Considering the recent research advances in the field of multiple sclerosis (MS) and the differing theories as to the disease’s pathologies and treatment, Stuart Cook, MD, President of the New Jersey Medical School, was asked to share his views on the future of MS care.

Dr. Cook identified what he believes to be the four key issues that lie at the heart of prospective MS treatment: “What is the cause of MS; What is the precise mechanism of tissue injury that occurs in MS; How do we develop better therapies to cure this disease; and How do we promote and repair regeneration so that people can recover from the deficits they have?”

Despite the magnitude of those issues, Dr. Cook maintains an optimistic outlook. “I think that in the next 20 or 25 years we will be able to control MS—to potentially arrest the disease process—and I suspect we may be able to identify susceptibility genes. I think we’ll know more about the environmental factors that trigger MS and the precise mechanism of tissue injury. Knowing these things will lead to much better therapies.”

HOW DO WE GET THERE?

In terms of the various approaches to tackle these unanswered questions, the scientific and technologic advances being made in the fields of molecular biology and genetics are certainly applicable to all these areas. Neuroimaging is another very promising area as it is becoming increasingly more sophisticated; advanced techniques for viewing the brain and spinal cord are being refined. As Dr. Cook illustrated, “In addition to conventional MRIs, we have magnetic transfer, we have nuclear magnetic spectroscopy, and we have diffusion studies that show us that normal-appearing white matter is also affected in this disease—we didn’t know that a few years ago.” Also, studies on regeneration of neural tissue hold promise for helping existing deficits not only for MS but also for trauma, parkinsonism, and other degenerative diseases. Advances in molecular biology, crystallography, and infomatics allow the screening of “huge numbers” of new drugs based on knowing the structure of receptors and have greatly increased the speed in bringing potential therapies to clinical trial. Additionally, in the area of infomatics, the expanded databases now allow large groups of patients to be tracked, which Dr. Cook noted was nearly impossible until fairly recently.

BUILDING A LADDER TO THE FUTURE

When it comes to breakthroughs in MS, one advance will probably accelerate the next, Dr. Cook predicts. “When you look at the four areas, the first two will direct the third and fourth. Once we know which genes and environmental factors contribute to susceptibility and progression, we’ll be able to better develop therapies and even preventions,” Dr. Cook said. “And assuming there are environmental and infectious agents involved, which is quite likely, there is the potential to prevent MS through vaccines.” This would be easier if there is only one or a few triggering agents or genes, and would be more difficult if there are multiple genes and infectious agents that cause MS. Dr. Cook believes that the proper understanding of how the immune system acts to produce MS lesions and defining the precise mechanism of injury will lead to better and more effective therapies.

THE BIGGEST CHALLENGE

“The first three goals are more doable; the cause of MS and the tissue-injury mechanism will be understood, but the development of better disease therapies will occur more slowly as we empirically uncover more evidence. The fourth, regeneration of damaged tissue, may take longer. For example, we now know what causes polio and can prevent it through appropriate vaccinations, but we still can’t reverse the neurologic deficits. If MS is caused primarily by one agent it may be possible someday to prevent MS through vaccination, like polio. If multiple agents are involved, this is less likely. I’m not optimistic that in the short term we’ll be able to reverse fixed neurologic deficits. It’s hard to come up with time frames, but regeneration is a more long-term process. Yet, I think there’s hope.” As he explained, it is necessary to stop the destruction before repair can begin. “In this sense MS is unlike polio, which is a hit-and-run—you have the disease and it leads to the deficit right away. MS is an ongoing, progressive disease in most people, and brain cells are continually being injured and destroyed. So, it’s going to be hard to get repair until we stop that destruction.”

MS—ONE DISEASE OR MANY?

One theory bandied about of late is that MS is not a single disease but a cluster of diseases. Dr. Cook remains skeptical. “I am not convinced yet it’s true. The phenotype or expression of the disease does not allow one to definitively conclude that MS is a family of diseases. We may find that different environmental factors or genes affect disease expression. Some people feel there may be different mechanisms between relapsing-remitting and secondary progressive MS because the former seems to be more of an inflammatory disease and later it appears to be a more degenerative disease,” he explained. The different mechanism theory is based on differences in neuroimaging, pathology, and response to therapy. A disease may have many clinical manifestations, though the causational mechanism is the same, he noted. An example of this is Guillain-Barré syndrome, in which acute demyelination of nerves and axonal damage is caused primarily by four or five agents that trigger an immune reaction against similar glycolipids present in both the infectious agent and peripheral nerves. One such agent, Campylobacter jejuni, can cause either an axonal version or a demyelinating version of the disease. “The pathology is different but it’s still the same agent,” Dr. Cook observed. “I think it’s too early to say if MS is one disease or multiple diseases. We have to keep an open mind until the knowledge base allows us to more definitively conclude which it is.”

THE TIMING OF TREATMENT

“Ideally, if you had safe and effective therapies you’d start them early,” he said. While current therapies are not curative, many are safe. “The ABCR drugs are derivatives of human proteins, and the risk/benefit ratio is quite good.” In general, Dr. Cook advised that it is better to treat early although the long-term effects of treatments are unknown. “We know that tissue damage can occur rather early in MS so I tend to treat patients quite early in this disease to try to prevent some of the damage.”

Dr. Cook remarked that those with benign MS may do very well regardless of treatment approach. “Since we can’t predict right now with great accuracy who those people are, and since there is damage occurring in the brain on MRI studies that we may not see clinically, and since these drugs have such a good risk/benefit ratio, I tend to treat most patients early in their disease.

“The exceptions tend to be newly diagnosed, young patients who may not be willing to accept daily or weekly shots as yet. I usually follow these patients very closely to monitor them for new brain MRI activity or new clinical activity. Early treatment has the added benefit of providing some peace of mind to patients that they’re doing everything possible to protect themselves. It’s like an insurance policy that they have,” he noted.

REDUCING EXACERBATIONS VERSUS PROGRESSION OF DISEASE

There are several approaches to MS treatment—reducing and treating exacerbations, attempting to delay progression of disease, providing symptomatic relief, and enhancing quality of life. “Exacerbations are the tip of the iceberg,” Dr. Cook said, “and progression often sneaks up on one. You’d like to think that if you’re stopping the exacerbations you’re slowing down disease progression, but that isn’t totally clear yet,” he said.

“Disease progression may be time-linked, and it can clearly occur with or without clinical or obvious MRI exacerbations,” he continued. “The goal of therapy is to decrease disease activity in the brain. I would like to think that if you’re blocking the mechanism of tissue injury you will eventually slow down progression.”

As Dr. Cook elaborated, “It’s not an either/or situation; we have to try to prevent both exacerbations and progression. To patients, disability is the biggest problem. People can tolerate exacerbations if they’re not getting worse and staying at their baseline. Exacerbations are disturbing and there is temporarily some increase in disability. So obviously we need to try to prevent both both attacks and progression.”

NR

—Heidi W. Moore

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