A Multifaceted Look at Multiple Sclerosis

At a Glance

  • More than 400,000 individuals in the United States and some 2.5 million around the world have been diagnosed with multiple sclerosis (MS)
  • 40 to 70 percent of patients with MS are cognitively impaired
  • Despite significant progress in treatment breakthroughs and research discoveries, the cause and cure for MS remain elusive

“Our efforts at Weill Cornell are focused on what we believe to be the two most important, unaddressed questions in MS: How does the disease start and why do patients progress?”

— Dr. Timothy Vartanian

“When people ask me about the symptoms of multiple sclerosis (MS), it is a bit of a loaded question,” says Claire S. Riley, MD, director of the Columbia Multiple Sclerosis Clinical and Research Center (CMSC) at NewYork-Presbyterian/Columbia University Medical Center.

Along with Timothy Vartanian, MD, Ph.D. at NewYork-Presbyterian/Weill Cornell Medical Center Judith Jaffe Multiple Sclerosis Clinical and Research Center (JJMSC), Dr. Riley leads a team of specialists that treat the physical, cognitive, emotional, and rehabilitative needs of patients living with MS. The centers provide adult and pediatric patients and their families with a full range of diagnostic, treatment, and research efforts.

“Every function of the nervous system requires myelin, so any of its manifold functions can be disrupted by the disease. The most common form—relapsing-remitting MS—is characterized by symptoms of neurologic dysfunction that evolve over a few hours or days, hang around for a few weeks, and tend to improve spontaneously,” Dr. Riley adds. “That improvement can be hastened with treatment that usually involves corticosteroids to help reduce inflammation.”

MRI of Brain

MRI of normal brain (left) and one of an individual with longstanding MS, which shows multiple hyperintense (yellow) lesions in the periventricular white matter, characteristic of demyelinating lesions.

Until recently there had not been any successful studies showing effective treatment for patients with progressive MS. However, last fall a large clinical trial, ORATORIO, showed patients benefit with ocrelizumab, a monoclonal antibody directed against a B-cell marker. A related drug, rituximab, is used to treat B-cell cancers—including leukemia and lymphomas.

If approved by the FDA, ocrelizumab will be the first treatment for slowing down disease progression that we’ve ever had for primary progressive MS. That would be really exciting,” she says.

As part of NeuroNEXT, NewYork-Presbyterian is participating in a clinical trial of ibudilast, a phosphodiesterase inhibitor for the treatment of primary and secondary progressive MS. “This experimental drug is given to people with primary and secondary progressive forms of the disease in which there’s no established or proven immunotherapy for slowing it down,” says Dr. Riley.

The Challenge of Cognitive Impairment

Studies have shown that 40 to 70 percent of patients with MS are cognitively impaired.

“That means approximately half of the people with MS will at some point during their disease course encounter cognitive issues,” says Victoria M. Leavitt, Ph.D., a clinical neuropsychologist, and researcher with the Columbia Multiple Sclerosis Center. “For many people, this occurs very early in the disease course and can happen even before physical disability becomes apparent.”

“Cognitive issues can be very isolating and very personal for individuals with MS because they aren’t as obvious as the physical symptoms,” says Dr. Leavitt. “If you wake up in the morning and your left leg doesn’t work, it’s clear you are unable to go to work. But if you wake up and your memory is a little off, or your ability to multitask is a little less sharp, and you feel it and know it, that’s a more challenging struggle.”

Cognitive impairment has only been recognized as a key symptom of MS for the last 25 years. “Now that we have years of research supporting the existence of cognitive impairment, it is very validating for people,” Dr. Leavitt says. “By evaluating patients’ cognition early on, we have a baseline that is essential for the future determination of the presence of cognitive decline.”

Dr. Leavitt’s clinical work informs her research. Her goal is to understand the neural basis of cognitive impairment in MS in ways that can help target neural structures for behavioral treatment and pharmacological interventions. “We know that patients with MS have a varying load of lesions and atrophy in their brain, but the amount of lesions and atrophy corresponds weakly to the degree of cognitive impairment exhibited,” continues Dr. Leavitt.

“Using the brain in a flexible manner and encouraging neural flexibility are important as well,” notes Dr. Leavitt. “I tell patients to think about their brain as a collection of roads and highways. If one of the main highways is shut down and you have the ability to flexibly change pathways, then you’ll do better. We believe that over a lifetime of intellectually stimulating activities, using the brain in ways to encourage that neural flexibility is the actual key.”

Leading Breakthrough Research

Dr. Vartanian’s laboratory at the Brain and Mind Research Institute at Weill Cornell Medicine has made groundbreaking discoveries in central nervous system remyelination, novel mechanisms of axonal degeneration and regeneration, and mechanisms of immune-mediated injury to myelin and axons in multiple sclerosis. The lab’s research interests center on the regeneration of the myelin internode in multiple sclerosis, preventing axonal and neuronal injury, and defining the complicated interactions between the immune and nervous systems.

“There are several aspects of MS that we simply don’t quite understand yet,” says Dr. Vartanian, a leading authority on neural regeneration. “We have the most knowledge about the role of the peripheral immune system in the relapsing phase of the illness. We understand it enough that very specific drugs have been designed that limit relapses. The problem is that limiting relapses doesn’t cure the disease. While the very potent medications used currently can dramatically reduce relapses as well as the appearance of active contrast-enhancing lesions on MRI, disability continues to accumulate. Our efforts at Weill Cornell are focused on what we believe to be the two most important, unaddressed questions in MS: How does the disease start and why do patients progress?"

I would postulate that the disease begins when the first MS lesion forms in the patient. I would further say that the mechanism by which that first lesion forms is exactly the same as the way all truly new lesions form.”

Examining the risk factors for MS, Dr. Vartanian points to studies of identical twins. “If one identical twin has MS, about 20 percent of the time the other twin will have MS, meaning that the disease is 20 percent genetic,” he says. “It also means that about 80 percent can be attributed to environmental factors. Is the environment simply contributory to making the disease worse, or is an environmental agent required for MS lesions to form, that is, for MS to occur in the first place?”

According to Dr. Vartanian, the best data to address that question comes from MS clusters. To date over 100 MS clusters have been reported in places that include the Faroe Islands located halfway between Norway and Iceland. Such studies continue to be of interest because they have the potential to offer clues concerning environmental and genetic factors that may play a role in causing or triggering MS.

“Not only is environment important and contributory, but environment is necessary for the disease to occur,” says Dr. Vartanian. “One can have a genetic background – that 20 percent risk factor – but you need this environmental trigger. Remembering that all new lesions – truly new lesions – are the same, then whatever the environment is doing must be playing some role in new lesion formation. So, then we have to ask the question, what do we know about new lesion formation?”

The answer is very little, says Dr. Vartanian. “MS is a chronic illness, but people rarely die from it. Therefore, the pathology that we are able to study when a person has donated their brain to science might be months, years, or decades old. The problem is that as time goes on, macrophages clear up that tissue, which is all part of the evolution of the lesion.”

In other research Dr. Vartanian and his team are investigating failure of remyelination, which is largely responsible for sustained neurologic symptoms in MS. They have identified possible approaches to improving remyelination by blocking hyaluronan deposits thatinhibit oligodendrocyte precursor cell (OPC) maturation, although the mechanism behind this inhibition is unclear.

“Inhibitors of Toll-like receptor 2 and its signaling pathway have been shown to be effective in blocking hyaluronan inhibitory effects, resulting in enhanced OPC maturation in vitro,” says Dr. Vartanian.

“Approaches like these will be of great importance in developing treatments for impaired remyelination in MS.” As evidence for this, recent research conducted by Yinghua Ma, PhD, in the Vartanian lab has identified a drug that potently induces remyelination in mouse CNS tissue. In a highly collaborative effort among Drs. Gauthier, Vartanian, and Ma, the research team is planning their first study to promote remyelination in people with MS.

“Because the drugs we are testing already have FDA approval for another disease, we can skip Phase I safety studies and move directly into Phase II or proof-of-concept studies, significantly lessening the time from drug discovery to impact on patients. At the Weill Cornell MS Center, there is definitely the atmosphere of moving as quickly as possible from bench to bedside.”

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