Multiple Sclerosis – The Search Narrows

Multiple sclerosis (MS) is a serious autoimmune disease that affects about 3 million people worldwide and over 900,000 in the United States. The disease symptoms are quite varied but typically begin between the ages of 20-40. Symptoms can include vision problems, impaired hearing, decreased taste and smell, headaches, weakness and fatigue, muscle tremors or pain, incontinence, and difficulty swallowing. Neurological issues are also common and include short-term memory loss, depression, and personality changes. The basis for all the symptoms is an immune attack on a fatty substance called myelin. Myelin forms an insulating sheath around the nerve fibers in our body much like the rubber coating on electrical cords and wires. The nerve fibers carry signals to and from the brain to enable our senses, movements, and brain functions. When the immune system attacks and destroys myelin it impairs the function of the affected nerve fibers. The location and extent of the nerve damage determine what type of symptoms occur and how severe they will be, so patients can present with a wide range of problems. Most MS patients will have relapsing-remitting disease symptoms. Symptoms will develop rapidly and then persist or improve slowly for a remission period of months to years before a relapse with new or worsening symptoms. While there is no cure for MS, there are numerous medications that can help control and manage the disease.

One of the mysterious and frustrating aspects of MS is the lack of a clear cause for this disease. Genetics appears to contribute to some cases as a family history of MS increases the risk for other family members, but many cases are sporadic with no known familial association. There are also environmental factors that increase the risk for MS including vitamin D deficiency, smoking, obesity, and even geographic location (case numbers increase in areas farther from the equator). Lastly, viral infection has been proposed as a triggering factor in MS development, and several viruses have been examined, including measles virus, canine distemper virus, human herpes virus-6, herpes varicella-zoster virus (VZV), and Epstein-Barr virus (EBV). Of these viruses, EBV has been the most tantalizing as numerous studies have suggested a link between EBV infection and subsequent development of MS.

EBV (also known as human herpesvirus-4) is a member of the herpes virus family and is most commonly known as the cause of infectious mononucleosis (IM). During an active infection, the virus is present in bodily secretions, particularly saliva. Transmission usually occurs by saliva contamination (e.g. sharing food or drink with an infected individual) or more directly through kissing (IM is often called the “kissing disease” because it is frequently seen in teenagers and young adults as dating begins). When IM occurs the patient can present with fever, fatigue, rash, sore throat, and/or swollen lymph nodes in the armpits and neck, and symptoms take 4-6 weeks to resolve. While the illness has a long duration and the fatigue can be debilitating, virtually all patients recover completely with no lingering after-effects. Surprisingly though only about 20-25% of infected individuals actually develop clinical IM with the rest having asymptomatic or very mild, nondescript infections. Because of the prevalence of asymptomatic infections, the virus often spreads unknowingly among families and schools. The result is that 90-95% of adults have been infected even though most people are unaware that they have contracted this virus. Importantly, like all herpes viruses, EBV establishes permanent, life-long infections even in asymptomatic individuals. For EBV, the target cells that it infects and persists in are the B lymphocytes, the blood cells that produce antibodies.

Because EBV infections are so widespread it has been difficult to establish the nature of its relationship to MS; most MS patients have been infected with EBV, but so have most people without MS. Also, just testing MS patients for evidence of EBV infection doesn’t give any indication of when they encountered the virus. Possibly the disease process that initiated MS started first and the EBV infection happened afterwards. To sort this out requires a large longitudinal study where people without either MS or EBV infection are followed for years to see who contracts EBV and who develops MS. A paper published in the journal Science provides the first such analysis and finds strong evidence of an EBV-MS link. The investigators of the study used a database of 10 million American military personnel who generally had yearly blood samples taken from 1993-2013. In this group, they found 955 individuals who developed MS, and 801 of these soldiers had adequate blood samples for analysis. Out of the 801 MS patients, only 35 were EBV negative at the time of the first blood draw, and these were the individuals analyzed. Of these 35 soldiers, 34 became EBV positive (97%) and then developed MS within an average of 5 years post-infection. In a randomly selected, matched control group of 107 non-MS soldiers, only 57% became EBV positive during the same time period. Statistically, this difference in infection rates translates to EBV increasing the risk for MS by 32-fold. As a further control, the MS and non-MS cohorts were examined for cytomegalovirus (CMV) infection. CMV is another herpes virus that is also transmitted via saliva and has a population prevalence similar to EBV. Acquisition of CMV infection did not enhance the risk for the development of MS and instead had a slightly protective effect as seen in other studies. These results indicate that MS risk is specific to EBV and is not due to a herpes virus infection in general.

The authors also examined a serum marker for neural degeneration called neurofilament light chain (sNfL). While not specific for MS, this marker can be found in the blood up to 6 years before an MS diagnosis and may reflect the very early stages of the disease process. The 35 EBV-negative individuals who went on to develop MS had normal levels of sNfL initially followed by a significant increase after EBV infection. In contrast, the control group had initial levels of sNfL similar to the pre-EBV MS group but showed no increase in sNfL after EBV infection. These findings support the conclusion that EBV infection in some individuals triggers a response that initiates neural damage that can proceed to clinical MS years after the infection.

Overall, this new study adds strong evidence for the role of EBV in most if not all cases of MS. Lacking still is the underlying mechanism by which EBV infection can trigger MS. It has been speculated that maybe for some people, the immune response to certain EBV proteins causes a cross-reaction against myelin. While certainly possible, the specific role of EBV in MS and the interplay of EBV with other risk factors still needs further study. On a positive note, if EBV is the dominant risk factor, then preventing EBV infections would greatly reduce if not eliminate MS. Several EBV vaccines are in development, including an RNA-based vaccine from Moderna. Maybe someday vaccines will make EBV infection a rarity along with both IM and MS.

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