example, if someone is very obese, a research case definition might exclude that person because the weight issue could be causing the person’s problems. In other words, for research purposes, we want to select only patients who do not have other psychological or medical conditions that could be causing the illness we are studying. For science to progress, the research case definition is critical, as it can standardize the selection of patient samples so that research groups around the world are all studying the patients with the same disease. So gaining consensus among international scientists for a research case definition is a most critical task, and one that unfortunately has still not been accomplished for our field. One of the parameters that’s important for a research case definition for this illness, in your view, is that psychiatric co-morbidities should be excluded. Can you explain the reason for that? Yes, and let me give an example that illustrates this issue. A patient with a major depressive disorder with melancholic features would probably have fatigue, aches and pains, as well as sleep and cognitive problems. Yet these are also symptoms of ME, so some clinicians and researchers could easily confuse these two conditions. But they are very different illnesses, as people with a major depressive disorder feel selfreproach, whereas those with ME do not. If you ask people with a major depressive disorder what they would do tomorrow if they were well, they would not be sure. In contrast, if you asked people with ME what they would do if they were well, they’d give you a long list of all the things they have wanted to do but been unable due to their illness. If you are studying ME, you need to exclude people who have a primary psychiatric disorder from your study. If researchers misclassify people with a major depressive disorder as having ME, this will have serious negative consequences for identifying biomarkers, estimating prevalence rates, and determining outcomes of treatment trials. The issue of selecting patients who really have ME is the most important issue facing our field. In a sense, the lack of a consensus on a ME research case definition is like building a pyramid of playing cards with a very shaky bottom, and then everything built on top of this foundation is vulnerable to collapsing. Let’s start with what is the broadest case definition that has been used, the so-called Oxford criteria for Invest in ME research (Charity Nr. 1153730) CFS. Can you describe that and explain why it presents a problem? If you have six or more months of fatigue, then you meet this case definition, so it’s a very broad category. Clearly, as I mentioned earlier, a lot of people who meet this criteria have medical or lifestyle reasons causing their fatigue. One of my students, Madison Sunnquist, just published her master’s thesis that indicated how the CBT theoretical model only works if you identify people with a very wide case definition, but when you have a better and more restricted case definition that requires core symptoms of ME, then the CBT model no longer works. In contrast to the CBT approach, my research group for the past 20 years has been doing research on what we call the energy envelope. But this pacing approach is not a cure, just a strategy to help better cope with ME. Our approach involves helping patients to better monitor their energy levels, learn how to stay within their energy envelope, and sustain lifestyle changes that involve reprioritizing activities. So how did the CDC come up with the Holmes and then the Fukuda case definitions? The Holmes case definition came out in 1988. The CDC investigators had gone to Incline Village and ultimately named this illness CFS. Their first case definition included too many symptoms. In fact, to meet their case definition, a patient would have needed to have eight or more symptoms out of a list of 11. But here is the problem that soon emerged–if you develop a case definition that requires so many unexplained somatic symptoms, you have a very high probability of unwittingly selecting people who have a somatoform disorder. And you don’t want to select people who have a purely psychiatric condition. So in 1994, the Fukuda case definition was developed to replace the Holmes definition. For the 1994 case definition, the authors selected eight of the symptoms that had been listed in the Holmes criteria, and a patient needed to have any four of those eight symptoms to meet the new Fukuda case definition. But here is the problem with the Fukuda CFS case definition–patients are not required to have postexertional malaise, cognitive problems and unrefreshing sleep, and as we know, these are core symptoms of ME. So, a person could have four of the eight Fukuda symptoms and be diagnosed with CFS, and not have any of the three critical symptoms. In that case, you would be including in your sample a person who does not have the core elements of the illness. www.investinme.org Page 41 of 56
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