Interview with Stephen Krieger, MD on the topographical model of multiple sclerosis


We interviewed Dr. Stephen Krieger to discuss his research in the implementation of the topographical model of Multiple Sclerosis.

What is the concept behind the topographical model of multiple sclerosis (MS)?

DR. KRIEGER: MS is an incredibly heterogeneous, and in many ways, unpredictable disease. Some people with MS will have a relapsing course, others will take a progressive course of disease, and many will have a disease course that spans both a relapsing phase and a progressive phase.

We have traditionally divided MS into phenotypes like relapsing-remitting MS (RRMS), secondary-progressive MS (SPMS), or primary-progressive MS (PPMS), and these phenotypes have been foundational in our field and used to define clinical trial cohorts and outcomes. They also have been used for the approval of our medicines. In practice, however, it sometimes can be difficult to know precisely what kind of MS, what phenotypes of MS, that an individual patient has.

The topographical model, which was proposed four years ago, tries to unify our concepts of MS in a way that spans across those phenotypes and animates the disease course in a more dynamic way to bridge from one phenotype to another.

As an individual patient, for example, develops clinically isolated syndrome (CIS) or first attack, and then RRMS, and then later SPMS, that gets depicted in a dynamic visualization through the topographical model. The model also makes use of the idea that where an MS lesion is in the central nervous system (CNS) defines the clinical symptoms that it causes.

This is something that we have long known, and the art of localization in neurology has existed for at least a couple hundred years. But we have not used that in the way we have depicted MS clinical course in recent decades. The topographical model tries to bring this idea of mapping an individual patient’s disease topography back into the clinical picture.

In the topographical model, the lesions are shown as different topographical peaks, via the hills and valleys of areas of MS damage across different regions of the CNS [ image]. They are compensated for by reserve, by the ability that the nervous system has to compensate and to keep a disease process from crossing the clinical threshold and causing symptoms. What the topographical model displays is that patients with MS lose reserve as time passes.

We know that there is brain atrophy, brain stem atrophy, spinal cord atrophy, and retinal nerve fiber layer thinning in this disease. The topographical model takes the concept that MS causes a loss of tissue across the CNS and applies it to where the lesions are in the CNS. The coming together of those two things brings about the clinical picture unmasking the deficit from those lesions over time. The short version is a depiction of disease course in MS. The way it looks has been likened to a leaking swimming pool, where there is a shallow end and a deep end, and as reserve drains over time more and more of that subclinical disease becomes unmasked.

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