Six years ago, when she was 24, Rachelle Alston woke up one morning and noticed she was having trouble seeing out of her left eye. “Everything was blurry from the bridge of my nose down,” recalls the slim Seattle native. “I thought my contacts must have scratched my eye or I had dry eyes, so I left my contacts out and went to work.”

She mentioned the problem to her co-workers. “I thought it was no big deal and I'd give it a few days, but they were older and pretty much pushed me out the door telling me I had to go see a doctor—now.” She saw an optometrist. He examined her and immediately referred her to a neuro-ophthalmologist, who sent her for an MRI of her brain. The scan revealed bright patches along nerves, a sign of the type of damage that characterizes multiple sclerosis.

“I went home and started looking up MS on the Internet. Boy, that's one thing you should not do!” Alston recalls. “I couldn't believe it. Here I was at the beginning of my life, wanting to have a family and a career, and I thought, How can I keep a job, and who would want to marry someone with this disease? Imagine saying to your date: ‘Hi, I have MS. Want to take care of me?'”

Multiple sclerosis is a disease of the brain and spinal cord that leads to a wide variety of motor, sensory and cognitive problems. It affects an estimated 2.5 million people worldwide, about half of whom will become disabled within 10 to 15 years of their diagnosis. Indeed, MS is the leading cause of nontraumatic disability among young adults: the disorder typically strikes between the ages of 15 and 50 years, with an average age at diagnosis of about 30.

Despite this grim prognosis, a stream of new treatments have brightened the prospects for patients' quality of life. Based on taming a damaging immune response, these therapies reduce the frequency and severity of symptoms and may slow the progression of the disease. During the past 19 years the U.S. Food and Drug Administration has approved nine new medications, and two more are up for review in the next few months.

Still, the cause of MS remains unknown, and eventually most patients will progress to an advanced phase of the disorder that remains unresponsive to medicine's best therapies. As research into more effective immune-altering remedies continues, many scientists are turning their attention to understanding what causes the progressive degeneration of neurons that lies at the heart of MS, with the goal of developing treatments that can completely halt or even prevent the disease.

Targeted Treatments

Over the years MS has been blamed on diet, infections, toxins and even repressed memories. Based on these theories, patients have been subjected to a host of treatments, many of which are potentially harmful. They were placed in hot boxes, infected with malaria, injected with milk and treated with radiation. In 1936 American neurologist Richard Brickner published a 29-page list assessing 158 different therapies in use at that time to treat MS.

Meanwhile advances in immunology in the early 1900s led to an appreciation of the immune system's role. In 1933 researchers found that they could produce an MS-like disease called experimental autoimmune encephalomyelitis in rhesus monkeys by injecting them with extracts of rabbit brains, which triggered the monkeys' immune system to mistakenly react to something in their own brain. Ultimately, researchers discovered that the targets of the immune attack were proteins in myelin, the fatty, protein-packed insulating material that surrounds the long tendrils of neurons called axons. Myelin nurtures these cells and allows them to conduct impulses efficiently. The discovery of this animal model bolstered the theory that MS is primarily an autoimmune disease and helped scientists study the disorder and test new treatments.

Most scientists now believe that in MS, the body's white blood cells attack these myelin proteins. The onslaught is thought to begin when susceptible individuals are exposed to a virus, bacterium or other environmental culprit that contains proteins similar to those in myelin. The encounter spurs the production of immune cells that “mistake” myelin for a foreign protein. According to the autoimmune model of MS, damage from this immune attack initially disrupts transmission of nerve signals and eventually destroys the nerves themselves. Yet scientists, despite decades of research, have not yet discovered what this trigger is.

MS afflicts only the central nervous system—that is, the brain, spinal cord and optic nerves. Areas of inflammation tend to move, flaring and fading in one area, then reappearing weeks, months and even years later somewhere else. At different times, a patient might experience any of a variety of possible symptoms in different body regions, including numbness and tingling, “pins and needles” sensations, pain, muscle weakness and tremor, and emotional, psychological or cognitive disturbances. For example, weakness in a leg may fade, only to be followed by facial paralysis. The waxing and waning of symptoms characterizes the most common form of the disorder, termed relapsing-remitting MS [see box on page 55]. After the first attack, patients may go months—even years—in remission before another relapse.

Almost all existing treatments are aimed at rolling back the immune attack. Back in the 1960s, patients took adrenocorticotrophic hormone, which stimulates the adrenal glands to produce cortisol, a powerful immune suppressor. Synthetic corticosteroids, such as methylprednisolone, are still used to treat flare-ups, but because of their severe side effects—which include diabetes, osteoporosis, an increased risk of infection and even psychosis—they cannot be prescribed over the long term.

A better understanding of the immune system's role, however, has led to more refined treatments [see table on page 57]. By targeting specific aspects of the immune onslaught, these pharmaceuticals result in far fewer side effects than corticosteroids, making it possible for patients to take them continuously, not just when symptoms worsen. That adjustment is important because we now know that only about one in 10 inflammatory flare-ups causes obvious symptoms. Nevertheless, these silent attacks inflict damage that accumulates and contributes to progressive disability. Studies conducted over the past few years show that continuous treatment not only reduces the frequency and severity of relapses but also appears to delay the onset of disability.

Some of the newer treatments target, while blunting the actions of, particular classes of immune cells now known to be involved in an MS attack. Others work even more subtly. For example, in MS, part of the immune reaction promotes changes in the blood-brain barrier, a tightly knit network of cells surrounding capillaries in the central nervous system. This filter normally keeps white blood cells, among other substances, from slipping into the brain or spinal cord. Yet the blood-brain barrier becomes more porous in MS, allowing immune cells to cross into the central nervous system. One new drug, the antibody (immune system protein) natalizumab, blocks receptors on blood vessel walls that white cells grab and use to pull themselves across the blood-brain barrier and into the brain or spinal cord. Disabling these molecular handholds means that far fewer immune cells slip into the central nervous system, where they can wreak havoc.

In another current approach, a pill called fingolimod prevents white blood cells called lymphocytes from leaving the lymph nodes and entering the circulation, so that they cannot reach the brain and spinal cord. Because the drug does not destroy these cells, they can still perform many of their important roles in normal immunity, and patients can fight off ordinary infections. Another oral agent, teriflunomide, approved in late 2012, stops rapidly dividing immune cells involved in MS from proliferating, thereby blunting the immune attack, while sparing cells that multiply more slowly and are important to normal disease resistance. Because these newer pharmaceuticals are designed to inhibit particular biochemical processes underlying MS, they are safer than treatments that suppress the immune system more broadly.

One treatment that the FDA is expected to approve this year is BG-12 (dimethyl fumaric acid), now is used to treat the skin condition psoriasis. This drug has anti-inflammatory and antioxidant effects that are thought to help protect neurons. It may also modulate immune cell function to reduce inflammation. In a large-scale study published in 2012, neurologist Robert J. Fox of the Cleveland Clinic and his colleagues found that patients with relapsing-remitting MS who took BG-12 for two years had fewer attacks, slower progression of disability and less pronounced lesions as seen on an MRI than did those taking a placebo pill.

Rebooting the Immune System

Not all the latest remedies are so delicate, however. Another emerging medicine under FDA review is an injectable drug called alemtuzumab. This antibody is now an approved treatment for chronic lymphocytic leukemia, a blood cancer. It destroys large numbers of white cells and causes severe immunosuppression. In MS, it is designed to reboot the immune system in the hope that after recovering from the drug's effects, the body's built-in defenses will no longer attack myelin. In a clinical trial, 376 patients taking alemtuzumab had 55 percent fewer relapses than did 195 patients receiving a standard treatment (the anti-inflammatory agent interferon beta-1a). In addition, 30 percent fewer patients receiving the experimental therapy became disabled during the two-year trial.

Still, the treatment carries a risk of infection: 67 percent of those taking alemtuzumab developed mild to moderate infections compared with 45 percent of those taking interferon. In addition, 20 to 30 percent of patients who received alemtuzumab ended up with thyroid disease that resulted from an immune system assault on the thyroid gland. Why this adverse event occurred is unknown, but scientists suspect it resulted from a defect in immune regulation that could be behind MS as well.

Another approach to restarting the immune system involves a bone marrow transplant. Last year my colleagues and I reported treating 26 seriously disabled MS patients, many of whom could not walk, with a combination of radiation, chemotherapy and antibody treatments that kills almost all of a patient's immune cells. We then gave them a bone marrow transplant to restore their immune systems—bone marrow contains stem cells that give rise to all blood cell types. We hoped that the reconstituted immune systems would no longer attack myelin.

The immune system did seem to back off its assault. The treatment appeared to reduce the flare-ups of symptoms, and it stabilized the disease for as long as six years in some of the patients, all of whom had previously been going rapidly downhill. In 11 patients, however, the illness continued to progress, leaving them less and less able to engage in normal daily activities. The approach, moreover, is not without risk. One patient died as a result of treatment-related complications, and another succumbed seven years later to a blood disorder to which the therapy may have contributed. Overall, patients with less advanced disease benefited more from the transplant, suggesting that reconstituting a patient's immune system might be more effective earlier on—a theory we are now testing in a follow-up study.

The fact that such severe immunosuppressive treatments fail to cure MS, however, suggests that autoimmune activity cannot fully explain the illness. In recent years researchers have come to understand that an apparently relentless neurodegenerative process appears to occur in parallel with the sporadic autoimmune attacks and may be at least partially independent of it. After all, destruction of neurons in MS continues even after the immune attacks appear to abate later in the disease.

A Theory Turned Inside-Out

Scientists have developed three different theories to account for such phenomena. Some propose that the damage from years of immune attacks triggers a self-perpetuating destructive cascade in neurons or in oligodendrocytes, which make myelin. This process severs and destroys axons and causes the death of neurons themselves. Other scientists suggest, meanwhile, that a chronic, smoldering autoimmune attack continues undetected throughout the illness. It persists despite immunosuppressive treatment and may rebound afterward, causing progressive neurodegeneration.

The most controversial hypothesis is that MS is primarily a neurodegenerative, rather than an autoimmune, disease. In this “inside-out” theory, neurons, oligodendrocytes or other cells in the central nervous system fall apart as a result of an inherited defect or environmental culprit, such as a virus. Products of this degeneration, perhaps proteins from dying cells, then provoke an autoimmune reaction. According to this view, an autoimmune attack may accelerate the neurodegeneration in MS, but it is not the principal cause of the disorder. This theory would explain why MS progresses in the face of aggressive immunosuppression. It would also clarify why some patients have lost neurons and axons in areas with little evident autoimmune activity.

In addition, this last theory jibes with other recent findings regarding the timing and location of the damage in MS. For decades scientists assumed this damage was confined to white matter—which is made up of axons surrounded by myelin—and occurred late in the disease, a pattern consistent with an immune attack on myelin. The latest data, however, show that the neuronal cell bodies in the brain's cerebral cortex, its outer covering, degenerate very early in the disease. (This cortical damage may, in fact, more closely parallel a patient's early symptoms than the often lesser damage to myelin.) Yet the immune onslaught does not directly target these cortical neurons, hinting that they may be victims of an early, independent degeneration process.

Although no neuroprotective drugs have been approved for MS, some of the immune-altering medications used to treat the disease—particularly BG-12—are thought to protect neurons, which may explain some of their positive effects. Researchers are also investigating whether other, approved drugs with neuroprotective effects may be useful in MS. These agents include the anemia drug erythropoietin, the hormones estrogen and testosterone, and the antiseizure drug lamotrigine. Yet another approach is to transplant stem cells that can stimulate the restoration of damaged tissue. Doctors have used these cells, called mesenchymal stem cells, to try to mend damaged hearts. They are thought to work by releasing chemicals that stimulate cellular repair systems.

Until such treatments are ready, the goal is mainly to keep patients from getting worse by taming the immune system. The latest medicines seem to make a significant difference. By taking fingolimod, Alston has been able to keep her symptoms at bay—and live the life she always wanted. She is married with two children, Langdon and Katie, and works full-time at an e-commerce company. How fast her disease will progress remains to be seen. But advances in our understanding of the biology of MS hold out the promise that we will soon have remedies that can roll back the disease and perhaps, one day, cure it.