ABLEnews Extra

                         Betting on Betaseron 

          [The following file may be freq'd as MS9403.* from
          1:109/909 and other BBS's that carry the ABLEFiles
          Distribution Network (AFDN). Please allow a few days
          for processing.]


Multiple Sclerosis: New Treatment Reduces Relapses 
by Marian Segal

Martha Krebs is tired today, having spent a long day at the University of
Maryland's medical school in Baltimore undergoing her last test as part
of a study for a new treatment for multiple sclerosis.

The 35-year-old Germantown, Md., woman was diagnosed with multiple
sclerosis--a disease caused by inflammation and scarring of brain and
spinal cord tissue--in August 1987, two weeks before her wedding day.

The treatment Krebs received in the study was Betaseron (interferon
beta-1b), a biologic product. In July 1993, after studies showed it to be
safe and effective, FDA licensed Betaseron, making it the first product
developed specifically for multiple sclerosis (MS) to come on the market.
Because of the importance of Betaseron, FDA gave its review top priority,
and it also became the first biologic to be licensed under the agency's
accelerated approval regulations.

Krebs is one of an estimated 300,000 Americans with MS. The disease
primarily strikes young adults between 20 and 40 years old, but, rarely,
can develop in children or in older adults in their 40s or even 50s. It
affects about twice as many women as men.

MS is a problem of communication within the nervous system. Nerve cells
send messages from the brain in the form of electrical impulses that
travel along nerve fibers (axons) branching out from the cell body
(neuron). These messages direct vital processes that, among others,
enable us to breathe, eat, see, feel, walk, and talk. When the impulse is
delayed or blocked, physical symptoms can result. Impaired optic nerve
function, for instance, can cause blurred vision or blind spots.

The electrical impulses are hastened on their way by myelin--a white,
fatty substance coating the nerve fiber.
     
"There are little gaps in the myelin called nodes of Ranvier," explains
Henry McFarland, M.D. "The impulses jump from one gap to the next, a bit
like a rock skipping across a pond. The myelin acts like a capacitor."
     
McFarland, a neurologist at the National Institute of Neurological
Disorders and Stroke, explains that in MS, inflammation destroys patches
of myelin in brain and spinal cord nerve fibers, leaving scar tissue.
When the impulse reaches a point stripped of myelin, its progress down
the bare axon is slowed. The more demyelination, the slower the
conduction.
     
Scientists don't know what causes MS, but suspect it's an autoimmune
disease, in which the body mistakenly reacts against its own tissues,
attacking the myelin (see accompanying article). The resulting
inflammation and edema (fluid buildup) further impede conduction. Once
they subside, symptoms often improve.
 
Blurred or double vision is often the first symptom of MS. Other early
symptoms are tingling, numbness, or weakness of a leg or hand,
clumsiness, fatigue, dizziness, and loss of balance. 
          
In many patients, symptoms get worse when their body heats up from
exercise or being out in the sun. "People get upset, thinking it means
the disease is getting worse," McFarland says. "It's not." He explains
that sodium channels along the axon are involved in creating the nerve
impulse, while potassium channels act the opposite. Demyelination exposes
the potassium channels, and when the body heats up, they become more
active and can completely block the impulse. When the core temperature
goes back down, the impulses normalize.

Unpredictable Course
     
MS most often begins as a "relapsing remitting" disease--flare-ups of
symptoms followed by recovery.
     
"One day you may wake up with blurred vision or be unsteady on your
feet," McFarland explains. "That may worsen a little the next few days
and then level off for a couple days or weeks. Then, it will usually get
better spontaneously, without treatment. You may then have no problem for
the next six months to a year or year and a half and then have another
attack somewhere else in the nervous system, with the same course."
          
Scientists don't know what triggers relapses; most have no evident
precipitating event. There is, however, some increased risk following a
viral infection. There is also greater likelihood of a relapse in the six
months after pregnancy, although during pregnancy the risk is decreased.
Some have argued that stress, injury and trauma can trigger attacks, but
these claims have not been supported scientifically.
          
Over time, recovery after each relapse may no longer be complete, and the
patient is left with some permanent disability. After some years,
additional episodes cause further physical decline in a "relapsing
progressive" pattern. Often, these patients go on to develop "chronic
progressive" MS, characterized by steady deterioration.
     
How the disease will progress in a given individual is impossible to
predict with certainty. Even so, McFarland says, the pattern of attacks
over the first five years may indicate the long-term course. Some
patients have very benign disease and never experience anything more than
mild disability, while others develop more severe problems, such as loss
of bowel or bladder control, sexual dysfunction, paralysis, and
confinement [sic] to a wheelchair. Krebs' doctors suspect her disease,
which has progressed little in the 10 years since her first attack, will
remain mild.
          
In some patients, MS is chronic progressive from the start and, rarely,
it can take a rapid, severely debilitating course that ends in early
death. Most patients, however, can expect to live a normal lifespan, and
many of those with mild relapsing symptoms may never even know they have
MS.

Difficult Diagnosis
     
To formally diagnose MS, there must be disease "disseminated in time and
space," McFarland says. That is, there must be at least two attacks that
affect different areas of the nervous system. This is needed to rule out
other problems, such as a stroke or tumor, that could cause the same
symptoms as MS. When the symptoms come and go and affect different
functions, a diagnosis of MS is strengthened.
          
The first symptom that sent Krebs to see her doctor in 1984 was optic
neuritis, which caused partial loss of her vision. In retrospect, she
remembers earlier instances of lethargy and problems with balance,
causing her to bump into objects. She had a second episode of optic
neuritis in late 1985. When, in 1987, she developed numbness and weakness
in her leg, MS was diagnosed. 

Even in disease separated in time and space, MS is only diagnosed if
there is no other reasonable cause for the symptoms, such as a
malignancy, another neurological disorder, or an autoimmune disease like
lupus erythematosus.
          
Laboratory tests, although not diagnostic in themselves, can help confirm
suspected disease and identify additional lesions. 
     
Magnetic resonance imaging (MRI) scans are very reliable in detecting MS
lesions. Although not everyone who shows central nervous system lesions
on MRI has MS, the test detects MS lesions in more than 90 percent of
patients who have clinically diagnosed disease. This makes it a valuable
tool for confirming disease and tracking its progress. In fact, McFarland
says, only a small portion of MS detectable on MRI manifests clinically.
     
"Many patients who have extensive disease activity on MRI don't have a
high rate of relapse," he says. "Someone with a relatively mild form of
MS may not experience symptoms for a long time. That may be, for example,
what's happening in the rare individuals who are not diagnosed until age
60."
     
Evoked response tests assess the integrity of the nervous system. In a
visual evoked response test, for example, electrodes are placed on the
patient's head and a visual pattern, such as a checkerboard, is flashed
on and off. The time it takes for the message, or pattern, to reach the
occipital cortex of the brain, where visual messages are recognized, is
measured in both eyes. Frequently in MS, there is a delay in conducting
that impulse. Similar tests are used to evoke other sensory responses, on
the arms or legs, for example.
     
The physician may also do a spinal fluid examination, drawing a small
amount of fluid from the spinal cord to measure levels of certain
antibodies that are elevated and have a distinct pattern in many patients
with MS.

Treatment
     
While a cure for MS still eludes science, treatment focuses on preventing
flare-ups or prolonging the time between them, shortening the duration of
attacks, and relieving symptoms. 

Betaseron, licensed to treat patients with the relapsing remitting form
of MS, is the only product on the market that can help stave off
relapses. Others treat the flare-ups and symptoms.
     
When Krebs was given her first dose of Betaseron in October 1988, she
didn't know at the time just what she was getting. As a study
participant, she didn't know if she was in the group of patients
receiving high-dose Betaseron, low-dose Betaseron, or a placebo--an
inactive substance.

Five years later she learned she was on the high-dose regimen--the one
shown to be effective--and she credits Betaseron with the lengthy
remission she's enjoyed since her last flare-up. 
     
"I haven't had an attack since February 1990, and that one was mild,"
Krebs says. "I didn't lose vision or have any numbness. My left foot was
dragging and that lasted a couple months, but it was a shorter time than
before I went on Betaseron."
     
"Betaseron is a synthetic version of interferon beta--a naturally
occurring protein the body uses to regulate the immune response," says
Janet Woodcock, M.D., director of FDA's Office of Therapeutics Research
and Review in the Center for Biologics Evaluation and Research. "We don't
know what property makes it effective in multiple sclerosis, but it does
help prevent flare-ups."
     
Woodcock notes that the agency's top priority review of Betaseron under
accelerated approval regulations is an example of getting an important
product onto the market as fast as possible with the most reasonable
amount of information needed to decide if it's safe and effective.
     
"In this case, we found that Betaseron was safe and effective based on a
two-year clinical trial of 372 patients," she says. "Patients on
Betaseron had fewer flare-ups and more patients were completely free of
flare-ups over the study period."
     
The main side effects of the biologic, which the patient injects every
other day, are inflammation and pain at the injection site and flu-like
symptoms. Occasional serious side effects include abnormal liver function
tests and severe depression.
     
Licensing was based not only on Betaseron's effectiveness in reducing
relapses, but on supporting data from magnetic resonance imaging (MRI)
brain scans. The scans showed that at the end of the study, patients
taking Betaseron had a smaller volume of brain lesions than those given
placebo.
     
"The most important thing in MS is not so much reducing flare-ups as
preventing ultimate disability," Woodcock says. "We think the MRI lesions
may be an indicator of disease progression and hope that Betaseron may
prove to curtail disability as well as relapses. Post-market testing of
the biologic will look into the relationships among treatment, MRI
findings, and disability."
     
McFarland adds, "The study showed that over two years, the probability of
not having a flare-up was 30 percent in patients on Betaseron as opposed
to 20 percent for those on placebo. The figures don't knock you off your
feet," he says, "but when you consider that every time you have an
exacerbation you may accumulate some permanent disability, the results
are significant."
     
Preliminary studies of another product, Copolymer 1, show this drug, too,
may reduce the frequency of MS episodes. Now being tested in large-scale
trials, Copolymer 1 has been available since January 1993 under a
treatment IND--a special category that, under certain circumstances,
allows patients with serious or life-threatening diseases early access to
experimental drugs and biologics. Other possible new treatments under
study include monoclonal antibodies, cytokines (chemicals produced by
immune cells), and general immunosuppressive drugs. 
     
Other current treatments--those most commonly used before Betaseron
became available--are corticosteroids (prednisone or dexamethasone, for
example) and the hormone ACTH, which stimulates the body to produce
steroids. These drugs are given during flare-ups to help reduce
inflammation and swelling, but they don't prevent new attacks. Often,
McFarland says, steroids are given intravenously in high doses the first
few days and then orally, tapering the dose for the next two to three
weeks. 
     
To ease symptoms, doctors can prescribe muscle relaxants like Lioresal or
Atrofen (baclofen) for spasms and stiffness. Anticonvulsives such as
Tegretol or Atretol (carbamazepine) can relieve facial pain and
twitching, and Ditropan (oxybutynin), an antispasmodic that relaxes the
bladder, may be given for incontinence.
     
Physical therapists can also help patients work on their muscle strength
and coordination, balance, and stamina. Occupational therapists can
introduce patients to devices that ease their lives in small and large
ways, helping with everyday tasks of dressing and eating, for example.
     
For information on multiple sclerosis support groups and physician
referrals, contact your local chapter of the National Multiple Sclerosis
Society. For general information, write to the society's headquarters at
733 Third Avenue, Sixth Floor, New York, NY 10017.
 
Marian Segal is a member of FDA's public affairs staff.

Culprit Hard to Nail
     
Over the years, scientists looking for the cause of multiple sclerosis
(MS) have pointed fingers at many possible culprits, but lacked
sufficient evidence to nail any one with certainty. 
    
The prime suspects include genes, viruses, and flaws in the immune
system. Interest is also focused on a breach in the blood brain barrier,
the gatekeeper that controls what substances pass from the blood into the
nervous system. 
     
MS is not a purely genetic disease, but its lower incidence or near total
absence in some populations suggests genes influence susceptibility. For
instance, Native Americans and African Americans have a lower incidence
than European Americans living in the same region.
    
Also, the incidence in families is somewhat higher than expected in the
general population. MS risk is difficult to calculate, partly because
regional prevalence rates vary greatly and because risk varies with age,
declining sharply after age 50. Based on an area with a high prevalence
rate, the risk for people 20 to 50 years old has been calculated at 0.1
to 0.2 percent. In families with a history of the disease, the risk may
be 2 percent or more--a 10- to 20-fold increase. And if a monozygotic
(identical) twin has MS, the risk to the other twin--who shares the same
genetic makeup--rises to 25 to 30 percent.
     
Experts believe MS is an autoimmune disease, in which the body mistakenly
reacts against itself. A healthy immune system is finely tuned to respond
to foreign substances, launching an attack to produce antibodies against
the invader and then calling off the troops when the job is done. In
autoimmune diseases, something goes awry and the system attacks the
body's own tissues--myelin, in the case of MS. One theory proposes that
the cells responsible for down-regulating immune activity are deficient
in people with MS, allowing it to attack the central nervous system.
          
Finally, there has long been speculation that something in the
environment provokes the problem in multiple sclerosis. Several
observations support this idea. MS is more common in colder and temperate
climates than in warmer ones. In the United States, it is more prevalent
in the North than the South, and it is more common in northern Europe
than southern Europe. People who migrate from a high-incidence area to a
low-incidence area--or vice versa--before age 15 take on the risk of the
new area. After age 15, they keep the risk of their area of origin. This
suggests something that exerts an influence around the time of puberty.
     
Some evidence for a virus as a possible cause of MS comes from
descriptions of disease clusters. One of the better known examples is the
occurrence in the Faroe Islands between Iceland and Scandinavia. Before
1940, there were no known cases of MS in these islands, but shortly after
World War II, a small epidemic of the disease occurred. The number of
cases continued to climb for many years after. The island population had
been relatively isolated before British troops arrived during the war.
Some investigators believe the British, who are at high risk for MS,
inadvertently spread a virus or other infectious agent they had brought
with them.
     
Researchers have studied a possible link between MS and various viruses
but have failed to find evidence of any specific one causing the disease.
Still, there is interest in the prospect that one or more viruses may
trigger an autoimmune response leading to the disease. 

--M.S.

     A Fidonet-backbone echo featuring disability/medical news and
     information, ABLEnews is carried by more than 325 BBSs in the
     US, Canada, Australia, Great Britain, Greece, New Zealand, and
     Sweden. The echo, available from Fidonet and Planet Connect, is
     gated to the ADANet, FamilyNet, and World Message Exchange
     networks. 

     ABLEnews text files--including our digests: Of Note and
     Mednotes (suitable for bulletin and file use) are disseminated
     via the ABLEfile Distribution Network, which is available from
     the filebone and Planet Connect.

...For further information, contact CURE, 812 Stephen Street, Berkeley
Springs, West Virginia 254511 (304-258-LIFE/5433).