An Entirely New Way to Think About Multiple Sclerosis?

Stephen Krieger, MD


May 14, 2015

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A New Model of MS

Hi. I'm Dr Stephen Krieger, a neurologist at the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai Hospital in New York. I'm here at the American Academy of Neurology meeting in Washington, DC, where I had the chance to present for the first time a new visualization of multiple sclerosis (MS) disease course that I call "The Topographical Model of MS," so I thought I would show that to you and present it here. We've had disease course categories in MS for 20 years: our relapsing-remitting, secondary progressive, and primary progressive types, but often those don't fully and neatly apply to individual patients. So I've come up with a different model of MS disease course that looks at the mixture of relapsing disease and progressive disease as more of a continuum rather than having discrete categories of disease course. This is because our differences between categories may not always capture the clinical nuance that individual patients have and perhaps could have implications for how we think about our therapies and our goals of treatment.

So the topographical model of MS looks at a few key factors, things like relapse rate, recovery, severity, and also what I'm calling the topographical distribution of lesions—really lesion localization, which is obviously so important in neurology and in MS particularly. And then there is the progression rate, and progression rate seems to be a really separate feature of the disease course in MS.

The main observation of this model is that progress in MS, when it occurs, seems to take the form of prior relapses. For example, take a patient who had a bad relapse of right leg weakness that recovered and got back to normal—if she begins to progress some years later, that progression begins again with the same right-leg weakness that she experienced as part of her relapse. That recapitulation of relapse symptoms permanently in the context of progression, I think, is an important feature in the MS clinical course, and that is what is shown in this model.

The model is principally a visual one and depicts the central nervous system as a pool with a shallow end and a deep end. The shallow end and the deep end refer to different amounts of neurologic and functional reserve—the spinal cord and optic nerves have little reserve, and most relapses in MS happen in these areas. The brain stem has a bit more reserve and is in the middle—certainly some relapses can occur there. Finally, the hemispheres have the most reserve, so most of our periventricular lesions that we think of as being so typical in MS rarely cross the clinical threshold to cause symptoms. That clinical threshold, I think, is really an important feature of the MS clinical course. It's what defines whether a patient develops signs and symptoms or whether their lesions remain subclinical. So I show, through a series of 3D-rendered models, how the disease course unfold over time.

Here I'll show you some of a secondary progressive disease course, which begins with relapsing-remitting disease and proceeds through early progression. In the earliest stages of the disease course in MS, we have lesion formation shown here as these topographical peaks. This is the radiologic isolated syndrome—nothing has crossed that clinical threshold. so there are no signs or symptoms. By year 5, a first attack occurs in the spinal cord, so this peak crosses the clinical threshold, causes a myelopathy, and then recovers below the threshold. A couple of years later, we have more subthreshold lesions that emerge and are consistent with additional brain stem or hemisphere lesions. Then in year 7, the second attack occurs. In this case, it is a brain stem syndrome that recovers right to the threshold. But you see that the threshold is declining, and so even as relapses and new lesions continue to occur, perhaps more significantly that threshold has declined as functional reserve is lost. The topographical peaks, the lesions, are now visible above the surface.

So even while there is continued disease activity, disability is really being driven here in years 11, 12, and 13 by the declining water level—that loss of reserve revealing a multifocal cord syndrome myelopathy (multifocal brain stem signs that are such cardinal manifestations of progressive MS). Here at year 17, we see a black hole that formed; it too crossed the threshold. Black holes are these more damaging lesions in MS, and so we see that here they're peaking above the threshold even in the cerebral hemispheres.

I think we can think of disease course in MS as having both effects from the floor—new lesions emerging—and also effects from the surface as the threshold declines as functional reserve is lost. This is a clinical manifestation framework. It's not making any new claims about mechanism of disease or the underlying biology. But I think if we look at disease course through this lens, we could think about how better to model and predict the emergence of relapses—and also the transition into progression, which happens so gradually—and think about the goals of our disease-modifying therapies as preventing lesions from rising from the floor of the tank but also acting on the surface by affecting the decline of functional reserve that happens over the course of progression. These two things may be fundamentally different goals of our disease-modifying therapies, and this may have implications for how we think about MS, how we teach it to our patients, how they distinguish between new relapses and stability, or relapses and pseudoexacerbations, or Uhthoff's phenomenon. It may help patients better understand MS, and we may be able to model and study disease course over time.


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