by Rich Cano
Multiple sclerosis (MS) is a chronic, often disabling disease of the central nervous system(CNS). Recent research evidence points to the possibility that the disease is associated with a disturbance in the function of the immune system. This disturbance permits cells of the immune system to inappropriately attack myelin, the insulating sheath that surrounds the nerve cell processes of the central nervous system. The loss of myelin is called demyelination. Demyelination produces the same consequences as when the insulation around speaker wire becomes cracked or torn. Under these circumstances the speakers would "short out" causing them to emit a broken signal (static). Loss of myelin surrounding nerve axons results in the "shorting out" of nerve pathways located in the brain and spinal cord. This ineffectiveness of the nerve impulse can lead to problems with vision, coordination, bladder control and sensory perception.
Although severe forms of multiple sclerosis can be devastating, the illness does not significantly reduce a persons life expectancy. Common symptoms of the disease include fatigue, and loss of strength. Patients often have increased muscle stiffness, a condition known as spasticity. There may be a loss of sensation in the arms and legs, or an ever present tingling sensation like pins and needles. Patients may also feel persistent facial pains. If the optic nerve is involved, the patient may have blurred, or reduced vision. Patients with demyelination of the brain stem, a region that controls eye movement, commonly have double vision, since each eye can no longer concentrate on the same object. If the illness has impaired the spinal cord, in addition to losing leg strength; the patient may become incontinent, constipated or impotent.
Symptoms of MS become worse when patients are exposed to heat. This is because elevated temperatures - whether from a hot bath, exercise, or exposure to the sun - increase the strength of electrical impulses in nerve fibers. Demyelinated areas of the CNS cannot adequately handle stronger signals; therefore, symptoms become amplified. Conversely, lowered temperatures reduce the strength of nerve signals to a level manageable by damaged areas. Therapies such as a cold bath can sometimes temporarily relieve symptoms or reduce the fatigue MS patients often feel.
MS cases are divided into two types of the disease. The first is known as exacerbating - remitting disease, which is characterized by fluctuations in nerve function. With this type, periods of deteriorating ability are followed by periods of recovery. Although as time passes recovery generally becomes less and less complete. The second type of the disease is known as chronic progressive disease. This type has more of a steady downhill course, typically without periods of temporary recovery. Frequently, patients who initially have the fluctuating form of MS develop the chronic form later.
The symptoms of multiple sclerosis depend largely on which nerve pathways are involved. However, the amount of damage to the CNS is not directly related to the severity of symptoms. Unlike the example of the single speaker wire, there are thousands of nerve pathways involved within the brain and spinal cord. This "networking" allows for many alternate pathways that signals can travel. Amazingly damage to the CNS in vast areas may not produce any symptoms of the disease. In most cases the physical damages of MS discovered upon an autopsy are far more severe than the patient's symptoms had led on to be.
Multiple sclerosis was chosen as the name for this disease because it described the multiple areas of scar tissue that develop in the brain and spinal cord as a result of demyelination. Damaged areas of myelin are called lesions or plaques. Plaques seen with a microscope are characterized by inflammation and destruction of the myelin sheaths. Larger plaques will appear as large white splotches on MRI scans of the brain and spinal cord. Before today’s technology, the positive diagnosis of MS was very difficult to ascertain. MRI’s are now the physician main tool for diagnosing the disease.
Although the cause of MS remains unknown, evidence suggest that the disease is produced by an environmental factor that triggers the illness in a genetically susceptible person. Studies of large immigrant area populations imply that people with MS were exposed to some environmental agent at a young age, possibly before the age of fifteen. Individuals who moved from an area before age fifteen had a prevalence of MS similar to the region to which they had moved. People who moved after the age of fifteen showed incidences of disease similar to the region they came from(1).
There are also lines of evidence to support that MS may be influenced by genetic factors. For example, MS is very common in Caucasian women, but rarely occurs in men and women of native African, American or Asian descent. This trend occurs even when these people live in the same community. It is also known that certain genes are found more frequently in people with MS than in people without MS. Studies of families in which more than one member has MS show that unaffected family members have an increased risk for MS, when compared to unaffected individuals in the general population. For example, the prevalence of MS in the general population is approximately 5 to 10 cases per 10,000 people. This works out to about 0.05 to 0.1 percent. In families with one member who has the illness, the chance of a sibling developing MS increases to 2 to 4 percent(2). In 1996 a group of researchers performed a study with 16,000 MS patients in Canada. The study concentrated on how many had full siblings (same parents), and half-siblings (different mother or father) with multiple sclerosis. The results showed that full siblings have a 3.46 percent chance of developing MS, while half-siblings only had a 1.32 percent chance. It could be argued that the reason behind the increased chance of acquiring MS within families is due to similar environmental conditions. However, the study also included data pertaining to the siblings who did live in the same environment with the afflicted individual, and those who did not. There was no significant difference in risk between siblings that lived together, and those that never did. Studies of twins could offer much more insight to genetic importance especially in cases of identical twins. However, due to the rarity of identical twins with both having MS, studies of siblings remains the most promising area of research.
Viruses are also under investigation as the possible cause for MS. There is only indirect support that a virus can cause or trigger an attack of MS. Attacks are generally higher during seasons when viral infections are common. It is known that some viruses are capable of causing demyelination and disruption of the brain and spinal cord of humans and animals. Despite these observations, there is still no convincing evidence that a viral infection of the brain or spinal cord causes MS. The most notable evidence supporting viral induction as the cause of MS comes from an epidemiology study conducted by Dr. Kurtzke in the Faroe Islands. Dr. Kurtzke noted that for about twenty years following World War II, the incidence of MS on the islands increased every year. During the war this region was heavily occupied by British troops, leading to the current hypothesis that troops may have brought with them a disease causing agent, or virus to the islands(3).
Recent research has shown that some viral proteins may "mimic" myelin’s proteins; therefore, inducing the immune system to respond to the tissue. Dr. Lawrence Steinman, of Stanford University, notes that adenovirus type 2 has amino acid sequences resembling those in the crucial fragment of myelin basic protein. This resemblance may prime the immune system to attack the corresponding self component of myelin(4). Mimicry has been seen in similar cases with strains of streptococcus, the species of bacteria responsible for strep-throat. In cases of strep throat that have gone untreated with antibiotics, the immune system eventually begins to mistake heart valve tissue as the disease causing agent. This malfunction leads to perforation of the heart valves rendering them incapable of function. Apparently, the major histocompatibility complex (MHC) proteins on the surface of these tissues resemble epitopes of the bacterium.
In healthy individuals the immune system naturally fights off infections from foreign invaders such as bacteria or viruses. Certain white blood cells called B-cells (formed in the bone marrow), transform into plasma cells to produce antibodies. Antibodies are specialized proteins that have attachment sites highly specific to the foreign agent they were produced for. With this high specificity, antibodies can circulate in the blood serving as an early detector upon second infections. B-cells usually require help from another white blood cell called T-helper cells (Th) to be fully effective. The collaboration between B-cells and Th cells is regulated by several factors including T-suppresser cells. Regulation by T-suppresser cells is critical because otherwise the collaboration between B-cells and Th cells would continue, even when antibodies are no longer needed. These cells could then go on to make antibodies against body tissues.
There is some evidence that an autoimmune response may be the sole cause of MS. In multiple sclerosis, as described earlier, the immune system attacks the body’s own tissues in a process known as an "autoimmune response". Researchers have found a way to induce an immune response in laboratory animals, a condition known as experimental allergic encephalomyelitis (EAE). This disease in animals causes inflammation and demyelination such as that seen with MS in humans. Researchers induced EAE in laboratory animals by injection of "myelin basic protein (MBP)" making them allergic. MBP is produced naturally by most organisms with advanced neural systems. The allergy causes the immune system to attack the nervous system and induce a disease that is very similar to MS (4). Thus, the disease is formed without the induction of a virus or conditions of genetic susceptibly. EAE has also been activated in animals by injection with MBP-activated T-cells indicating colonies of these cells in the body could generate the disease (5).
Since the cause of MS seems to be far from being understood, research projects are mainly attempting to develop drugs for treatment of symptoms in MS. Many of these drugs concentrate on controlling the T-cell response. On December 23, 1996 the Food and Drug Administration (FDA) approved the use of Copaxone, a drug shown to be effective in controlling MS. Copaxone is an immunomodulator that appears to block myelin specific autoimmune responses. The active ingredient, glatiramer acetate, consists of the acetate salts of synthetic polypeptides from four naturally occurring amino acids (L-glutamic acid, L-alanine, L-tyrosine. and L-lysine) with a defined molecular weight range (6). With a structure resembling MBP, Copaxone inhibits the binding of T-cells to myelin proteins by suppressing their activation. This action in turn then induces T-suppresser cells. In a double blind trial, 50 patients with relapsing MS were treated for 24 months with daily subcutaneous injections of 20mg of Copaxone or placebo. The patients had an annual relapse rate of 0.32 with the drug and 1.35 with placebo, a statistically significant difference (7). Subsequent studies involving more patients showed similar results. There was an indication that patients with early disease symptoms (newly diagnosed) responded better to the treatment. Individuals with chronic type (non-remitting) MS who did not respond to the drug. When injections were ceased, effects of the treatment did not last. The average cost of Copaxone is about $10,528 for a yearly regimen of treatment. Insurance companies still vary on coverage for the treatment.
As common practice our society practices the use of vaccination to discourage the spread of disease. One method of vaccination is to introduce attenuated, or inactivated organisms to the body to generate immunity to active form of the organism. The same practice has been applied to MBP-activated T-cells. In a pilot trial of eight patients with MS who were administered attenuated MBP-activated T cells, five demonstrated a reduction in the amount of relapses over a two years. The relapses decreased from approximately sixteen to three a year(5). MRI scans also showed only an 8.0% increase in brain lesions compared to the 39.5% increases seen in non-vaccinated patients(5). Inactivation of MBP-activated T-cells was achieved by irradiation techniques not fully explained. Treatments such as these, along with many others, are being developed at a constant pace in hopes to find a cure.
Multiple sclerosis, like the common cold, leukemia, and cancer, remains a mystery. Researchers have discovered many clues regarding the cause of the disease, but the case remains unsolved. However, research in the area of MS has provided many advancements in the fields of genetics, virology and immunology. Geneticists are finding more and more information of genomic responsibility in disease, virologists are finding fascinating new roles viruses might play in the mechanism of disease, and immunologists are finding out the vast complexities of our built in defense system. Yet, it seems that until we fully understand the absolute complexities of the immune system MS will remain unsolved. We can only hope to continue developments in drug research to aid the thousands who are afflicted with MS, until the exact cause of this mysterious disease is known.
References:
1. Panitch, MD, Fishman MD, PhD, Beaver Jr., MD, (1997) Neurological Diseases: Medical Immunology 9th Edition; p579-82.
2. Sadovnick, Dyment, Ricsch, (1996), Evidence for Genetic Basis of Multiple Sclerosis, The Lancet : vol347, p1728-30.
3. National Multiple Sclerosis Society, (1997), An Unsolved Mystery in the Faroe Islands, Inside MS : v15, n2, p10(2).
4. Steinman MD, L., (1994), Autoimmunity and Neurological Disorders, URL: http//aspin.asu.edu/msnews/autoimm.htm.
5. Medaer, Stinissen, Truyen, Raus, Zhang, (1995), Depletion of Myelin-Basic-Protein Autoreactive T Cells by T-cell vaccination : Pilot Trial in Multiple Sclerosis : The Lancet, vol346, p807(8).
6. Copaxone: Effective Multiple Sclerosis Therapy That is Easy to Live With, URL: http//www.tevamarionpar...com/copaxone/qal.html#C1
7. Abramowicz, MD, Mark, (1997), Glatiramer Acetate for Relapsing Multiple Sclerosis : The Medical Letter, vol39, p61(2).
Copyright © 1998 Rich Cano and Koni Stone
BACK to the May 1998 Table of Contents