For 20 years neurologists have divided the neurological disorder multiple sclerosis (MS) into four distinct categories—subtypes that are supposed, in part, to help patients get the right treatments. But a new theory erases the distinctions between these groups and suggests that MS is a single disease after all. The idea was developed by Stephen Krieger, a neurologist at Icahn School of Medicine at Mount Sinai in New York City, and presented in late April at the American Academy of Neurology (AAN) annual meeting in Washington, D.C. If the theory holds up, it could lead to more effective management for a wider range of patients.

In MS the body produces antibodies that attack the central nervous system, i.e. the brain and spinal cord. Specifically these antibodies ravage myelin, a fatty substance that insulates neurons, allowing them to conduct electricity. The nerves develop scars or sclerotic lesions (sclerosis is Greek for hard) in the aftermath of such attacks. As a result, patients can suffer from weakness, pain and walking difficulties—not to mention vision loss and a host of undesirable bowel, bladder and psychiatric ills.

The current classification system arose as a way to describe the various ways MS symptoms tend to unfold. The most common type of MS is called relapsing-remitting disease; patients experience flare-ups—in which, for example, they suddenly lose vision in one eye—followed by periods of neurologic normalcy. Presumably their immune system has gone into overdrive when the flare-ups occur and then the activity subsides for months or even years.

Less common are primary and secondary progressive MS. In the former, symptoms progress from the get-go and never remit; in the latter, patients first experience relapses and remissions but then progress to continuously worsening symptoms. Finally there’s progressive-relapsing MS in which patients experience continuously progressive disease on top of which more severe exacerbations occur. Krieger’s hypothesis is a metaphoric reunion of these four otherwise separate divisions of disease—one that can perhaps best be explained by analogy with a swimming pool in need of repair.

Imagine a pool with mountains rising up from the bottom. The mountains represent scars in the central nervous system; the water surface is the threshold at which symptoms appear. Lesions below the water line do not cause symptoms whereas those jutting out of the water do.

The water surface can also be seen as the body's neurologic reserve capacity. Our brains are astoundingly resilient: If one part of the brain is injured, neighboring neurons can step in and take over. But according to Krieger, as we age and as MS progresses, not only does the scarring worsen (that is, the mountains grow higher), the brain also loses its ability to compensate for injured tissue—meaning water starts draining out of the pool and more lesions and resulting symptoms become apparent.

Krieger calls his view of MS the topographical model (referring to the mountains jutting out of the water). He believes his concept unites the MS categories and demonstrates the relationship between relapsing and progressive disease. Relapsing-remitting patients have mountains that temporarily rise above the waterline but then sink again. In those with the other three forms of MS—the more consistently progressive forms—the mountains emerge above the surface but never recede and the symptoms never go away.

If Krieger’s hypothesis is correct, the four MS divisions could be reenvisioned as different stages or different expressions of the same disease. It’s not that the disease completely goes away during ‘remission,’ Krieger explains. "We can see old lesions there on MRI the whole time." But the brain’s ability to compensate for the effects of the lesions declines.

In other words, after the immune system’s assault has waned and a patient with relapsing-remitting disease is symptom-free, some of the neurons are nonetheless still scarred. The nervous system, however, is somehow able to compensate—until one day it cannot and the disease is considered progressive. This could explain why many patients look and feel better than their brain scans would suggest; and also why some patients, in Krieger’s words, catch up to their MRI."

Krieger acknowledges that the existing categories—incidentally developed by his mentor, Fred Lublin, director of the Center for Multiple Sclerosis at Mount Sinai Medical Center—have been incredibly helpful in MS care. He just feels they need to be appreciated collectively. "Neurologists find that it’s very hard to apply the current categories to individual patients," he says. "We’ve shown that diagnostically we don’t really know when someone goes from relapsing-remitting MS to progressive MS. And often times when we think someone has a progressive form of MS, they stay stable for years and don’t actually progress."

Although this new model is in its infancy, it is quickly turning heads among MS experts. In an e-mail, Lawrence Steinman, professor of neurology, pediatrics and genetics at Stanford University, wrote, "at first glance, it looks quite exciting in the way it integrates visually the ‘topographical’ distribution of lesions and the relapses they cause; relapse frequency, severity and recovery; and progression rate." It looks quite "promising," Lublin wrote. "The model provides an individual dynamic to the MS disease courses that we’ve described. It has potential usefulness for practitioners and for enhancing patient understanding of the illness."

The idea that MS is caused not only by worsening immune activity but also by declining general brain health opens new therapeutic possibilities. "We can think of our medicines as working on the floor of the pool, Krieger says. "They prevent lesions But I don’t think they affect the decline of reserve. People with MS can stay neurologically well for a long time with their disease below the surface."

A two-pronged attack that aims to boost brain health as well as prevent lesions would be ideal. Data from some studies suggest that approach may already possible. Exercise has been shown to prevent the degeneration of brain tissue in patients with MS whereas smoking and diets low in antioxidants are associated with a worsening of the disease. Also beyond just targeting aberrant immune activity, drug companies could pursue compounds that increase the brain’s ability to compensate.

In fact, a separate study of 154 people presented at the AAN meeting showed that large doses of the vitamin biotin (found in a range of foods from grains to meats to vegetables) reduced disability in patients with MS, possibly by helping to preserve myelin. A drug that helps regenerate myelin might also be on the way. Early data on an antibody called BIIB033, which was also presented at the conference, suggest it improves electrical conduction in the optic nerves of MS patients, possibly by improving the function of oligodendrocytes, the cells that produce myelin. According to developer Biogen, this is the first evidence of remyelination occurring with a drug therapy. A means to repair myelin would go far to increase brain and nervous system resiliency in MS patients.

In the meantime, if Krieger’s idea catches on, it could have more immediate influence on diagnosis and patient care. Most research into MS treatments has focused on the relapsing-remitting subtype; treatment options for those with progressive MS are few and far between and primarily off-label, meaning they’re not approved by the U.S. Food and Drug Administration. If MS comes to be thought of as a single disorder, it could encourage clinicians to consider using treatments that they had previously reserved just for relapsing-remitting disease to the other subtypes as well. It could also help distinguish between a true relapse and a temporary decline in neurologic function that briefly renders lesions symptomatic, like, say, when a patient has the flu.

When the brain is fatigued for whatever reason—infection, fever, stress—its resiliency can wane and cause MS symptoms to emerge. But according to Krieger’s new model, this might not represent a true relapse but rather a temporary leak in the pool.

 

A visual representation of how multiple sclerosis lesions and symptoms might progress over 20 years. Credit: Courtesy of Stephen Krieger