Exploring the Clinical Implications of the New Subtype of Multiple Sclerosis

Recently, a team of investigators from the Cleveland Clinic, including Daniel Ontaneda, MD, have made the discovery of a new subtype of multiple sclerosis (MS) referred to as myelocortical MS (MCMS). The condition, categorized by a lack of cerebral white matter demyelination, carries a number of clinical implications for those treating patients with MS.

In an exclusive interview, Dr. Ontaneda, clinical director of the brain donation program at Cleveland Clinic's Mellen Center for Treatment and Research in MS, spoke with Rare Disease Report^® (RDR^®) about the recent discovery and what it means for providers working in the rare disease space.

RDR^®: How was the discovery made?

Ontaneda: The study is a result of our observations in doing autopsies on the brains of individuals that died with MS. We have a unique autopsy program here at the clinic where the patients donate their brain and spinal cord to our research program upon their deaths. We then, very rapidly, obtain the corpses after death and do 2 hours of imaging in the brain in the skull and then take the brain out and analyze it. We have no autopsied over 170 brains in this program by this protocol.

For the first couple of these [autopsies] that were identified, Bruce asked us to take a look and confirm if they had MS or not. We looked at their clinical history, and these patients were patients who had been followed at the Mellen Center—which is our center for multiple sclerosis—and clinically, they fit with what we would call a classical case of MS, and the MRIs looked like the MRIs of our typical MS patients.

That was when we went to second step, which was identifying all the subjects that had this myelocortical form of MS, and we actually went back in their charts quite extensively. The data we gathered indicated we couldn’t distinguish them (MCMS patients) based on clinical grounds of MRIs between those that had cerebral white matter demyelination and those who didn’t.

We also showed the MRIs to our radiologists, and when we ‘blinded’ our radiologists and asked them to predict which ones wouldn’t have demyelination of the white matter, they weren’t able to, so I think that was further evidence that it was hard to distinguish between these 2 groups.

RDR^®: What are the clinical implications of these findings?

Ontaneda: From the clinical perspective, this has significant implications—mainly because of what we define as MS. The clinical characteristics—the imaging characteristics—has the cardinal features absent (demyelination of the white matter). This begs the questions: is there something other than cerebral white matter demyelination that is driving the disease?

One, it has implications for actual underpinnings of what MS is. The second point, 1 of the findings of the study, is that these patients with cerebral white matter who had intact myelin didn’t have as many inflammatory cells in the lesions than those who had typical MS. We don’t have any data to support this claim, but it makes us question if those patients respond differently to MS disease-modifying medications.

We know MS disease modifying medications primarily work through preventing or reducing the number of new brain lesions—that’s mainly white matter lesions—so one could hypothesize that perhaps these MCMS patients respond differently to treatments, and that might be an explanation for the heterogeneity that exists in clinical trial results and perhaps even the lack of response patients can display to these therapies.

Finally, currently in MS, 1 of our goals is to develop re-mylenating therapies. There are several compounds that have been identified with potential re-mylenating capacity, and those are entering into the clinical trial world. Several compounds have already been tested, and we even have positive results from one clinical study.

How one designs a trial that detects for myelination may have to consider 10% of patients will have normal cerebral white matter content. For example, the outcome of the study is a putative measure of myelin in the white matter in the lesions. The patients who have MCMS probably will be relatively uninformative for that study—effectively reducing the power to detect an effect.

I think we can leverage these MCMS patients to develop tools to that are specific to myelin detection in vivo. We can run experiments on the tissue itself to examine the content of myelin, and if we’re able to differentiate the myleocortical from the typical using some type of MRI marker, then we could potentially apply that information learned in pathology to the live patients and create biomarkers so we can identify these individuals while they are still alive.

RDR^®: What does the discovery of this new subtype of MS mean for clinicians and providers treating MS?

Ontaneda: The take-home point for the clinicians from this will be that we have been able to identify this new subtype of MS, and it’s radically different in the sense that the myelin content is normal in the brain white matter. That probably is what is adding a layer of heterogeneity in the disease.