Why MS patients develop progressive disability

In a study published in Neurology, Mayo Clinic researchers and colleagues assessed if inflammation leads to permanent scarring in these three diseases:

• MS.
• Aquaporin-4 antibody positive neuromyelitis optica spectrum disorder (AQP4-NMOSD).
• Myelin oligodendrocyte glycoprotein antibody associated disorder (MOGAD).

They also studied whether scarring may be a reason for the absence of slow progressive disability in AQP4-NMOSD and MOGAD, compared with MS.

"The differences in scarring that we found will help physicians distinguish these three diseases more easily to aid in diagnosis," says Eoin Flanagan, M.B., B.Ch., a Mayo Clinic neurologist and senior author of the study. "More importantly, our findings improve our understanding of the mechanisms of nerve damage in these three diseases and may suggest an important role of such scars in the development of long-term disability in MS."

In all three of these diseases, the body's immune system targets the myelin, the insulation around nerves. This causes inflammation and leads to removal of myelin, called demyelination, within the brain and spinal cord. Visual problems, numbness, weakness, or bowel or bladder dysfunction are common symptoms. Areas of demyelination, known as lesions, appear as white spots on an MRI. The repair mechanisms within the body try to reinsulate the nerves and repair the lesions, but this may be incomplete, leading to a scar that remains visible on future MRIs. Just like an electrical cable without its insulation, this scar may leave nerve fibers vulnerable to further damage and to degenerate over time.

The study included 156 patients, consisting of 67 patients with MS; AQP4-NMOSD, 51; and MOGAD, 38. These patients had172 attacks, or relapses, combined.

With MS, the researchers found that areas of inflammation reduced only modestly in size and led to a moderately sized scar. When scars are in regions of the brain and spinal cord that control arm and leg muscles, nerve fibers can degenerate and lead to slow worsening of disability in the secondary progressive course of MS.

"Our study highlights the importance of the currently available MS medications that very effectively can prevent attacks, new lesions and subsequent scar formation" says Elia Sechi, M.D., a former Mayo Clinic fellow and first author of the study. Dr. Sechi is now at the University of Sassari in Sardinia, Italy.

But AQP4-NMOSD and MOGAD are different from MS in that they do not have the same slow worsening of disability typical of the progressive course in MS.

With AQP4-NMOSD, large areas of inflammation occur during attacks, which often results in severe symptoms. Scars are common, but they tend to be smaller and in less important locations than in MS. Thus, less long-term problems result from those scars.

With MOGAD, despite having large areas of inflammation during an attack, the researchers found lesions tended to disappear completely over time and not leave any scar. This fits well with the excellent recovery from episodes and overall good long-term prognosis without the slow worsening disability seen in MS.

The reasons behind this recovery are not clear, the researchers note. It may suggest an enhanced ability to put the covering back onto nerves, or remyelination.

"We hope that the improved understanding on the ways MOGAD repairs its lesions so well may lead to novel treatment avenues to prevent scar formation in MS," Dr. Flanagan says.