Ryan Grant was in his 20s and serving in the military when he learned that the numbness and tingling in his hands and feet, as well as his unshakeable fatigue, were symptoms of multiple sclerosis. Like nearly a million other people with MS in the United States, Grant had been feeling his immune system attack his central nervous system. The insulation around his nerves was crumbling, weakening the signals between his brain and body.
The disease can have a wide range of symptoms and outcomes. Now 43, Grant has lost the ability to walk, and he has moved into a veterans’ home in Oregon, so that his wife and children don’t have to be his caretakers. He’s all too familiar with the course of the illness and can name risk factors he did and didn’t share with other MS patients, three-quarters of whom are female. But until recently, he hadn’t heard that many scientists now believe the most important factor behind MS is a virus.
For decades, researchers suspected that Epstein-Barr virus, a common childhood infection, is linked to multiple sclerosis. In January, the journal Science pushed that connection into headlines when it published the results of a two-decade study of people who, like Grant, have served in the military. The study’s researchers concluded that EBV infection is “the leading cause” of MS.
Bruce Bebo, executive vice president of research at the nonprofit National Multiple Sclerosis Society, which helped fund the study, said he believes the findings fall just short of proving causation. They do, however, provide “probably the strongest evidence to date of that link between EBV and MS,” he said.
Epstein-Barr virus has infected about 95 percent of adults. Yet only a tiny fraction of them will develop multiple sclerosis. Other factors are also known to affect a person’s MS risk, including genetics, low vitamin D, smoking, and childhood obesity. If this virus that infects nearly everyone on Earth causes multiple sclerosis, it does so in concert with other actors in a choreography that scientists don’t yet understand.
Amid that lingering uncertainty, scientists are discussing how to proceed from here. Antivirals or drugs that target infected cells, some of which are already in development, might help MS patients. Vaccines against EBV are in development, too. The authors of the Science paper say widespread vaccination could prevent most instances of MS. But other researchers aren’t so sure the case is closed, and they suggest putting more emphasis on understanding how the virus might interact with social factors such as stress.
“Patients often want to know why this disease happened to them,” said Lindsey Wooliscroft, a neurologist and associate director of research for the VA’s Multiple Sclerosis Center of Excellence in Portland, Oregon. “It’s frustrating when I can’t tell them.”
Epstein-Barr most often strikes in early childhood, with few or no noticeable symptoms. After the initial infection, the virus lurks inside certain immune cells for the rest of a person’s life.
If someone avoids EBV until adolescence or adulthood, the virus is more likely to cause mononucleosis, an illness characterized by fever and fatigue. Mono is more common in Western countries, where kids encounter fewer germs early in life, said Alberto Ascherio, a professor of epidemiology and nutrition at the Harvard T. H. Chan School of Public Health and senior author of the Science paper.
Like mono, multiple sclerosis is most prevalent in the U.S. and parts of Europe. Scientists first suggested more than four decades ago that the two conditions might be linked. In the following years, the evidence piled up: Nearly everyone with multiple sclerosis has latent EBV in their cells. People who recall being sick with mono have a heightened risk of MS. Immune cells harboring the virus are more prevalent in the brains of MS patients.
“We’ve long suspected that Epstein-Barr virus had a role” in the development of MS, Wooliscroft said. “But it’s just been very hard to prove.”
The surest way to prove causation would be to start with a group of healthy, uninfected adults and divide them at random into two groups. Researchers would infect just one group with the virus and then monitor both groups afterward to see who develops MS.
In the real world, such an experiment isn’t ethical. Ascherio and his coauthors wanted to do the closest possible thing: find a group of people who hadn’t yet been infected with EBV at a given time point, then see whether those who eventually did get infected were more likely to develop MS. “Conceptually, our study is very simple,” Ascherio said. “In practice, it seemed virtually impossible to conduct.”
That’s because the scientists would need a large number of study participants to monitor over the course of years, as MS can be slow to develop and diagnose. For help, the research team turned to the US military, which collects regular blood samples from active service members for HIV screening. In the end, it took two decades for the team to accrue enough data to perform its statistical analysis.
