above paper provides an excellent summary of why it is no longer tenable to group persons with MS solely on clinical course, and why biologically-based disease parameters must be used to better define individuals recruited into clinical trials and to individualize treatment recommendations.

Key Points:

1. MS is heterogeneous disease, with different degrees of severity, different patterns of disability with differing areas of the central nervous system affected. Most importantly, there are differing responses to treatment, and trying to categorize persons with MS into similar groupings for inclusion in clinical trials and for predicting responses to disease-modifying therapies has been difficult.

2. As noted above, initial attempts at grouping persons with MS were based on their patterns of disease, such as whether this was their first neurologic event (“clinically isolated syndrome”), whether they had relapsing disease (“relapsing forms of multiple sclerosis”), whether their course was progressive from onset (“primary progressive multiple sclerosis”) or had evolved into a progressive pattern (“secondary progressive MS”). The above paper argues this must change.

3. With major new insights into the underlying pathology of MS there is now the ability to categorize persons with MS based on the underlying biology of their disease, to assess responses to therapy using these biologic, rather than clinical parameters, and to start personalizing disease-modifying therapies.

4. Among the most important insights came from careful evaluation of autopsy and brain biopsy tissues. These revealed changes suggestive of chronic, low-grade inflammation, characteristic of progressive MS, that were present from onset of the illness and diffusely affected what otherwise appeared to be normal white matter.

5. In addition, some individuals had accumulations of immune cells, mainly B-lymphocytes, in node-like structures in the covering of the brain (the meninges). These changes were associated with a loss of outer brain nerve cells or neurons.

6. Further insights came from central nervous system MRIs. Using exceptionally strong, high field MRIs researchers were able to see the nodes of lymphocytes described above and to correlate them with the clinical picture. In addition, loss of brain volume (atrophy) was present even at the earliest stages of disease, particularly in areas like the thalamus, with the atrophy not directly related to areas of acute inflammation.

7. New MRI techniques also allowed the identification of slowly progressive, destructive lesions called “paramagnetic ring lesions,” areas of low-grade inflammation with minimal immune cell activation but tissue loss due to activated brain cells called microglia.

8. With stronger MRIs and new markers to identify myelin it also became possible to measure the formation of new myelin in the central nervous systems of persons with MS. It became clear that healing and remyelination varied greatly among individuals. Some persons with MS had a pattern of disease with essentially no new myelin formation while other individuals had brisk remyelination, associated with a milder clinical course.

9. Optical coherence tomography (OCT) also emerged as a technique to assess brain injury. OCT is a technique for measuring the thickness of nerve layers in the retina. The optic nerve is an extension of the brain and in persons with MS the retinal nerve layers are often thinned, even without a history of nerve inflammation or optic neuritis. OCT is not a perfect marker of the how much brain or spinal cord inflammation is occurring, but it is a simple test, quickly performed, that can be used as a marker of tissue degeneration and tissue healing. In combination with measuring how well the optic nerve conducts electrical impulses (a test called visual evoked responses or VER), health care providers can use OCT to follow MS-related disease activity in the eyes as well as measure healing or stabilization due to a disease-modifying therapy.

10. In the past decade the profound effects of aging and the presence of other illnesses (comorbidities), on the course of MS, on changes in central nervous system MRIs and on the response to immune modulating therapy have become apparent. The risks of toxicities from disease-modifying therapies increase with age and with age the benefits of such therapies are outweighed by their adverse effects. In addition, separating the changes on brain MRIs due to MS from those of comorbidities (diabetes, hypertension, vascular disease, etc.) becomes increasingly difficult, requiring new techniques as noted above to separate disease processes.

11. Great effort was put forth in the past decade to discover a blood test that indicated central nervous system injury. While not perfect, testing for neurofilament light chains (NfL) in the blood and/or spinal fluid of persons with MS correlated with evidence of brain injury. Researchers found that levels of NfL often rose before attacks of MS and were chronically elevated in some individuals even in the absence of clinical changes. While not specific for MS, since elevations can occur with any central nervous system injury, using NfL levels to identify persons with ongoing central nervous system damage and to assess changes in NfL levels with immune modulating therapy, provides another powerful tool to identify and categorize persons with MS based on their underlying disease processes.

12. Finally, it is now well documented that persons with MS can have increasing disability in the absence of relapses even early in their illness, a phenomenon called PIRA (“progression in the absence of relapse activity”). This phenomenon is another indicator that distinguishing and separating relapsing and progressive forms of MS is artificial. This concept has important implications regard treatments as discussed below.


Categorizing persons with MS on the basis of just their clinical course is no longer reasonable. As outlined above there are now multiple ways to assess the underlying biologic processes of MS that vary from individual to individual and that better predict disease course and response, or lack of response, to treatment. It is also now clear that distinguishing progressive from relapsing forms of MS is also not fully accurate, since patterns of disease progression, both at the tissue level, on MRIs, and clinically occur throughout the disease course.

The implications of these observations are significant. Most importantly they now explain why the current panoply of disease-modifying therapies, whose main effect is on subduing acute relapses, are mostly ineffective in preventing disease progression. While there are data suggesting that arresting acute inflammation may slow the rate of progressive disease, it’s also clear that an entirely different category of disease-modifying therapies is needed, not only to delay or prevent tissue degeneration, but also to promote healing and remyelination.

The past several decades has witnessed a revolution in MS care with the advent of highly effective disease-modifying therapies for relapses. Given the current efforts and successes in understanding mechanisms of progressive MS, the next decade may well result in the discovery of agents more fully able to prevent progression and accumulation of disability.

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