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 examples
1. 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 Formula
Factor 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 MS
The 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 sclerosis
The 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 future
Getting 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 interest
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General Disclaimer
Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have any problems, please tell your healthcare professional, who can help you.
