In addition, in our fast-paced technological society some people are overworked and overstressed. And this could be a reason they feel six or more months of fatigue. So this is this group here (top circle). This group is overworked, over-stressed could certainly be causing this fatigue. It could be explaining this proportion of fatigue (overlap of top circle and red circle). Yet these people who are over-stressed and overworked, if they took a vacation and rested they would no longer feel fatigued. It’s easy to see that there are many reasons for a person feeling chronically fatigued and yet here is where the diagnostic confusion occurs. These individuals do not have ME/CFS, and if we inappropriately bring these individuals into our case definition, our studies of etiology and pathophysiology will be based on mixtures of samples in which some have ME/CFS and some have different illnesses or conditions. So we’re going to go through this point again and again in this presentation because it is such an important one.
On this slide you see the international case definition. The eight core symptoms are on the slide. [sic] In 1988, investigators at the CDC took an illness that had been called myalgic encephamyelitis by Ramsay and others in Great Britain and renamed it chronic fatigue syndrome. Now in 1994, a major revision occurred and this is called the Fukuda criteria because Fukuda was the first author of the paper describing the revised criteria. So we’re going to be talking primarily in this presentation about these particular criteria, so we’ll call them the Fukuda and other 1994 criteria. And as you can see, to meet the case definition a person would need to have six or more months of chronic fatigue and four out of eight core symptoms.
These eight core symptoms are actually on this slide. But here is the conceptual problem: we know that three of the critical symptoms of ME/CFS are unrefreshing sleep, post-exertional malaise lasting more than 24 hours, and persistent or recurring impairment in short term memory or concentration, and these in red are the critical symptoms. But these three symptoms are not required of everybody. In other words, if we have core fundamental symptoms that patients with CFS almost always have, but with the Fukuda criteria, a person could have none of these symptoms and still meet the case definition. Hard to believe, but that’s the case. Let me give a concrete example of what this could do for investigators. Say there’s two studies going on in different parts of the country and one investigator selected patients who had these three core symptoms: unrefreshing sleep, post-exertional malaise, and impairment in short term memory or concentration. So one group had these three symptoms plus headaches, so they met criteria; they had four symptoms. And the other investigator selected patients who only had these symptoms up here (points to first five bullet points) and none of the core symptoms. These two laboratories would have an individual who met the criteria for CFS but they’re very different. It’s like comparing apples and oranges and ultimately, replicating the findings from one lab to the other would be close to impossible if the basic symptoms of these two groups differed that prominently.
Here we have some fancy terms: “polythetic criteria.” What it means is that scientists who developed the Fukuda case definition in 1994 allowed researchers and clinicians to select four out of eight symptoms That’s what polythetic means. So you have a choice of four out of eight, rather than saying you have to have these core symptoms. So if you have a choice, that’s the way the Fukuda criteria was developed but they could have done it differently. They could have said these are basic symptoms. They could have said that a critical symptom is, for example, post-exertional malaise and they would say that you have to have it. But they didn’t say that. Is it not possible that it would be more methodologically sound to require such symptoms in the identification of patients? We’ll come back to this issue.
Let’s give another example of the types of problems that the current case definition might encounter. One of the more prevalent psychiatric conditions is Major Depressive Disorder. And many people with this psychiatric condition have chronic fatigue and four Fukuda symptoms such as unrefreshing sleep, joint pain, muscle pain, and impairment in concentration. But Major Depressive Disorder and ME/CFS are two distinct disorders. Let me just emphasize, they can be overlapped - some people with ME/CFS might certainly have a Major Depressive Disorder - but there is pure Major Depressive Disorder and there is ME/CFS which does not have major depressive disorder. And most people with ME/CFS have, for example, the types of physical exertion, night sweats, sore throats, swollen lymph nodes. People with Major Depressive Disorder do not have those. Illness onset with ME/CFS often occurs over a few days or even a few hours. With primary depression generally it’s a gradual onset. So the question is whether some research groups studying ME/CFS have mistakenly brought into their samples patients who have a primary psychiatric disorder and not ME/CFS. If these investigators thought there was no difference between psychiatric disorders and ME/CFS, they would not see this as a problem. However, these are distinct illnesses. If you asked a person who has Major Depressive Disorder what would they do tomorrow if they were well, they would probably not know. They would not know what it is they want to do. That’s part of the illness. In contrast, if a person who had ME/CFS was asked the same question, they’d probably start giving you a list of activities they’ve wanted to do but have been prevented from. You can see these are two classic different illnesses. Combining them together is a major conceptual methodological problem.
In this diagram, you can see that those with chronic fatigue (that means six or more months of fatigue) are only a small proportion of the people who have ME/CFS. There’s only a small proportion of this group here (circling ME/CFS) within a larger group (chronic fatigue circle) with chronic fatigue. Many people with major depression also have chronic fatigue (overlap between depression and chronic fatigue circle) this group right here. But if slippage due to the case definition allows investigators to bring into the ME/CFS category all those with depression and chronic fatigue, then these investigators will be studying mostly depression rather than ME/CFS.
In a study I conducted with Caroline King a number of years ago we selected two groups of patients: those with depressive disorder and those with ME/CFS. In that study, we were able to differentiate these two groups with 100% accuracy using the variables that are on this slide. And these were the variables: percent of time fatigue was reported; post-exertional malaise severity; unrefreshing sleep severity; confusion or disorientation severity; shortness of breath; and severity of self-reproach. You can see here (circling symptom list) we are talking about severity not just occurrence. That’s a very important issue we’ll talk about later. So we were able to differentiate these two groups. And the differentiating variable shortness of breath, for example, is not even found on the Fukuda criteria. Patients with depressive disorder have high levels of self-reproach, lots of negative things they say to themselves, but this is not found among patients with ME/CFS. This study suggests that these are two separate disorders, and it is critical for our case definition to distinguish these different illnesses.
Is it possible that this failure to differentiate Major Depressive Disorder from ME/CFS has led to variant prevalence rates of this illness? Let’s look at that on this slide. From 1997 to 2007, over a decade, the CDC presented prevalence data suggesting that rates of ME/CFS had gone from a relatively rare disorder affecting maybe 20,000 people to one affecting more than 4 million in the United States. So in 1997, we see 4 to 8 persons per 100,000 in a four-city study, and then in 2003 we see the rate go up to 240. In 2007, the rate going up to 2,540 cases of CFS per 100,000. This is an exponential, almost unprecedented, rise in a disorder. As you might imagine, I am skeptical about the CDC’s sizable increase in the numbers of estimated patients with ME/CFS in the U.S. over the past decade. The question is what might account for these escalating rates? And it is possible that changes in the case definition might play a large role.
I contend that changes from 1997, which is this little sliver right here (pointing to leftmost column), this is cases per 100,000 (pointing to y-axis) to 2003 (pointing to middle column) that this jump that occurred might be due to the way the CFS cases were identified. The larger jump from 2003 to 2007 (pointing to right column) might have been due to changes in the operationalization of the case definition. I might add that similar increases in prevalence rates have been reported by some investigators in Great Britain.
Now let’s try to figure out what these changing rates are about and see if we can come up with some possible explanations for that. In the late 1980’s and early 1990’s, the CDC engaged in a prevalence study that involved having medical personnel in four cities identify patients who have CFS, and then these individuals were medically examined. So individuals were referred by the physicians and then they were evaluated to see whether or not they had the illness. The findings released by the CDC in 1997 indicated that CFS was a relatively rare disorder affecting about 20,000 people. Yet if the physicians did not believe that CFS existed, they would not refer patients to the study. In addition, if patients didn’t have physicians because they were poor due to the illness, and had many of their resources having been used to try to get medical care, then they also would not have been referred. Therefore, these findings were likely underestimates of the true prevalence of CFS. And as we said earlier if an illness is perceived as relatively rare, less public and federal resources will be devoted to that illness.
Our group in Chicago used a different method to collect data by telephone and we would call a random sample of people in the Chicago area. Those who had the core symptoms were invited in for a complete medical and psychiatric evaluation. This is called community-based sampling, and using this method we estimated that about 800,000 people or more had ME/CFS which was - as you recognize - was considerably higher than the prior CDC estimates. In addition, we found that 90% of the patients had never been diagnosed with ME/CFS prior to our study. You can see this is the rate that of CDC and this is the rate that we got from our Chicago study. (pointing out graph on right of slide) I might add that in 2003, the CDC also reported on a community-based prevalence study and their findings were comparable with the DePaul sample. However, in 2007 in another report by the CDC, prevalence rates had soared. It is possible that changes in the case definition accounted for these increases. But first let’s go back to considering the essential elements for an illness case definition to see where the problem might be.