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Research Offers New Pathway Of Multiple Sclerosis

December 8, 2011

Biopsies reveal nature of brain lesions early in MS progression, countering conventional wisdom

Working together, researchers at Cleveland Clinic and Mayo Clinic have for the first time examined early multiple sclerosis (MS) brain lesions in the cerebral cortex. These lesions are thought to be critical to MS progression and the researchers found that the lesions are distinctly different than previously speculated, giving clues to better disease management.

The long-accepted theory has been that MS begins in the myelin on the inner layers of the brain, also known as white matter. However, the findings of this collaborative study show the opposite — that the disease likely can move from the outer (cortical) layers of the brain toward the white matter, offering new insight into the progression of MS.

“For patients, the key idea of this research is that we have discovered an entirely new concept of how MS may start,” said Richard Ransohoff, M.D., Director of the Neuroinflammation Research Center of the Department of Neurosciences at Cleveland Clinic’s Lerner Research Institute, who co-led the study. “This research shows that a non-inflammatory form of MS is much less likely, and the prevailing research path has been going in the right direction.”

While the causes of MS remain undetermined, it is thought to be a disease in which the body’s immune system attacks and destroys its own myelin, a fatty insulator of the crucial nerve fibers that are responsible for communication between different sections of the brain.

However, in autopsy tissues of MS patients, lesions in the cerebral cortex show demyelination without inflammation, raising a challenging issue: if cortical lesions form entirely without inflammation, then cortical demyelination would not be explainable by current theories of MS nor treatable by current MS therapies.

The present study, published in the December 8 issue of the New England Journal of Medicine, was a collaborative effort by Dr. Ransohoff, also a staff neurologist at the Mellen Center for Multiple Sclerosis Treatment and Research at Cleveland Clinic’s Neurological Institute, and by Claudia Lucchinetti, M.D., of the Mayo Clinic’s Department of Neurology.

The study involved examination of 563 brain biopsies resulting in the diagnosis of inflammatory demyelinating disease of the central nervous system, with 138 being determined to have sufficient cortex for study. Of these, 77 cases provided long-term follow-up data, with 58 cases (75 percent) going on to develop verified MS. The vast majority of biopsies were performed at community hospitals with the brain tissue being sent to the Mayo Clinic for neuropathological consultation services. Dr. Lucchinetti leads the National MS Society’s MS Lesion project housed at the Mayo Clinic. This study was funded in part by that project as well as the National Institutes of Health.

MRI neuroimaging studies in early multiple sclerosis can’t detect cortical lesions but have revealed cortical abnormalities, suggesting that the cortex may be damaged near the time of disease onset. The current research shows that the cortex harbors inflammatory lesions accounting for MRI indicators of damage.

“The next step in this research is to study the lesions to uncover new molecular targets for treatment. We also need to push forward to develop imaging techniques to view these cortical lesions,” said Dr. Lucchinetti. “In that way, effects of treatment can more easily be measured.”

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