During the 1960s, scientific research into the cause of MS came to focus on two main lines of inquiry that are still being explored today.
The first emerged from analysis of the immune system. White blood cells that react against myelin, specifically against a component called myelin basic protein, were discovered in both EAE and human MS. This led scientists to consider the possibility that MS involves a direct immune-system attack on myelin.
The second idea came from studies that showed that people with MS have altered antibodies against viruses. This revived the older thinking that MS could be caused by a virus. But rather than a viral infection directly damaging the central nervous system, viruses involved in MS were now thought to alter the immune system and trigger it to damage myelin.
These two ideas remain closely mingled today: MS may combine features of both an infectious and an autoimmune disease. The treatments that were later developed for MS all targeted either an infectious or an immune mechanism.
In 1978, the first CAT (Computed Axial Tomography) scans were performed on people with MS. And, in 1979, a Nobel Prize was awarded for development of this powerful new tool. CAT scans use a computer to link a circular array of x-ray images to create detailed pictures of the human brain.
The diagnosis of MS was further improved with the introduction of brain wave tests called “evoked potentials” which measure nerve conduction throughout the optic nerves, brain and spinal cord and often detect hidden areas of scarring and damage.
Scientific research began to yield direct therapeutic dividends as well. Steroids to suppress immune activity were now widely used to treat MS attacks, and the first small studies were performed using interferons (substances that modulate the immune system). The first studies of beta interferon for MS began at the end of the 1970s.
In 1970, scientists studying EAE in lab animals suspected that some myelin protein fragments prevented the disease and actually seemed to protect the animals. Spurred by this finding, they synthesized a mix of protein fragments and used it to treat first animals with EAE and then humans with MS. The product was named copolymer1 and is today an approved disease-modifying therapy under the new name glatiramer, or Copaxone®.
Scientists began to understand in more detail how white blood cells are activated by foreign substances to mount attacks. One activating trigger can be a virus. Scientists also learned that parts of some viruses look so much like normal human tissue that white blood cells will inadvertently attack that tissue when they attack the virus. This is yet another mechanism by which viral infections could lead indirectly to destruction of myelin—when immune attacks on myelin-like viruses spill over onto the myelin itself.
At about the same time, the white blood cell type that causes the actual damage to myelin in MS was finally identified. It is the macrophage (or “Big Eater” in Greek).
The first studies of identical and fraternal twins begun in this decade extended knowledge about the genetics of MS. The twin of a person with MS often does not develop the disease, proving that genes determine only part of the MS risk, though their influence is important. Meanwhile, psychosocial and mental-health issues, as well as the cognitive changes that can be caused by MS, began receiving long overdue research attention.
CAT scanning technology was refined to produce the MRI (Magnetic Resonance Imaging) scan, which shows the brain in greater detail. The first MRI scans of people with MS were performed in 1981 by Dr. I R Young, in England.
By 1984, it became apparent that MRI could actually see MS attacks within the brain, including many which did not cause any symptoms. By 1988 sequential MRI scans changed the entire concept of MS by showing that it is a constant, ongoing disease even though relapses with symptoms may appear only sporadically.
The 1980s may legitimately be called the “treatment decade” in MS. There was an explosion of new drug trials. Guided by the National MS Society, scientists reached a consensus on the design and conduct of research for new treatments, and dozens of different therapies were tested in attempts to control or cure MS. Major clinical trials conducted during this decade finally found the first drugs in history shown to affect the course of this disease.
As the final decade of the 20th century approached, the Congress of the United States made a special eff ort to accelerate medical research. Recognizing the paramount importance of neurological disease, they designated the 1990s as the “Decade of the Brain” and purposefully funnelled funds, time, and talent into the treatment of illnesses that affect the nervous system. Multiple sclerosis benefited enormously from these eff orts, and an explosion of drug trials occurred during this period.
Many of the decade’s advances sprang from the incredible power of new technology. Sophisticated techniques added to MRI allowed it to detect MS plaques earlier and more accurately than ever. That led to more rapid diagnosis of the disease. In 1970, the average time from a person’s first symptom of MS until a definite diagnosis was 7 years, but use of MRI technology reduced the time to six months.
Now the plaque that causes symptoms could often be seen immediately. The power of a rapid, painless MRI scan to provide information is an incalculable blessing for doctors and patients alike. Studies with a series of MRI scans over time showed how MS plaques actually develop and permitted researchers to track the “burden of disease” (total plaque area) in individual patients.
At the same time, MRI scanning gave researchers faster and more sophisticated ways of testing drugs to treat MS. The benefits of a new drug can be seen on MRI scans before they can be seen in patients themselves. Research on the treatment of MS was thus greatly accelerated.
Most diseases yield their secrets only through the painstaking laboratory work of research scientists. Laboratory work on MS showed us many essential aspects of the disease. A key culprit in MS is the white blood cell called a T cell.
Although many details about the sequence of events in the process still remain to be learned, we know that T cells become activated, leave the bloodstream, and enter brain tissue to damage myelin, the fatty tissue that insulates and protects nerve fibers. This T cell has now been identified and characterized in detail.
Recent discoveries also emphasize that myelin is not the only target for destruction in MS. Often the underlying nerve cells, the neurons and their axons, are damaged as well, which is thought to account for some of the permanent disability MS causes.
During the 1990s, the American-led project to discover and decode all the genes in the human body focused attention on the role of genes in many diseases. A monumental study of 15,000 people with MS, including some identical twins who were reared miles apart in different families, clearly demonstrated that genes play a role in determining who gets MS and who does not.
Although there does not appear to be any single “MS gene,” there does seems to be something fundamental to each of us (i.e., something in our genes) that makes one person susceptible to developing MS and another not. This is yet another clue for the cause of the disease.
Of course, the sophisticated technology of the 1990s was not limited to medicine. There were quantum leaps in computers as well. During the “Decade of the Brain” computer scientists built the information superhighway and wove the Internet.
Faster, better communications and data analysis brought MS doctors and researchers from all over the world together in increasingly powerful coalitions. Large databases were assembled to track and analyse thousands of patient histories to clarify their disease variations and their responses to treatment. Characteristic patterns of MS began to emerge. MS clinics and research laboratories are now linked and share and evaluate new findings.
The symptoms of MS have never been as amenable to therapy as they are now. Tizanidine was introduced for management of spasticity. Use of the intrathecal baclofen pump for severe spasticity became more widely available. It delivers medication directly to the spinal cord to relieve intense muscle stiff ness and spasms. Improvements were made in medications for bladder management (e.g., tolterodine) and for fatigue (modafinil).
Treatment of sexual problems, a long-neglected aspect of MS, took a major leap forward with the introduction of sildenafil (better known as Viagra®) and other similar medications. Gabapentin was introduced to treat many painful symptoms ranging from severe face pain (trigeminal neuralgia) to burning pains in the limbs. Other drugs are being developed at a rapid pace.
Research also revealed many ways in which MS can alter the mind, slowing down thinking and affecting memory. New drugs, such as donepezil, used to treat these problems in Alzheimer’s disease, are now being tested in MS.
Refinements in rehabilitation, exercise, and physical therapy also benefited people with MS. These and many other new treatments have markedly enhanced the ways physicians can calm symptoms and improve the quality of life.
Years of research with drugs to treat the actual disease—and not just its symptoms—came to fruition when beta interferon 1-b (Betaseron®) was introduced in 1993. Beta interferon 1-a (Avonex®) was introduced in mid-1996, and glatiramer acetate (Copaxone®) arrived in late 1996.
In 1999 mitoxantrone (Novantrone®) was approved for treating MS and was especially useful against the slow chronic progressive forms of the disease, which none of the other therapies had been able to retard.
Two years into the new century, a variation of beta interferon 1-a (Rebif®) was also introduced. The course of MS could now be altered by reducing disease activity and preventing many attacks.
Nataluzimab (Tysabri®), the first of a whole new class of drugs called monoclonal antibodies, significantly suppressed relapses of MS in several large trials. Treatments began in 2004, but widespread use was delayed while procedures were developed to minimize the serious infections some patients developed during treatment with the drug.
Progress has thus been remarkable. Throughout history MS was an untreatable disease. Then in one decade (1993–2004) researchers developed 6 drugs that suppress attacks and alter the course of MS. Many more drugs are being tested.
These include oral cladribine, which may well be the 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; and Fingolimod, a drug that blocks those cells from entering the nervous system. Further studies will clarify the value of these treatments, but whatever their ultimate role, there are nearly 100 more drugs being tested now.
The history of MS is still being written, but more has been accomplished to fight MS in the last decade than in the preceding century. Let us hope the new century will see our victory.
SOURCE Loren A. Rolak, MD
© Willeke Van Eeckhoutte and Ireland, Multiple Sclerosis & Me, 2011-2014. Unauthorized use and/or duplication of this material without express and written permission from this blog’s author and/or owner is strictly prohibited. Excerpts and links may be used, provided that full and clear credit is given to Willeke Van Eeckhoutte and Ireland, Multiple Sclerosis & Me with appropriate and specific direction to the original content