Fall 1996 Volume 5, Number 4
Imagine having a disease that can strike at any time,
that can leave you blind or paralyzed for days, months, or forever. Then,
imagine that this disease might spontaneously go into remission, only to return
months or years later. This is life with multiple sclerosis (MS).
Unfortunately, this is not an unusual scenario.
MS is a common neurologic illness, affecting approximately 300,000 Americans. Perhaps cruelest is that it strikes otherwise healthy young men and women who are often just beginning to start families and gain advancement in their jobs. It is the second most common neurologic cause of disability of young adults (after head trauma) in the United States. It begins in two-thirds of all patients between the ages of 20 and 40; it is rarely diagnosed in young children or the elderly.
MS is thought to be an autoimmune illness, wherein the immune system mistakenly recognizes normal body tissues (in this case, brain and spinal cord tissues) as "foreign" and tries to get rid of them, resulting in inflammation and damage. The precise target of autoimmunity in MS has not yet been identified, but it appears to be a constituent of myelin, the material that wraps like insulation around axons, the long, threadlike filaments that extend from nerve cell bodies.
In MS patients, the inflammation disrupts myelin --and in some cases actually destroys the nerve cell axons --impeding the ability of the nerve cells to communicate. The region of demyelination and inflammation, anywhere from millimeters to more than a centimeter in diameter, is called a "plaque."
Eventually the active inflammation and demyelination subside, apparently because of offsetting influences of "suppressor" immune cells, although this is still not fully understood. Depending upon the severity and duration of inflammation, remyelination within the plaque and recovery of function may occur.
Symptoms
MS symptoms are diverse; they seem to reflect the number and severity of
the plaques as well as the "strategic" effects of plaques at especially
important sites in the nervous system. Many patients have mild sensory
symptoms (tingling, burning, itching, warmth), frequent urination or profound
fatigue. But in the absence of detectable abnormalities, the diagnosis of MS
cannot be made until major symptoms develop.
Major symptoms of established MS include weakness, paralysis, tingling or
numbness of the limbs, loss of vision from one or both eyes, double vision,
imbalance, incoordination, slurred speech, impaired bladder and bowel control,
chronic pain, and profound fatigue. Although many of these can signify other
neurologic illnesses, the tendency for symptoms to spontaneously disappear
(remit) and recur in multiple locations is characteristic of MS. Many MS
patients also find that exercise or even small rises in body temperature may
exacerbate symptoms. This phenomenon, relatively specific for MS, is
attributed to interruption of signals at points where nerve fibers are denuded
of their myelin-insulation.
However, some of the most disabling MS symptoms are not attributable to plaques in a specific part of the nervous system. For example, the majority of MS patients experience severe fatigue, resembling the lassitude we all experience during viral infections. MS fatigue can be chronic, lasting for months or years, or it can have a relapsing-remitting pattern much like typical MS "flares" (episodes of neurologic dysfunction). Recent studies suggest that this fatigue may have many causes, including substances secreted by immune cells (cytokines), disrupted sleep, or MS-induced changes in brain neurotransmitters. About half of MS patients find partial relief of fatigue with amantadine, a drug that promotes release of the neurotransmitter, dopamine, within the brain.
Longterm Consequences
The functional consequences of MS are often profound. According to some
studies, 50 percent of patients are disabled within 10 years and fewer than
two-thirds of patients are able to walk after 30 years. About 15 to 25 percent
of MS victims have a relatively mild form of the disease; about one-third of
patients have extremely severe disease.
Risk Factors
Like many autoimmune disorders, MS disproportionately affects women
--the ratio of women to men is about 2 to 1. Women do not have more severe MS
than men, which suggests that the sex difference is due to something that makes
women more likely to acquire the disease.
MS is primarily a Caucasian disease, especially affecting those of northern European ancestry (e.g. Scandanavians, English, Irish). Its prevalence is low in African blacks, Asians and other ethnic groups with little Caucasian admixture. Recent studies suggest that eight or more genes may affect the potential to develop MS. The strongest link thus far is to a region on chromosome 6 containing genes involved in control of immune function
But, clearly, genetic tendencies are only part of the story. This has been demonstrated in studies of identical twins, fraternal twins and siblings of MS victims. If MS were purely determined by inherited genes, a "concordance-rate" (both twins similarly affected) of nearly 100 percent would be expected in identical twins of MS victims; instead, they are affected in only 30 to 50 percent of cases. Non-twin siblings and fraternal twins, are affected in about 5 percent of cases, while the general population has a rate of about 0.1 percent. These data suggest that genes contribute susceptibility to MS, but that an unknown environmental "trigger" may tip the balance toward developing the disease.
Animal studies support this conclusion. In one recent study, mice were genetically engineered to have immune genes that might predispose to an illness resembling MS. Animals housed in a completely sterile laboratory did not become neurologically ill, whereas genetically-identical mice in a nonsterile facility had a high rate of neurologic illness. No specific infection could be singled out in the affected mice; instead, several different viral illnesses seem to be involved.
These data fit with recent studies in MS patients indicating that a substance, gamma-interferon, produced by activated lymphocytes (a type of white blood cell), may provoke flares in patients with MS. Normally, gamma-interferon is produced as part of the body's defense against viral infections. This linkage may explain why upper respiratory infections (colds) seem to trigger MS flares in some patients.
Another explanation is the "molecular mimicry" theory, which suggests that normal immune responses to specific viruses may cross-react with particular body tissues, resulting in viral "triggering" of autoimmunity. Whether viruses actually trigger the onset of MS is not proved, but evidence supporting this hypothesis is accumulating.
Another "environmental" influence on MS is pregnancy. Women have a significantly reduced risk of MS flares during the last three months of pregnancy. Unfortunately, after delivery, the situation reverses; the risk of flares increases during the next six to nine months. Fortunately, the net effect of a pregnancy on MS is minimal, and women are no longer discouraged from having children.
The changes in MS during and after a pregnancy suggest the possibility of treating MS with drugs to mimic the beneficial immune effects of pregnancy. Of equal importance, researchers would like to identify the deleterious factor that increases flares after delivery. Animal studies suggest a role by hormonal changes, with one candidate being prolactin, the pituitary hormone that principally causes milk production after delivery. In rodents, prolactin has been shown to affect the immune system, chiefly by intensifying a variety of immune responses. In animal studies, inhibition of prolactin was found to inhibit signs of a neurologic illness resembling MS. Whether prolactin has a similar role in immune function in humans is not yet known.
Types of MS
MS is generally classified according to the pattern of disease activity,
particularly the degree of recovery of function, and the presence or absence of
distinct flares. These classifications are used for deciding which drugs are
appropriate for specific patients.
In the mildest form, "relapsing-remitting" (R/R) MS, patients have definite flares lasting days to months, followed by complete (or nearly so) recovery. Patients with incomplete recovery from a flare, but without disease progression between flares are also classified as R/R. About two-thirds of patients initially have R/R disease.
Over time, many patients evolve from the R/R form into the "secondary-progressive (S/P) form of MS. S/P patients have progressive deficits that develop in between identifiable flares. About 10 percent of patients have steadily progressive deficits without any remission from the onset of the illness, and are classified as "primary-progressive" (PP) MS.
Until recently, a finding of specific abnormalities in the cerebrospinal fluid, which circulates within and around the brain, was routinely used for the diagnosis, as these abnormalities are present in the majority of MS patients. Now, a new brain imaging technology, magnetic resonance imaging (MRI), has given neurologists a powerful and sensitive new tool for the diagnosis.
Brain MRI scans are abnormal in more than 90 percent of MS victims. Typically, areas of abnormal brightness, suggesting increased water content, appear on "T2-weighted" scans; dark areas on "T1-weighted" scans suggest focal areas of tissue destruction; and abnormal brightness after a dye is injected into the patient's bloodstream ("enhancement"), suggests that inflammation has damaged the blood-brain barrier (blood vessel tissue that shields the brain from undesirable molecules in the blood).
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| MS plaques are bright oval or linear areas on "T2-weighted" images. | On "T1-weighted" scan, an active plaque is indicated by brightness of the oval area on right after giving dye. |
(Scans coutesy of J. Madsen.) | |
Similar abnormalities are sometimes seen with other diseases, so MRI abnormalities are not by themselves sufficient to make a diagnosis of MS. Fortunately, recent studies indicate that the next generation of MRI techniques may be able to detect much more specific abnormalities and thereby have even more diagnostic power in MS patients.
Since the diagnosis of MS requires multiple areas of inflammation separated in time, a peculiar aspect of MS is that it cannot be diagnosed at the time of the initial episode. Early in the disease we cannot reliably distinguish between a one-time event versus the first of many episodes. But in the near future, it may be possible; already, we can determine which patients are at particularly high-risk.
Treatment
The treatment of MS has been revolutionized in the past few years by the
development of safe, generally well-tolerated drugs that not only speed
recovery from acute flares, but also help to reduce the frequency of flares and
partially retard progression of disability.
Severe MS flares are generally treated with high doses of methylprednisolone, a synthetic adrenal steroid hormone similar to cortisone that has powerful effects upon the immune system and on inflammation, often shortening the flare. Although these benefits are of great importance, methylprednisolone has not been shown to permanently retard progression of disability, and the drug's side effects limit the frequency of treatment.
Fortunately, newer drugs hold the promise of longterm beneficial effects. Two versions of a natural immune substance, beta-interferon, (known by the trade names Betaseron and Avonex) reduce the frequency of flares by about 30 percent in patients with R/R MS. In addition, both drugs substantially improve the MRI abnormalities of MS, suggesting a sustained benefit. An important finding with Avonex was that it helps slow the progression of disability in some patients.
A third drug, copolymer 1 (or Copaxone), recently recommended for approval by an FDA advisory panel, also has great promise, especially for patients with mild, early R/R disease. In such patients, Copaxone has been shown to reduce the frequency of flares and partially inhibit progression of disability.
While these results are extremely important, flares and progression of disability are not completely halted by these drugs, and we are not yet at the point of substantially "curing" MS.
A quickened pace against MS is clear, but the effort still has a long way to
go, particularly to help patients with more advanced MS. For now, these
patients are treated on a selective basis with powerful immune-suppressive
medications that have greater risk of toxicity than drugs for R/R disease, and
even less expectation of halting the disease.
Still, progress begets progress --and it must, to spare future generations of young adults from the immune system's terrible mistake. *
