The Clinical Director of the Brain Donation Program at Cleveland Clinic’s Mellen Center for Treatment and Research in MS provided some insight into the consequences of this discovery.
Daniel Ontaneda, MD
With a robust pipeline of therapies in development for multiple sclerosis (MS) and the increasing role of disease-modifying therapies, the research community has a long list of developments to look forward to.
Yet, after a group of researchers from Cleveland Clinic, including Daniel Ontaneda, MD, announced that they had identified a new subtype of MS, myelocortical MS, that list grew quite a bit. The condition, categorized by a lack of cerebral white matter demyelination, carries a number of clinical implications for those treating patients with MS.
Onetaneda, the Clinical Director of the Brain Donation Program at Cleveland Clinic’s Mellen Center for Treatment and Research in MS, spoke with NeurologyLive to provide some insight into the consequences of this discovery.
Daniel Ontaneda, MD: The cases were identified postmortem, and one the first steps was figuring out clinically, what do these patients look like? We went back and did as full a characterization as we possibly could in patients who had passed away, and all the clinical characteristics and imaging characteristics were those of typical MS. This is garden variety MS, it seemed like the typical cases we see in our clinics day in and day out. On first pass review, it didn’t seem like they were different and then with more exhaustive clinical characterization, both on the clinical aspects and the MRI aspects, it was also clear that it was very difficult to differentiate these two groups based on clinical and MRI characteristics alone. I think we require the pathology, really, to differentiate them now.
Is this something we can identify in vivo? Currently, we can’t, but I think that these data and these samples provide a platform in order to develop biomarkers to potentially differentiate between these 2 types of MS.
DO: The study has tremendous implications for the MS field as a whole. We know that there is a significant amount of heterogeneity in MS, and clinicians who see patients with MS recognize that MS is quite different from one individual to another individual. Predicting how patients will do over time is a significant difficulty in our field. What this data shows us is that, possibly, one of the explanations—one of the layers—of this heterogeneity is that some MS patients will not have white matter demyelination in the brain, therefore, they probably will be quite different.
This, from a scientific standpoint has implications in terms of clinical trials. We found that 12% to 13% of patients in our cohort had no cerebral white matter demyelination, and therefore these patients may be patients that would respond differently to disease-modifying treatments. We don’t find as much inflammation in these brains, in the white matter abnormalities, as we do in patients with typical MS, and therefore they might respond differently to anti-inflammatory therapies. And then, when we’re putting patients into clinical trials, for example, when examining remyelination, these patients might be quite uninformative because they don’t have demyelination in the white matter. I think that there are significant implications.
Now, for the individual neurologist in practice today, it’s going to be difficult to put any of these implications into practice because currently we cannot identify these patients in vivo, and it’s difficult to differentiate between them using our typical clinical and MRI tools. The implications for the field are great. For general neurologists, knowing that this subtype of MS exists is important. Now will that make them change treatment direction in a given patient? At this point, probably not. What we need to do is to be able to identify these patients while they’re still alive.
DO: From the clinical perspective, the first step is understanding that there is this subtype of MS. Once you’ve done that, you can continue to look at postmortem samples as clinical characterization improves. That is, the patients that we’ve collected going back 10 years, if we fast forward 10 more years, those patients will have better clinical characterization, better MRI, probably a stored blood sample so we can examine these patients for potential biomarkers.
The other way of accelerating discovery in trying to identify these patients in vivo is using these samples along with advanced MRI techniques. These 2 groups provide the perfect platform with which to test MRI or other imaging modalities that would be sensitive to myelin. We know that our conventional MRI is quite sensitive to myelin, but it’s not specific. In patients who have lesions, MRI detects almost all patients who have demyelination, but it also detects some patients who don’t have demyelination. Getting to that specificity using an MRI measure, using these samples, for example, is something that we can do and already are doing.
DO: The findings have a profound impact on those types of studies, specifically on remyelinating studies. I wouldn’t say remyelinating therapies are obsolete, I think we have to recall that these patients do have demyelination in the cortex and in the spinal cord, and those could still be targeted. But, for example, it will inform what type of outcomes one would select. If one has a patient with myelocortical MS, and the primary endpoint for a phase II clinical trial is a putative myelin measurement from a white matter lesion, that will be a patient that won’t be informative to that study. It will probably increase the required sample and will effectively reduce the power to find an effect. This will have implications, both in selection of patients—that is to select patients that are more likely to have demyelination—and also in methodology and what outcomes to look at.
Transcript edited for clarity.
Trapp BT, Vignos M, Dudman J, et al. Cortical neuronal densities and cerebral white matter demyelination in multiple sclerosis: a retrospective study. Lancet Neurol. Epub August 21, 2018. doi:10.1016/ S1474-4422(18)30245-X.