>January 29, 1998

Study of Brains Alters the View on Path of M.S

By GINA KOLATA

Medical scientists thought they understood multiple sclerosis. Its
central feature, they said, was a relentless loss of the insulation that
sheathes nerve cells, causing a short-circuit in the electrical signals
passing through the cells.

But now it turns out that this loss of nerve cells' insulator, a fatty
substance called myelin, is only part of the story. Using a
laser-scanning microscope, researchers have observed the severing of
nerves in the brains of patients with multiple sclerosis cells,
presumably by chemicals in the brain.

The severing and death of these spaghetti-like nerve cells could explain
why people with multiple sclerosis eventually become unable to walk, for
example, or why they may lose vision in an eye. Once nerve cells die,
their functions are lost.

It also suggests strategies for treatments with experimental drugs that
can prevent nerve cell death, at least in laboratory experiments, with
the ultimate goal of stopping the progress of the incurable disease.
Such drugs are being tested in other diseases, like Alzheimer's and
Parkinson's, caused by the death of nerve cells. But no one had thought
to test such drugs in multiple sclerosis.

In a study being published today in The New England Journal of Medicine,
the researchers compared brains taken in autopsies from 11 patients with
multiple sclerosis and 4 people who did not have brain disease. The
investigators, led by Dr. Bruce D. Trapp, chairman of the department of
neurosciences at the Lerner Research Institute of the Cleveland Clinic
Foundation, examined 47 affected areas in the brains of patients with
multiple sclerosis.

The researchers found that the number of severed nerve cells per cubic
millimeter of affected brain ranged from 875 to 11,236, depending on how
active the disease was in the brain region. But they found less than one
severed nerve cell, on average, in similar regions of brains of people
who did not have the disease.

Although there had been previous hints that multiple sclerosis might
involve nerve cell death, "this is the first study to rigorously
quantify" the effect, said Dr. Barry Arnason, professor of neurology and
director of the multiple sclerosis clinic at the University of Chicago.

Multiple sclerosis experts, including the study's authors, were taken
aback by the findings. "I was surprised," said Dr. Roland Martin, an
acting section chief at the National Institute of Neurological Disorders
and Stroke. He said loss of myelin, or demyelination, was considered the
hallmark of multiple sclerosis.

"Every textbook article starts by saying that the most important
demyelinating disease is multiple sclerosis," Dr. Martin said, and that
it is only the myelin that is damaged, while the nerve cells are
unharmed. He also said the notion that the disease also involves the
death of huge numbers of nerve cells "would change our view
dramatically."

Others talked of possibilities for seeking new treatment. "This isn't
just a new pathological finding," said Dr. Stephen G. Waxman, chairman
of the neurology department at the Yale University School of Medicine
and director of the Paralyzed Veterans of America Neuroscience Research
Center at Yale. "It puts the disease in a totally different light and it
also gives us a new target as we search for therapies"

That, he said, is important because the disease is so common and
disabling. About 250,000 to 300,000 Americans have the disease,
according to the National Multiple Sclerosis Society. Patients suffer
extreme fatigue and can have slurred speech, difficulty walking,
problems controlling their bladders and bowels, difficulty thinking and,
in extreme cases, complete paralysis.

The disease typically begins when patients are age 20 to 40 and
progresses over time.

Three drugs that are thought to inhibit an immune system attack on
myelin have been approved for treating multiple sclerosis. But at best
they slow the disease's progress.

Dr. Stephen Reingold, vice president for research programs at the
National Multiple Sclerosis Society, said he was already persuaded from
previous indirect evidence that nerve cells were dying in patients with
multiple sclerosis. For example, a study in 1992 by Dr. W. Ian McDonald
of the Institute of Nuerology in Queens Square, London, found that a
nerve cell chemical, N-acetyl asparate, is present in reduced amounts in
affected areas of the brains of people with multiple sclerosis, which is
indirect evidence that brain cells might be dying. Dr. Reingold said he
still viewed multiple sclerosis as primarily a disease in which myelin
is lost.

Nonetheless, experts said, the new study will lead investigators to
focus on finding ways to protect nerve cells from an otherwise certain
demise, including possibly testing the neuroprotective drugs being tried
on patients with Alzheimer's and Parkinson's, to see if the progress of
multiple sclerosis could be slowed.

But it may be that the type of killing of nerve cells in multiple
sclerosis requires a different class of drugs.

The finding also raises questions about why patients with multiple
sclerosis develop its symptoms. Until now, many assumed that symptoms
arose because the loss of myelin short-circuited signals passing through
nerve cells. As more myelin was lost, symptoms worsened until healthy,
but uninsulated, nerve cells were all incapable of functioning.

So prominent was this belief that Dr. Richard Rudick, an author of the
new paper and the director of the Mellen Center for Multiple Sclerosis
Treatment and Research at the Cleveland Clinic Foundation, said he
started his chapter on demyelinating diseases in the current edition of
a leading medical textbook by writing, "Multiple sclerosis is a
demyelinating disorder that tends to spare nerve cells."

But in retrospect, said Dr. Trapp of the Lerner institute in Cleveland,
this hypothesis is not entirely credible. A nerve, or axon, that is
losing its insulation should not stop functioning entirely, he
explained. "If you remove myelin, the axon will still be able to
function, although maybe a little bit slower," he said. But if you cut
the axon, he added, "the function of that axon is gone forever."

Yet the new study left a crucial question dangling: Which comes first,
loss of myelin or severing of the nerve cells? The question, experts
said, is important because its answer can provide clues to how best to
stop the progress of the disease.

Copyright 1998 The New York Times Company