Necessary, but insufficient

I keep getting pushback from people, including many colleagues, when I claim that the Epstein-Barr virus (EBV) is the cause of MS. This claim is based on a large body of epidemiological studies over the last 20 years and on applying causation theory. The most important observation supporting my claim is that people who are EBV-seronegative are protected from getting MS. In other words, EBV is necessary to get MS, but is clearly insufficient as not all people who are infected with EBV develop MS, i.e. other factors must contribute to causing MS in addition to EBV.The phrase “necessary but insufficient” describes a condition or factor that must be present for a specific outcome to happen, but cannot make that outcome happen on its own. Think of it as a “required ingredient” rather than a “guarantee.”The Breakdown* Necessary: You absolutely cannot develop MS without EBV. If EBV is missing, MS is impossible.* Insufficient: Having EBV alone does not guarantee you will get MS. Other factors are then required for someone to develop MS.Other examples1. Oxygen and Fire* Necessary: Oxygen is required for a fire to burn. You cannot have fire without it.* Insufficient: Just having oxygen isn’t enough to start a fire. You also need fuel and heat.* Therefore, oxygen is necessary but insufficient for fire.2. A Lottery Ticket* Necessary: You cannot win the lottery if you don’t buy a ticket.* Insufficient: Buying a ticket doesn’t guarantee you will win. You also need luck (the right numbers).3. In a Medical Context (Revalidation)* Necessary: Attending your annual appraisal is necessary to keep your license to practice.* Insufficient: Merely showing up is insufficient to successfully complete your appraisal. You must also demonstrate quality improvement, gather feedback, and show you are up to date.A Simple FormulaFactor A + [Other Factors] = Success* Factor A is “necessary but insufficient.”* If you remove Factor A, the equation fails.* If you only have Factor A, the equation is incomplete.Why is this distinction important?In logic and critical thinking, confusing these two helps avoid errors in judgment. For example, a politician might argue, “We increased police funding, so crime will drop.”A critic might reply: “Funding is necessary for a good police force, but insufficient to solve crime on its own—you also need social programs and economic stability.”EBV-negative MSThe counter-argument a lot of people make is that they have MS, but are EBV-negative. I counter this by saying that they may not be EBV-negative. All assays have false-negative and false-positive rates. To illustrate this in an International Clinically Isolated Syndrome (CIS) study, we found that 41 (3.9%) of 1,047 subjects with CIS were EBV-negative using screening serology. When we tested them with more sensitive assays, only one remained EBV-negative.EBV (true-positive) + [Other Factors] = multiple sclerosisThe other issue is whether we are sure the person who is EBV-negative (true negative) has MS or another disease. We know that at least 1 in 20 people diagnosed with MS in life turn out to have another disease. This is why I think EBV-seronegativity is an important clinical flag and should make one reconsider the diagnosis of MS.I am firmly in the camp that EBV-seronegative MS is likely not to exist, i.e. if you are truly EBV-negative, then you have another disease. Please be aware that the McDonald criteria for diagnosing MS completely ignore this, and there is no mention of EBV serology as a diagnostic aid in helping make the diagnosis of MS or in not making a diagnosis of MS.The futureGetting naysayers to understand and accept “EBV is necessary, but insufficient to develop MS” is important, as they often review and reject grant applications. And this statement underpins using an EBV vaccine to prevent MS. My domino model of MS attempts to illustrate this. Is it clear enough, or do I need to simplify it to illustrate the point? Do any of you have any suggestions to make it easier to grasp?If you are interested in learning more, you can watch my lecture on EBV and MS, which I recently gave at the Nobel Symposium in Stockholm.I would be interested in hearing your thoughts on the concepts in this newsletter. Do you agree with me, or not? If you don’t, can you let me know why?Paper of interestDobson R, Kuhle J, Middeldorp J, Giovannoni G. Epstein-Barr-negative MS: a true phenomenon? Neurol Neuroimmunol Neuroinflamm. 2017 Feb 3;4(2):e318. doi: 10.1212/NXI.0000000000000318.Accidental readersIf you have been forwarded this email and are not an MS-Selfie subscriber, please consider subscribing and helping MS-Selfie expand its resources for the broader MS community. MS-Selfie relies on subscriptions to fund its curated MS-Selfie microsite, MS-Selfie books, MS-Selfie Infocards, and other activities that extend beyond the MS-Selfie Substack newsletters.Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite and other related activities, as I don’t have time to do this myself. You must be a paying subscriber to ask questions unrelated to the newsletters or podcasts. 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