New Data Challenge Theories Of Multiple Sclerosis

Earliest Pathology Exams Uncover Unexpected Cell Death

A new view of multiple sclerosis (MS) may arise from the first extensive study of brain tissue from the earliest hours during a bout of the disease. The results, published February 23, 2004, in the online edition of the Annals of Neurology, suggest that the earliest event is not, as previously believed, a misguided immune system attack on a brain substance called myelin. The full study will be available on February 23 via Wiley InterScience(http://www.interscience.wiley.com/annalsofneurology).

Instead, the first event appears to be the death of the brain cells that produce myelin, triggering a subsequent immune system mop-up operation to clean up the cells and the myelin, said author John W. Prineas, MBBS, of the University of Sydney in Australia.

Multiple sclerosis is an enigmatic disorder of the nerve fibers of the brain and spinal cord. Scarring (sclerosis) replaces myelin, which normally insulates the nerves from damage and speeds electrical conduction through the fibers.

Depending on which nerve fibers are hindered, patients can experience problems ranging from weakness and clumsiness to numbness, visual disturbances, and even emotional and intellectual alterations. In some patients, MS manifests itself in cycles of relapse and remission; in other patients, the disease may progress to a stage of severe debilitation, either slowly or rapidly.

According to Prineas, the study he conducted with co-author Michael H. Barnett, MBBS, began several years ago while he was working at the New Jersey Medical School in Newark. A fellow neuropathologist in Manhattan asked whether Prineas and his colleagues would be interested in examining brain tissue from a 14-year-old girl who died unexpectedly 17 hours into a relapse.

Sudden death can occur in MS if the damage (or lesion) occurs in parts of the brain that control vital functions such as breathing and blood circulation.

"This patient proved to be unique in the history of multiple sclerosis in that there was lesion available for study that was less than a day old," said Prineas.

According to the dominant theory of MS, when the researchers examined the hours-old lesion, they should have found the beginnings of an immune system attack.

But Prineas and Barnett noticed that the myelin in the lesion was still intact, and there was no evidence that the typical armada of immune system cells and molecules had moved into the area yet. Instead, oligodendrocytes cells, which produce the myelin, were dying. Myelin is, in fact, an extension of oligodendrocytes that wraps itself around nearby nerve fibers.

"This encouraged us to re-examine other early MS cases in our brain bank," said Prineas. "Similar lesions, albeit extremely rare, were identified in a number of other early MS cases, which allowed us to conclude that the changes observed probably occur at the onset of any typical new lesion."

The results could have significant consequences for MS research, much of which is focused on understanding why the immune system attacks myelin. The focus may have to shift to understanding why the myelin-producing cells begin to die.

"The important point, at this stage of our investigation, seems to be that we have no laboratory model for this sort of pathology," said Prineas.

Article: "Relapsing and Remitting Multiple Sclerosis:
Pathology of the Newly Forming Lesion," by Michael H.
Barnett, MBBS and John W. Prineas, MBBBS, Annals of
Neurology online edition; February 23, 2004.