The History of MS Th e Basic Facts
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The Basic Facts
The History of MS
Loren A. Rolak, M.D., Marshfield Clinic, Marshfield WI
THE HISTORY OF MS system, pour into the brain and spinal
cord, and destroy myelin. The specific
The history of multiple sclerosis (MS) is
triggering mechanism that releases the
a detective story spanning more than a
immune system to attack its own healthy
century. Multiple sclerosis is one of the most
tissue remains unknown, however, and
common diseases of the nervous system,
the cause of MS is still its biggest mystery.
affecting people of almost all ages in many
How its other puzzles have been solved is a
parts of the world, although it has a special
fascinating story.
preference for young people, for women,
and for those in northern latitudes. MS
THE DISCOVERY OF MS
has a genetic susceptibility, but it is not
directly inherited. It usually causes attacks Until the early years of the 19th century,
of neurologic symptoms including vision physicians relied on superstition, hearsay,
loss, paralysis, numbness, and walking and “the wisdom of the ancients” to
difficulties. These symptoms can be diverse care for the sick. Medical ideas were not
and confusing, often coming and going scientifically tested. Even so, physicians
without any pattern—making it difficult were often good observers and we can
to diagnose, even today. These symptoms look back today and identify people who
appear because nerves in the brain and undoubtedly had MS from descriptions
spinal cord lose their ability to transmit written as long ago as the Middle Ages.
signals. Myelin, a complex substance that
Once doctors began to analyze illnesses
surrounds and insulates nerve fibers, is
scientifically, MS was among the first
essential for nerves to conduct electricity
diseases to be described.
and carry out their function. Myelin is
damaged in MS, as well as some of the Drawings from
nerve fibers themselves. autopsies done
as early as 1838
The attacks strike when cells and proteins of
clearly show what
the body’s immune system, which normally
we now recognize
defend the body against infections, leave
as MS. Then, in
the blood vessels serving the central nervous
1868, Jean-MartinCharcot, a professor at the University of Further knowledge of MS could not
Paris who has been called “the father of advance without better understanding
neurology,” carefully examined a young of biology and better research tools. For
woman with a tremor of a sort he had never example, MS could not be considered an
seen before. He noted her other neurological immune disease because the very existence
problems including slurred speech and of the immune system was still unknown
abnormal eye movements, and compared (doctors of the time assumed a disease
them to other patients he had seen. When rarely struck the same person twice because
she died, he examined her brain and found the disease “used up” the materials in the
the characteristic scars or “plaques” of MS. body it needed to live, much the way crops
Dr. Charcot wrote a complete description of use up soil nutrients and die unless they
the disease and the changes in the brain that are rotated).
accompany it. However, he was baffled by
In the 19th century, scientists first learned
its cause and frustrated by its resistance to
that bacteria cause many diseases. As the
all of his treatments, including strychnine,
20th century began, they discovered even
a deadly poison that in small doses can
smaller organisms, viruses, and developed
stimulate nerves. He also tried injections
techniques for growing and studying
of gold and silver, as they were standard
bacteria and viruses in the laboratory. This
treatments for the other major nerve
later led to research on viral causes of MS.
disorder common at that time—syphilis.
In 1906, the Nobel Prize for Medicine was
A PRISONER OF awarded to Dr. Camillo Golgi and Dr.
BIOTECHNOLOGY Santiago Ramon y Cajal, who perfected
new chemicals to enhance the visibility of
In the last decades of the 19th century, the nerve cells under the microscope. With this
leading physicians of the world came to new technology now available, Dr. James
understand that MS was a specific disease. Dawson at the University of Edinburgh
MS was recognized in England by Dr. in 1916 performed detailed microscopic
Walter Moxon in 1873, and in the United examinations of the brains of patients who
States by Dr. Edward Seguin in 1878. By had died with MS. Dr. Dawson described
the end of the century, much of what can be the inflammation around blood vessels and
learned about MS from careful observation the damage to the myelin with a clarity and
was known—that the disease is more thoroughness that has never been improved
common in women than men, that it is not upon—but so little was known about the
directly inherited, and that it can produce brain’s function that the meaning of these
many different neurological symptoms. changes could only be guessed at.
2 THE HISTORY OF MSCOMPLEXITIES—AND of MS was developed out of research on
AN UNRECOGNIZED vaccines. It had been known that people
BREAKTHROUGH vaccinated against viral illnesses, especially
rabies, sometimes developed a disease
In the decade after World War I, MS resembling MS. It had been assumed that
research grew more sophisticated. this occurred because the virus in the
Abnormalities in spinal fluid were vaccines was not completely inactivated,
noted for the first time in 1919, though and so it attacked the myelin. In 1935, Dr.
their significance was a puzzle. Myelin, Thomas Rivers at the Rockefeller Institute in
which had been discovered in 1878 by New York City, demonstrated that immune
Dr. Louis Ranvier, was studied intensively cells, not viruses, produced the MS-like
under the microscope and the cells that illness. By injecting myelin he knew to be
make myelin (the oligodendrocytes) were virus-free into laboratory animals under the
discovered in 1928. proper conditions, he could induce their
The first electrical recording of nerve immune systems to attack their own myelin,
transmission, by Lord Edgar Douglas producing a disease very similar to MS.
Adrian in 1925, established techniques This animal form of MS, called
needed to study the activity of nerves experimental allergic encephalomyelitis,
and launched a series of experiments to or EAE, would later become an important
determine just how the nervous system model for studying the immunology and
works. Ultimately, six Nobel Prizes were treatment of MS. In fact, it paved the way
awarded for these studies. The resulting to modern theories of “autoimmunity”—the
knowledge included clarification of the process by which the body generates an
role of myelin in nerve conduction and a immunologic attack against itself. But most
realization that demyelinated nerves cannot doctors in the 1930s were still analyzing
transmit impulses efficiently. toxins in MS and the importance of EAE
At this time, scientists suspected that some was overlooked. It would be many years
form of toxin or poison caused MS. Because before the similarity of EAE and MS was
most MS damage occurs around blood understood and a link between the immune
vessels, it seemed reasonable that a toxin system and MS was forged.
circulating in the bloodstream leaked out Instead, a flurry of experiments in lab
into the brain, even though no researcher animals demonstrated that blocking the
could find a trace of it. blood supply to the brain sometimes caused
Just before World War II, an important myelin to die. The damage looked a bit
breakthrough occurred. An animal model like MS. Doctors abandoned their search
THE HISTORY OF MS 3for toxins and instead wondered if MS was A PROMISING START
caused by circulation problems. So they
With remarkable foresight, the very first
tried therapies to stimulate blood flow,
research grant from what was then called
including blood thinners and drugs to dilate
The Society for the Advancement of
blood vessels. X-rays were also used to treat
Multiple Sclerosis Research was awarded
MS, although more for their novelty than
to study the immunology of MS—the
for any sound scientific reason.
relationship between the body’s immune
system and the central nervous system (the
1940s: THE COMING OF THE
brain and spinal cord). This 1947 grant went
NATIONAL MS SOCIETY to Dr. Elvin Kabat at Columbia University.
World War II focused the energies of He subsequently identified abnormal
the scientific world on new technologies, immunologic proteins in the spinal fluid of
and research continued despite the global people with MS. These proteins appeared
upheaval. In 1943, for example, the actual in patterns known as oligoclonal bands.
composition of myelin was determined. Oligoclonal bands not only proved to be
Then, when peace came, one of the most valuable in diagnosing MS, but also a major
important catalysts in the fight against MS demonstration that MS and the immune
was created when the National Multiple system are connected.
Sclerosis Society was founded in 1946.
A WORLD-WIDE RESEARCH
Sylvia Lawry, an extraordinary woman
whose brother suffered from the disease,
EFFORT BEGINS
placed a classified advertisement in The In the next few years, the renamed National
New York Times asking to hear from Multiple Sclerosis Society awarded grants
anyone who had recovered from MS. But to dozens of scientists in 17 countries in
all the letters she received came from others all fields of medicine, pushing forward
who also sought help and hope. Instead of research that ranged over every aspect of
being discouraged, Ms. Lawry mobilized MS from description to diagnosis to causes
a group of friends and advisors, including to cures. Recipients of early National MS
some who had answered her ad. From Society grants included Nobel Prize winners
this the National MS Society was formed such as Dr. Jonas Salk, who studied the
to promote contacts among neurologists immunology of MS, and Dr. Rita Levi-
around the country who treated MS and to Montalcini, who described proteins that
raise money to fund a search for answers. help nerve cells grow and stay healthy.
4 THE HISTORY OF MSA NEW MAJOR PARTNER produced the oligoclonal bands in MS
spinal fluid.
In 1950, the new Society helped persuade
Congress to establish a special section of There were more studies of EAE.
the National Institutes of Health. With the Experiments showed that EAE could be
birth of what is now called the National transmitted by transferring T cells (another
Institute for Neurologic Disorders and type of immunological white blood cell)
Stroke (NINDS), the movement against from an affected animal to a well one,
MS gained one of its strongest partners. showing that EAE was an immune disease.
NINDS and the National MS Society— And at last, scientists recognized that EAE
along with members of the International was in many ways a model of human MS.
Federation of MS Societies (founded by
However, beyond the world of research,
Sylvia Lawry in 1967)—have provided
doctors who treated people with MS
support for virtually every major MS
in the 1950s continued to suspect the
researcher from that day to this.
cause lay in impaired blood flow, so
circulation stimulators still dominated
NEW RESEARCH DIRECTIONS treatment. Nevertheless, doctors had not
An unforeseen consequence of World yet thought to analyze these therapies with
War II was the availability of medical controlled studies to track the results, so
information on the huge population of no reproducible or valid information could
young men who had served in the military. emerge about their safety or effectiveness.
Studying their MS, doctors discovered the Treatments were still based more on
uneven distribution of the disease. A strong opinions than facts.
geographical gradient was apparent, showing
that the incidence and prevalence of MS BREAKTHROUGHS EXPAND
increased steadily as one moved northward KNOWLEDGE BUT INCREASE
away from the equator. CONFUSION
Meanwhile, the immune system became In 1953, one of the major medical
an object of intense scientific study. Special breakthroughs of the century occurred
immunological white blood cells called B with the Nobel Prize-winning description
cells were discovered and shown to produce of the structure of DNA by Francis Crick
proteins called antibodies. It was soon and James Watson. The way in which genes
learned that antibodies neutralize viruses control biologic functions became clearer,
but are also capable of attacking the body’s including how the immune system is
own tissues. It seemed that B cells also regulated by sequences of genes.
THE HISTORY OF MS 5Additional studies on nerve conduction THE FIRST VALID
showed how chemicals generate electricity SCIENTIFIC TRIAL
as they flow through channels in the nerve
fiber membranes. And myelin was further With the ability now to make an accurate
broken down into its components, isolating diagnosis and measure how therapies
the basic protein suspected to be the target affected disability, it was possible to begin
of the MS attack. scientifically testing MS treatments. A group
of patients who were having exacerbations—
Scientists studied B-cells, T-cells, genes, or acute attacks of their MS—were given
and myelin but without uncovering a clear adrenocorticotropic hormone (ACTH),
unifying thread to direct MS treatment. which is a hormone normally produced by
The emerging scientific complexity of MS the pituitary gland. It stimulates production
confused rather than clarified, and research of steroids by the adrenal glands. Increased
gave doctors very little guidance on what secretion of these natural steroids provides
was best for their patients. an anti-inflammatory and immune-
suppressing effect. The ACTH group was
CHAOS ADDRESSED BY THE compared to a similar group that received a
NATIONAL MS SOCIETY placebo (an inactive look-alike substance).
The ACTH proved superior in speeding
The National MS Society, which by 1960
recovery. In subsequent years, treatment
had established 114 chapters to provide
with ACTH was replaced by the high-dose,
services for individuals and families, kept
intravenous steroid therapy that is in use
up the scientific assault. To bring order to
today for acute exacerbations. This 1969
the medical management of MS, the Society
study was the first to prove that a therapy
funded a panel of experts, headed by Dr.
could be developed that would improve the
George Schumacher, to draw up standard
symptoms of MS. For the first time, there
guidelines for MS diagnosis. Although
was a scientific treatment for MS.
they have been refined since, the basic
concept of these standards is still in use
today. At the same time, a rating scale for
1960–1970: TWO BIG IDEAS
determining the level of disability and the During the 1960s, scientific research into
parts of the nervous system affected by MS the cause of MS came to focus on two
was developed by Dr. John Kurtzke. These main lines of inquiry that are still being
tools allowed doctors to make earlier, more explored today.
accurate diagnoses and permitted research
The first emerged from analysis of the
on treatments that would otherwise have
immune system. White blood cells that
been impossible.
react against myelin, specifically against a
6 THE HISTORY OF MScomponent called myelin basic protein, were spinal cord and often detect hidden areas of
discovered in both EAE and human MS. scarring and damage.
This led scientists to consider the possibility
Scientific research began to yield direct
that MS involves a direct immune-system
therapeutic dividends as well. Steroids to
attack on myelin.
suppress immune activity were now widely
The second idea came from studies that used to treat MS attacks, and the first small
showed that people with MS have altered studies were performed using interferons
antibodies against viruses. This revived the (substances that modulate the immune
older thinking that MS could be caused system). The first studies of beta interferon
by a virus. But rather than a viral infection for MS began at the end of the 1970s.
directly damaging the central nervous
In 1970, scientists studying EAE in lab
system, viruses involved in MS were now
animals suspected that some myelin protein
thought to alter the immune system and
fragments prevented the disease and actually
trigger it to damage myelin.
seemed to protect the animals. Spurred
These two ideas remain closely mingled by this finding, they synthesized a mix of
today: MS may combine features of both protein fragments and used it to treat first
an infectious and an autoimmune disease. animals with EAE and then humans with
The treatments that were later developed for MS. The product was named copolymer1
MS all targeted either an infectious or an and is today an approved disease-modifying
immune mechanism. therapy under the new name glatiramer,
or Copaxone®.
1970–1980: LABORATORY
ADVANCES 1980–1990: TREATMENT TRIALS
BEGIN IN ERNEST
In 1978, the first CAT (Computed Axial
Tomography) scans were performed on Scientists began to understand in more
people with MS. And, in 1979, a Nobel detail how white blood cells are activated by
Prize was awarded for development of foreign substances to mount attacks. One
this powerful new tool. CAT scans use a activating trigger can be a virus. Scientists
computer to link a circular array of x-ray also learned that parts of some viruses
images to create detailed pictures of the look so much like normal human tissue
human brain. The diagnosis of MS was that white blood cells will inadvertently
further improved with the introduction of attack that tissue when they attack the
brain wave tests called “evoked potentials” virus. This is yet another mechanism by
which measure nerve conduction which viral infections could lead indirectly
throughout the optic nerves, brain and to destruction of myelin—when immune
THE HISTORY OF MS 7attacks on myelin-like viruses spill over onto the National MS Society, scientists reached
the myelin itself. a consensus on the design and conduct of
research for new treatments, and dozens of
At about the same time, the white blood
different therapies were tested in attempts
cell type that causes the actual damage to
to control or cure MS. Major clinical trials
myelin in MS was finally identified. It is the
conducted during this decade finally found
macrophage (or “Big Eater” in Greek).
the first drugs in history shown to affect the
The first studies of identical and fraternal course of this disease.
twins begun in this decade extended
knowledge about the genetics of MS. The 1990–2000: DECADE OF THE
twin of a person with MS often does not BRAIN
develop the disease, proving that genes
determine only part of the MS risk, though As the final decade of the 20th century
their influence is important. Meanwhile, approached, the Congress of the United
psychosocial and mental-health issues, as States made a special effort to accelerate
well as the cognitive changes that can be medical research. Recognizing the
caused by MS, began receiving long overdue paramount importance of neurological
research attention. disease, they designated the 1990s as the
“Decade of the Brain” and purposefully
CAT scanning technology was refined to funneled funds, time, and talent into
produce the MRI (Magnetic Resonance the treatment of illnesses that affect the
Imaging) scan, which shows the brain in nervous system. Multiple sclerosis benefited
greater detail. The first MRI scans of enormously from these efforts, and an
people with MS were performed in 1981 explosion of drug trials occurred during
by Dr. I R Young, in England. By 1984, it this period.
became apparent that MRI could actually
see MS attacks within the brain, including MRI TECHNOLOGY
many which did not cause any symptoms.
By 1988 sequential MRI scans changed the Many of the decade’s advances sprang from
entire concept of MS by showing that it is the incredible power of new technology.
a constant, ongoing disease even though Sophisticated techniques added to MRI
relapses with symptoms may appear only allowed it to detect MS plaques earlier and
sporadically. more accurately than ever. That led to more
rapid diagnosis of the disease. In 1970, the
The 1980s may legitimately be called the average time from a person’s first symptom
“treatment decade” in MS. There was an of MS until a definite diagnosis was 7
explosion of new drug trials. Guided by years, but use of MRI technology reduced
8 THE HISTORY OF MSthe time to six months. Now the plaque underlying nerve cells, the neurons and
that causes symptoms could often be seen their axons, are damaged as well, which
immediately. The power of a rapid, painless is thought to account for some of the
MRI scan to provide information is an permanent disability MS causes.
incalculable blessing for doctors and patients
alike. Studies with a series of MRI scans GENE RESEARCH OFFERS CLUES
over time showed how MS plaques actually
During the 1990s, the American-led project
develop and permitted researchers to track
to discover and decode all the genes in the
the “burden of disease” (total plaque area)
human body focused attention on the role
in individual patients. At the same time,
of genes in many diseases. A monumental
MRI scanning gave researchers faster and
study of 15,000 people with MS, including
more sophisticated ways of testing drugs
some identical twins who were reared
to treat MS. The benefits of a new drug
miles apart in different families, clearly
can be seen on MRI scans before they can
demonstrated that genes play a role in
be seen in patients themselves. Research
determining who gets MS and who does
on the treatment of MS was thus greatly
not. Although there does not appear to be
accelerated.
any single “MS gene,” there does seems to
be something fundamental to each of us
HIGH-TECH LABORATORY
(i.e., something in our genes) that makes
DISCOVERIES one person susceptible to developing MS
Most diseases yield their secrets only and another not. This is yet another clue for
through the painstaking laboratory work the cause of the disease.
of research scientists. Laboratory work
on MS showed us many essential aspects THE INFORMATION AGE
of the disease. A key culprit in MS is the
Of course, the sophisticated technology
white blood cell called a T cell. Although
of the 1990s was not limited to medicine.
many details about the sequence of events
There were quantum leaps in computers
in the process still remain to be learned,
as well. During the “Decade of the Brain”
we know that T cells become activated,
computer scientists built the information
leave the bloodstream, and enter brain
superhighway and wove the Internet. Faster,
tissue to damage myelin, the fatty tissue
better communications and data analysis
that insulates and protects nerve fibers.
brought MS doctors and researchers from
This T cell has now been identified and
all over the world together in increasingly
characterized in detail. Recent discoveries
powerful coalitions. Large databases were
also emphasize that myelin is not the only
assembled to track and analyze thousands
target for destruction in MS. Often the
THE HISTORY OF MS 9of patient histories to clarify their disease rehabilitation, exercise, and physical therapy
variations and their responses to treatment. also benefited people with MS. These and
Characteristic patterns of MS began to many other new treatments have markedly
emerge. MS clinics and research laboratories enhanced the ways physicians can calm
are now linked and share and evaluate symptoms and improve the quality of life.
new findings.
Years of research with drugs to treat
the actual disease—and not just its
THE TREATMENT PAYOFF IN THE symptoms—came to fruition when beta
NEW MILLENNIUM interferon 1-b (Betaseron®) was introduced
The symptoms of MS have never been in 1993. Beta interferon 1-a (Avonex®) was
as amenable to therapy as they are now. introduced in mid-1996, and glatiramer
Tizanidine was introduced for management acetate (Copaxone®) arrived in late 1996.
of spasticity. Use of the intrathecal baclofen Two years into the new century, a variation
pump for severe spasticity became more of beta interferon 1-a (Rebif ®) was also
widely available. It delivers medication introduced. The course of MS could now
directly to the spinal cord to relieve intense be altered by reducing disease activity and
muscle stiffness and spasms. Improvements preventing many attacks.
were made in medications for bladder In 1999 mitoxantrone (Novantrone®) was
management (e.g., tolterodine) and for approved for treating MS and was especially
fatigue (modafinil). Treatment of sexual useful against the slow chronic progressive
problems, a long-neglected aspect of forms of the disease, which none of the
MS, took a major leap forward with the other therapies had been able to retard.
introduction of sildenafil (better known
as Viagra®) and other similar medications. Nataluzimab (Tysabri®), the first of a whole
Gabapentin was introduced to treat many new class of drugs called monoclonal
painful symptoms ranging from severe antibodies, significantly suppressed relapses
face pain (trigeminal neuralgia) to burning of MS in several large trials. Treatments
pains in the limbs. Other drugs are being began in 2004, but widespread use was
developed at a rapid pace. delayed while procedures were developed
to minimize the serious infections some
Research also revealed many ways in which patients developed during treatment with
MS can alter the mind, slowing down the drug.
thinking and affecting memory. New
drugs, such as donepezil, used to treat Progress has thus been remarkable.
these problems in Alzheimer’s disease, are Throughout history MS was an untreatable
now being tested in MS. Refinements in disease. Then in one decade (1993–2004)
10 THE HISTORY OF MSresearchers developed 6 drugs that suppress Written by Loren A. Rolak, MD.
attacks and alter the course of MS. Many Reviewed by the Client Education Committee
more drugs are being tested. These include of the National MS Society’s Clinical Advisory
oral cladribine, which may well be the Board.
first oral disease-modifying therapy to be
approved for MS; two new monoclonal
antibodies, rituximab (Rituxan®) and
alemtuzumab (Campath®), which destroy
the immune cells regulating MS attacks; Avonex is a registered trademark of Biogen Idec
and Fingolimod, a drug that blocks those Betaseron is a registered trademark of Bayer
Schering Pharma Aktiengesellschaft
cells from entering the nervous system.
CamPath is a registered trademark of
Further studies will clarify the value of Genzyme Corp.
these treatments, but whatever their Copaxone is a registered trademark of Teva
ultimate role, there are nearly 100 more Pharmaceutical Industries Ltd.
Novantrone is a registered trademark of
drugs being tested now.
Immunex Corp
The history of MS is still being written, but Rebif is a registered trademark of Ares Trading S.A.
Rituxan is a registered trademark of Biogen
more has been accomplished to fight MS Idec Inc.
in the last decade than in the preceding Tysabri is a registered trademark of Elan
century. Let us hope the new century will Pharmaceuticals, Inc.
see our victory. Viagra is a registered trademark of Pfizer, Inc.
The National Multiple Sclerosis Society is proud to be a source of information about multiple
sclerosis. Our comments are based on professional advice, published experience and expert
opinion, but do not represent individual therapeutic recommendation or prescription. For
specific information and advice, consult your personal physician.
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