Expert Voices: What Causes Multiple Sclerosis?
No one cause known, but Epstein-Barr virus likely to play role, neurologist says
In this installment of our “Expert Voices” series, Multiple Sclerosis News Today asked Brandon Beaber, MD, to answer some of your questions about research into the causes of multiple sclerosis (MS).
Beaber is a board-certified neurologist and MS specialist. He makes videos about MS on YouTube and posts about MS research on Twitter @Brandon_Beaber. He has written a book called “Resilience in the Face of Multiple Sclerosis,” which is available on Amazon. It’s about five people with MS who live incredible lives, the science and psychology of resilience, mindfulness, and ho’oponopono. He lives with his wife and two children in Los Angeles.
Why is it so difficult to find the cause of MS?
Likely because there is no single cause. While some diseases have a straightforward cause, such as mesothelioma (asbestos exposure) or scurvy (vitamin C deficiency), most conditions are complex and multifactorial. We may never know exactly why one person gets appendicitis or diabetes while another doesn’t. The closest thing to a “cause” of MS would be the Epstein-Barr virus, the virus which causes mononucleosis (aka, glandular fever). In reality, MS is probably the end result of numerous genetic and environmental factors working in concert to produce a “perfect storm.” Here are some well-documented risk factors for MS that likely contribute to an aberrant, “confused” immune system:
- family history of MS
- the human leukocyte antigen (HLA) DRB1*1501 gene
- low vitamin D levels
- low sunlight exposure
- low parasite exposure
- living in a region with high MS prevalence prior to age 15 (and presumably, the associated “Western” diet)
- living far from the equator
- childhood obesity
- mononucleosis history
- high antibody levels against the Epstein-Barr virus (EBV)
- born in the month of May
When one outside the research community wonders about “the cause(s) of MS,” what misconceptions likely leap to mind?
Again, the intuitive but likely erroneous idea of a single cause. For decades, we have touted hypotheses: nitrates from smoked/cured meats, candida overgrowth, vertebral artery stenosis, saturated fat, and abnormal veins. Indeed, some of these could be valid. There is an epidemiological link between saturated fat and MS, and candida overgrowth may trigger gut dysbiosis, but none of these ideas are proven as the sole cause of MS.
Many in the MS community eye Epstein-Barr virus as the culprit behind MS. What do you think?
This is legit! EBV is transmitted by saliva and causes a respiratory infection. It is usually acquired in children, adolescents, and young adults and can be asymptomatic or cause symptoms such as swollen tonsils or fatigue.
We have known the link between EBV and MS for 50-plus years. Many studies have shown nearly 100% of adults with MS have antibodies against EBV, indicating prior exposure (compared to the roughly 95% of adults without MS). People with a history of clinical mononucleosis, which can be caused by EBV, have double the risk of MS. Those with higher antibodies against EBV have a greater risk of MS.
We know EBV can infect memory B-cells and “immortalize” them, making them immune to T-cell regulation. There are also reports of autopsies on people with MS showing EBV-infected B-cells within the brain.
But the astute reader may retort, “Maybe the link to EBV is due to confounding [factors]. Perhaps the abnormal immune system in people with MS leads to EBV, not the other way around.”
A 2022 publication from Harvard says otherwise. Dr. Alberto Ascherio and his colleagues studied more than 10 million adults in the U.S. military, and they found the risk of MS increases only after EBV exposure.
They also looked at neurofilament light chain (sNfL), a blood marker indicating damage to the central nervous system, which can be elevated up to six years prior to MS symptom onset. In people eventually diagnosed with MS, it was elevated only after EBV exposure. This strongly supports the idea that EBV almost always occurs prior to MS.
Do you have any insights into the role of lacking vitamin D or sunlight exposure as a potential trigger of MS?
In a world with clothing and ceilings which block the sun, vitamin D deficiency is nearly universal, and an association between low vitamin D and MS is well-known. We have linked low vitamin D to greater risk of MS, more new MRI lesions, and more MS relapses. In identical twins where one has MS and the other doesn’t, the twin with MS has lower vitamin D on average. We know that vitamin D reduces autoreactive T-cells, and the gene most associated with MS (HLA DRB1*1501) is modulated by vitamin D.
However, the benefit of taking vitamin D supplements is less clear. One meta-analysis of five randomized trials showed no clear benefit over placebo. A possible explanation for this is it may be ultraviolet radiation exposure (which naturally stimulates vitamin D production in the skin), which is protective against MS.
In a famous publication called the MS Sunshine Study, my former fellowship mentor, Dr. Annette Langer-Gould, was able to demonstrate that in African Americans and Hispanics, vitamin D levels are not linked to MS, but low lifetime sun exposure is.
Nonetheless, I recommend vitamin D supplementation to people with MS because it may be beneficial, and the safety profile is excellent.
How about regarding the geographic components of MS, such as why we see higher rates of MS in developed countries?
Perhaps the strongest evidence for an environmental cause is the incredible variability in prevalence. In Cuenca, Ecuador, the risk of MS is only 1 in 25,006, while in Syracuse, New York, it is 1 in 2,227! Also, MS appears to be rapidly rising in countries like Iran, Mexico, and India, where it was previously uncommon.
EBV exists throughout the globe and causes other human diseases, such as Burkitt’s lymphoma, in regions where MS is rare. Hence, I strongly suspect something about modern society is predisposing us to MS. Could it be diet, hygiene, sunlight deprivation, stress, or some combination of these factors? Your guess is as good as mine.
Has the existence of young-onset MS thrown a wrench in, or guided, theories about the causes of MS?
I don’t think so. MS prior to puberty is and always has been rare. Migration studies have found that even though the average age of diagnosis is 30, the risk of MS is determined early. For instance, people who move from a low-prevalence region to a high-prevalence region after the teenage years retain a low risk of MS.
Studies show that by age 6, over half the population is infected with EBV. One study did surprisingly show an EBV-infection rate of “only” 86% of children with MS, though this is an unusual, isolated finding, and there are technicalities regarding antibody measurement.
In theory, pediatric MS is a boon for research because we are seeing MS early, close to the “biological onset” of the disease. Some studies have shown a modest link between childhood obesity and MS, and others have exonerated common viruses aside from EBV, but there is no single smoking gun.
Has any recent research into the cause of MS surprised or fascinated you?
The single most surprising fact about MS was published in 2000, though I did not know it until 2013. (To my credit, in 2000, I was still in high school.) It comes from the laboratory of the legendary neuropathologist Bruce Trapp, who studies brain autopsies on people with MS.
He found that even in people with advanced progressive MS, the cells that are capable of remyelination, oligodendrocyte precursor cells (OPCs), are present within chronic lesions. They just don’t remyelinate. Hence, though MS is initiated by inflammation, its progression may be driven by remyelination failure and degeneration. In fact, his later research suggests white matter lesions and degeneration don’t correlate strongly.
We know the development of immune-modulating therapies has improved prognosis and quality of life, but they leave something to be desired. I believe Trapp has revealed the missing link, and modern scientists look for ways to “trick” OPCs to differentiate into mature oligodendrocytes that form new myelin. Some early drug candidates like opicinumab have failed, and others like clemastine have ongoing trials.
I can’t predict the future, but it’s likely our generation will see a proven remyelinating therapy for MS.
Expert Voices is a monthly series involving a Q&A with an expert in the MS space about a specific topic. These topics and questions are curated from a survey in which we ask readers what they want to learn more about from experts. If you’d like to submit topics or questions for consideration in a future installment of the series, click here to take the survey.
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