Patricia K. Coyle, MD, on Fluid and Neurophysiological Biomarkers for the Early Diagnosis of Progression of RRMS to SPMS

In this podcast, Dr Coyle discusses the clinical course of progression from relapsing-remitting forms of multiple sclerosis (MS) to secondary progressive MS, as well as the current state of evidence on the role of fluid and neurophysiological biomarkers in the early diagnosis of progression of relapsing-remitting MS to secondary progressive MS (transcript below).

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Patricia K. Coyle, MD, is professor and interim chair in the Department of Neurology at Stony Brook University in New York, and director of the Stony Brook MS Comprehensive Care Center.

Transcript:

Christina Vogt: Hello everyone, and welcome back to another podcast. I’m Christina Vogt, associate editor of the Consultant360 Specialty Network. Today, I’m joined by Dr Patricia K. Coyle, who is professor and interim chair in the Department of Neurology at Stony Brook University in New York, and director of the Stony Brook MS Comprehensive Care Center. Today, we will be discussing fluid and neurophysiological biomarkers for the early diagnosis of progression of relapsing-remitting multiple sclerosis to secondary progressive multiple sclerosis. Thank you for joining me today, Dr Coyle.

Dr Coyle: Thank you.

Christina Vogt: So first, most patients with relapsing-remitting forms of MS at diagnosis ultimately progress to secondary progressive multiple sclerosis within a decade or 2 after developing MS. What is known about the clinical course of this progression?

Dr Coyle: Well, secondary progressive MS is one of the 4 clinical phenotypes of MS. It probably makes up about 30% of the MS population. Every secondary progressive MS individual started out with relapsing MS, but at midlife, in the age range of 45 to 55, they are at risk to transition or move into a gradually worsening clinical phase that we describe as progressive MS. This slow, worsening phase seems to represent the neurodegenerative damage of MS–the injury to synapses, axons, and neurons.

There are actually 2 phenotypes of progressive MS: primary progressive, which shows gradual worsening from onset, and secondary progressive, and we believe the neuropathologic basis is identical for those 2 types

In the pre-treatment era, natural history, at least 50% of relapsing MS patients within 15 years would develop secondary progressive disease. Now, that's down to about 15%, and it appears at the very least that our disease-modifying therapies can delay the transition from relapsing to progressive disease. And when we talk about gradual worsening, you can actually see clinical stability that can actually last for up to several years. Really, what that probably reflects is, the damage is so subtle that it truly takes some time to accumulate. You can even rarely see some spontaneous improvement in progressive MS, but the course is inexorably downhill, and everyone that enters a progressive phase of MS is going to ultimately develop disability. So, this is a very, very significant clinical phenotype.

The speed of the progression, the worsening, may vary. There can be people that worsen rapidly or in the middle or very, very slowly. Part of that may reflect, what sort of brain reserve do you have? How good is your CNS? Are you somebody who's very healthy, follows a wellness protocol, doesn't have comorbid disorders, or has a number of issues? I think that will really affect how well you can weather progression and aging because it's accompanied by aging. The good news is that the progression tends to stay at the same speed. You don't see people switching from slow worsening to rapid worsening. So, you have an idea in the first year, 2, 3, of secondary progressive MS, what the speed of development, of worsening will be. It should not change.

Christina Vogt: What do available data currently indicate about the role of fluid and neurophysiological biomarkers in the early diagnosis of progression from relapsing remitting MS to secondary progressive MS?

Dr Coyle: We really don't have good predictors for the onset of secondary progressive MS. Older age, male sex, a lot of brain volume loss–these have all been touted as predictors. People would love to have some good biomarkers or predictors. When we talk about body fluid, one popular concept is, would neurofilament light protein be helpful? That can be measured, ultra-low levels can be measured in the blood using a Simoa Assay, and it's promising. This is an injury marker from axons. However, we don't have a harmonized, single assay that everybody has agreed on, and we really don't have global cutoffs. Neurofilament light protein will increase with age. This may be a fluid biomarker that may be helpful in the future to track progressive MS, but we are not there yet.

In addition, other fluid potential biomarkers are high-resolution mass spectrometry to look at metabolites, metabolomics. They've been suggested to have a different metabolic pattern for relapsing vs secondary progressive MS, and also studies of microRNAs. These are short, non-coding single strands. There have been microRNAs that have been associated with secondary progressive MS as opposed to relapsing MS.

With regard to neurophysiologic markers, I think this is an even less developed area, but things like advanced evoked potentials, transcranial magnetic stimulation, blink reflex, somatosensory temporal discrimination thresholds, have been suggested as potential electrophysiologic, neurophysiologic markers of progression. Absolutely none of these are established. These are all, really, research studies waiting to get better validation.

Christina Vogt: What areas of future research are needed going forward to help improve early diagnosis of this progression?

Dr Coyle: Well, one of the very interesting things is that it's clear that patients don't really recognize when they're entering a secondary progressive stage, and the doctors are not recognizing when they enter a secondary progressive stage. The worsening, the progression may be so subtle, that there's a real delay in picking it up. That means that we need better assessments for the neurodegenerative component of MS, that we're relatively insensitive to it. Imagine if you have ongoing injury to the central nervous system, neurodegenerative injury, but you have a basically pretty healthy brain or younger brain, it's going to be much more difficult to detect subtle abnormalities. So, we need better testing. For example, 25-ft timed walk is something that, it's been suggested may be more sensitive to deterioration than the neurologic examination. Optical coherence tomography–looking at the retinal nerve fiber layer in the back of the eye, where you have no myelin, where you just have axons and neurons–has been suggested to perhaps be a marker of who is going to show clinical signs of neurodegeneration. Following very carefully brain volume loss, brain atrophy, and spinal cord volume loss, spinal cord atrophy, may be extremely helpful.

And, there's an interesting new MRI biomarker: the slowly expanding, chronic active lesions with and without a rim. These are expanding and getting larger and showing increasing CNS damage over time without gadolinium enhancement, a completely different type of lesion that's actually been described in all phenotypes of MS, but particularly secondary progressive, and if they have a rim, that seems to be activated microglia in that, the rim. This may be an MRI marker for, really, risk for a neurodegenerative phase. But, if we think about neurodegeneration as being present at the earliest time point, we really need, from a research point of view, better markers to track it, to pick it up, and it would also mean that if we can figure out better treatments to minimize or manage neurodegeneration, we would probably want to start them at the early CIS and relapsing phase of MS before the patient is showing clinical features of progression.

Christina Vogt: What key takeaways do you hope to leave with MS specialists, neurologists, and other health care practitioners treating MS on this topic?

Dr Coyle: Well, I want to leave on a positive note, because people are kind of down on progressive MS when I say once you reach that phenotype, it is inevitable disability. We are understanding the damage mechanisms of progressive MS much, much better than we ever have before–attacks on the mitochondria, attacks on the metabolic health of the axon, excitotoxicity damage, activated microglia. As we understand the damage mechanisms, we can target and develop much better therapies that are going to hit neurodegeneration, and we have a whole vista of CNS repair. We're actually doing studies for CNS repair in MS individuals right now. We don't have any established yet, but this really gives hope for the future.

And, we do not want to forget about the fact that it seems that early use of our current DMTs, at the very least, is delaying transition to secondary progressive MS and perhaps will even be able to prevent it in a cohort of patients. Only time will tell, but we're clearly having an impact and decreasing relapsing patients going on to secondary progressive disease, and we're much more cognizant now of the importance of a wellness program and promoting CNS health and allowing the CNS to age better, which I think is critical for progressive MS, and the importance of identifying and making sure any comorbid conditions, particularly things like depression and vascular disorders, are optimally managed to, again, promote CNS health and minimize issues with aging and vulnerability to the neurodegenerative damaged component.

So, I want to end on that really promising note. I think the future really looks bright, that we're going to begin to tackle this big problem and come up with some meaningful treatments and meaningful answers.

Christina Vogt: Thanks again for joining me today, Dr Coyle.

Dr Coyle: You're welcome.