A Differing View: The 'Inside-Out' Explanation of How Multiple Sclerosis Occurs

July 16, 2020

A minority camp of MS researchers argue that the disease may begin within pathologically processes within the central nervous system.

For decades, multiple sclerosis (MS) has been depicted as a disease of the immune system running amok and attacking the whitish myelin sheath that encases the axons of the neurons in the central nervous system. The myelin is commonly analogized to insulation of electrical wiring; once compromised, the signals traveling through those axons get garbled and people with MS experience a range of neurological symptoms. In this telling, directionally MS is an “outside-in” condition of the immune system compromising the central nervous system.

But there is a camp of MS researchers who want to flip the narrative — or at least get their version considered — and have MS viewed as an “inside-out” phenomenon starting inside the central nervous system and resulting in secondary inflammation.

“There is no dispute that MS is an autoimmune disease. Really no one is disagreeing with that because of all the biology and the radiology and the chemistry and the pathology — it’s all there,” says Peter K. Stys, M.D., FRCP, an MS researcher at the University of Calgary in Canada and leading “inside-out” proponent. “The real question in my mind is whether MS is a primary autoimmune disease.”

“The debate is fierce. The debate is colorful. And in my view, the debate is very necessary,” Stys said in an interview with Managed Healthcare Executive.® The inside-out formulation could open up research into new treatments for MS, especially for the progressive form, he argues.

In his conversation with MHE, Stys put the evidence for an inside-out characterization of MS into three groups.

First, the the current crop of MS drugs is proving to be very powerful at quelling inflammation and dealing with the relapsing-remitting form of the disease. But Stys says the disease still progresses in about half of relapsing-remitting patients and, in those patients, becomes disabling. “If inflammation from autoimmunity were driving the progressive phase, we should expect very good results with the anti-inflammatory agents in the progressive phase of the disease, and we are not seeing that."

Second, autopsies have shown that in some rare cases of MS that there is significant demyelination virtually no evidence of autoimmune inflammation. “How can we have such significant damage to myelin without any trace of autoimmune infiltration?” Stys asks rhetorically, answering that it suggests that demyelination occurred first as a result of pathological changes within the central nervous system. In the outside-in vs. inside-out debate, these cases are sometimes dismissed by the outside-inners as atypical and perhaps not even MS.

“But I would counterargue, as I do when I give these talks,” says Stys, “and say, ‘Well, what if our strict definitions are actually incorrect?'"

Stys continues, “Maybe these cases are instructive. Maybe that is the ‘real’ MS that we should pay attention to because on the rare occasion we were fortunate — of course, not for the patient — but as investigators to catch another snapshot that shows a lesion without any autoimmunity yet and had you waited a few days or weeks or months then you would have the typical MS situation.”

In Stys’ third bucket is evidence from MRI scans that have been done as part of research studies that show subtle changes in brain cells in advance of, or apart from, the typical demyelination lesions — “MS plaques” — seen with MS. “That suggests that something is happening much earlier,” says Stys, although he concedes that the pathology of these changes has not yet been sorted out. Researchers are beginning to see “diffusely abnormal” white matter in the MS.

“The white matter in virtually the entire MS brain is not normal," says Stys. “It’s all very subtle but it’s very widespread and it occurs in area that are well away from your typical inflammatory demyelination lesions, which suggest that the MS plaque is the tip of the iceberg.”

Stys says the inside-out camp is still in the minority but it is getting larger, and its arguments are gaining traction.

“The evidence is mounting, and it has gone from ‘you know, this can’t be right because there’s such overwhelming evidence in favor of outside-in’ to much more acceptance of the possibility that this could be right.”