PHOENIX RISING

A Guide To Chronic Fatigue Syndrome (ME/CFS)

RESEARCH

Another ‘Smoke-Filled Room’ - examines the conditions under which the new definition was created.

Testing the Definition: the Early Results – some worry that the new definition will lead CFS research to take a more psychological bent. This article examines if it has thus far.

Increased Prevalence Rates - What Increased Prevalence Rates? -  this short article questions whether it was new definition that increased the prevalence rates so dramatically or some other aspect of the study?

Metrosexual Problems in Georgia – do the greatly increased female prevalence rates in the metropolitan area (12x’s the men!) suggest a flaw in the study?

A Self Correcting Problem? –are the tools to fix the definition – if it needs fixing –  included in the definition itself. 

An Inevitable Conclusion – questions whether the discounting of post exertional malaise in the International (Fukuda) definition in 1994 made a definition based on unwellness an inevitability.

Another ‘Smoke-Filled Room’. -In his critique of the 1994 definition Dr. Reeves noted that it was created by a bunch of people sitting in a ‘smoke filled room’ – a criticism, ironically, that can be applied to this definition as well. While the CDC went to great efforts to have a varied and representative group (ICFSWG) create the recommendations for the new definition, the actual creation of the definition – the most critical aspect of it – was left to a small CDC research team meeting in turned out to be another ‘smoke filled room’. In fact this room was smokier than ever. Instead of the international group of 25 people who created the 1994 Fukuda definition only 10 people - almost all of whom were associated with the CDC - participated in producing the empirical definition (ED). – a

The CDC has been wrongly accused by some CFS advocates of intentionally producing a bad definition. The group the CDC put together to produce the Fukuda definition had significant numbers of both behaviorally and physiologically oriented researchers. Besides the Wessely’s and Straus’s of the CFS community it also contained Anthony Komaroff, Nelson Gantz, Daniel Peterson, Brigitta Evengard, Benjamin Natelson and others. It was indeed an ‘International definition.

CFS is, as Dr. Reeves aptly noted a ‘moving target’, and any definition would have undoubtedly raised some questions but the Reeves team could have easily produced a much less controversial definition. Dr Reeves recognizes, for instance, that pain is common in CFS; “Many people have more problems with pain, memory or concentration than they do with fatigue”, yet except (indirectly) in the symptom list pain does not enter at all into the new definition. Researchers studying fatigue in post-cancer patients have employed the vitality subscales of the SF-36 test but this was not used either. A definition focusing more on the physical aspects of CFS without the emotional subscale or activity subscales or the low requirement for fatigue would presumably have met with satisfaction from almost everyone.

That Dr Reeves did not convene a representative group of CFS researchers to create the new definition suggests that he believed his conception of CFS would not meet with wide acceptance. Dr. Jason, a major author of the ICFSWG’s recommendations paper that prepared the foundations of the new definition reported that he was surprised at the direction the new definition took . We can only trace the broad lines of Dr. Reeve’s conception; it de-emphasizes fatigue, it appears to place more emphasis on emotional issues and it is less concerned with pain. It is unfortunate that the CDC, with its checkered past, has  - at least in this matter – acted in a way that will undoubtedly arouse suspicion in a markedly suspicious CFS community.

Hopefully Dr. Reeves will continue to elucidate his reasons for picking the criteria he did and choosing the cut-off points he did.  It should be noted that Dr. Reeves has not said that this definition is set in stone. Whether that means it’s amenable to change is another question. In the chorus of questions raised by the prepublication reviewers one reason Dr. Reeves gave for keeping the definition as it was was simply that it had been used before and thus could be retained (for comparative purposes) -  not a strong indicator that Dr. Reeves will display much flexibility in this matter.  

Testing the Definition – The Early Results. One way to check on the effects of the new  definition is to see how the studies that use it are turning out. There are at least three things to look for:

A New Psychological Emphasis – will research studies using the ED turn CFS research in a direction the emphasizes psychology over biology? This could happen if psychologically oriented studies – which now often have mixed results now  - have more positive results or if physiologically oriented studies – which also have had mixed results but have had more positive results in last few years – have fewer positive results. In this scenario the lack of positive laboratory findings and increasing evidence of psychological abnormalities could lead CFS to be more viewed as a psychological disorder.  –

More Consistent Results – Since a poor definition was believed to cause many of the inconsistencies seen in CFS research studies the new definition should either result in more consistent results or it should, through it’s more explicit characterizations, point out subsets that are confounding those results.

A corollary of this is that the new definition should continue to highlight the consistencies already present in CFS research. The old definition wasn’t all bad; despite its vagueness a fairly large number of consistencies did emerge over time. These indicate that Fukuda definition did define at least a somewhat homogenous group of people. Studies employing the ED should continue to highlight poor NK cell functioning, increased rates of RNase L dysfunction, low blood volume, lowered cortisol levels and HPA axis functioning, low heart rate variability levels, altered brain imaging patterns, low blood flows to the brain, increased rates of oxidative stress (and probably more). Their failure to do so would indicate a markedly different group of patients has emerged and negate decades of research efforts.  

Referral Bias - We also need to know if referral bias really has been a big problem in CFS/ME. To their credit the CDC appears to be examining this question; they have been gathering CFS/ME patients from clinics and are comparing them to those found in their random sampling efforts.  

The Early Results. Thus far the ED has been used on at least six studies . As noted above one study indicated a high percentage of CFS patients had an abusive childhood. Two studies did not find evidence of orthostatic intolerance or sleep abnormalities in CFS. The OI study was so small, however, that its veracity was questioned and it should be noted that not all OI or sleep prior studies have found high levels of abnormalities in CFS patients. One study found decreased heart variability and increased heart rate during sleep. Dr. Reeves also recently reported finding basal ganglia abnormalities in a fMRI study.

Thus it’s too early to tell if the new definition will lead to a more psychological interpretation of CFS; there is one red flag (child abuse study), two studies with an unclear interpretation and two studies that back up former findings.

Increased  Prevalence Rates – What Increased Prevalence Rates? Throughout this paper we have assumed that the new definitions  less stringent criteria with  regard to fatigue and symptom severity  and  the introduction  of  a new group of emotionally distressed patients  was responsible for the greatly  increased prevalence rates. Yet some evidence suggests other factors in the study were responsible for the increased prevalence rates.

Table Two in the document suggests that instead of increasing the number of people classified with CFS  6-10 fold the Empirical Definition actually reduced  them by about 20%. During a detailed telephone interview the CDC classified 292 people who met the Fukuda criteria as CFS-like. They were called CFS-like because they had not been evaluated by a doctor yet. Once they got them into the clinic and removed all those who didn’t meet the exclusionary criteria they had 150 CFS patients left who met the Fukuda criteria (CFS-like).Of this group 56% or 84 met the Empirical criteria for CFS. Another 29 patients from the other categories of unwellness (unwell not fatigued, unwell with fatigue, etc.) plus one  person formerly  classified as one of the healthy controls were deemed to have CFS ED. At the end113 people met the Empirical Definition criteria for CFS while 150 met the Fukuda criteria – the prevalence rates appeared to have declined not increased (?) under the Empirical Criteria.

So if fewer numbers of patients in the study were classified with CFS using the ED than the Fukuda definition where did the 6-fold increase come from? We know that asking if people were unwell rather than fatigued added about 11% more people. But where did the rest come from? Was it from the ‘weighting’ or some other aspect of the study? If you can explain this conundrum please e-mail me (phoenixcfs@gmail.com).

Metrosexual Problems in Georgia – The study found that women in the metropolitan areas were 11x’s more likely to have CFS than men – an highly unusual findings. The Reeves team couldn’t account for this dramatic upswing in female prevalence except to suggest that ‘gender’  - a sociological construct -rather than ‘sex’ –a biological construct- may have played a role. Since the prevalence rates weren’t increased in the metropolitan area this data would appear to suggest not just that women living in  metropolitan areas are more susceptible to CFS but than men are much less so (!). Dramatically different findings like these raise a red flag that suggests that something somewhere went wrong in this study.

A Self Correcting Problem?(???) The argument can be made that the most important part of the new definition is not the specific criteria but the fact that there are measureable criteria at all. We already knew CFS patients were a mixed bunch; some appear to have heart problems, others have orthostatic problems, some CFS patients catch every bug under the sun, others don’t seem to catch any, some CFS patients can’t handle salt, others crave it, some have low libido, others do not, some have problems with chemical sensitivities, others do not. It’s a very mixed bunch of people –and it just got more mixed up; as Kim McCleary said CFS patients were like apples, oranges  but were now like apples, oranges, pineapples and skateboards.

Characterizing CFS patients using the SF-36, MFI and Symptom Inventory could begin to break this group up. If researchers look they should be able to determine, for instance, if emotionally disturbed people who do not demonstrate post-exertional fatigue are showing up in large numbers in their studies. A study on antidepressants could determine if anti-depressant usage helped only those with high scores of emotional distress or if it helped others as well.

Ironically, given the fears that CFS will be interpreted in more emotional terms, this new testing procedure, could, one would think, be able for the first time to differentiate people with more emotional problems from those who have more physical problems. As such it could conceivably lead to the breakup of the CFS label. This could not be done using the old definition.

An Inevitable Conclusion? - A case can be made that the Empirical Definition is an inevitable consequence of the 1994 International (Fukuda) definition – that it was only a matter of time before it appeared. Why? Because the Fukuda definition discounted the importance of one symptom - post-exertional malaise (PEM) - that some researchers believe to be the hallmark symptom of CFS.

Post-exertional fatigue/malaise has come to take a more and more prominent place in some CFS/ME physicians and researchers conception of CFS/ME . The two latest definitions (Canadian Consensus, IACFS Pediatric) as well as the earlier Lloyd definition require post-exertional fatigue/malaise to be present for CFS to be diagnosed. Although it is one of eight major symptoms the Fukuda definition does not require it to be present.

Thus the sample sets for CFS research studies were around people with a less concise symptom – fatigue. If PEM is a central characteristic of CFS then its not surprising that researchers would have such trouble understanding it given the patient set they were studying. From fatigue – a very general measure – it wasn’t much of a step to ‘unwellness’ – the thrust of the current definition. Given the difficulty one has in measuring fatigue

The big question, of course, is whether post-exertional malaise (PEM) is a defining characteristic of CFS? It is clear that it is not unique to CFS. One study found about 50% of depressed patients reported they experienced PEM and the CDC’s efforts to find a unique symptom signature in CFS vs fatigued patients failed to despite the inclusion of PEM in the study.

On the other hand a CDC study examining the symptoms in a wide variety of fatigued groups (prolonged fatigue, chronic fatigue, CFS-like, CFS) found that as the levels of fatigue increased the percentage of people reporting ‘unusual fatigue after exercise’ did as well (Nisenbaum 2006). That only 1.6% of people with no fatigue reported this symptom indicated it is rarely found in healthy people. About 14% of people with prolonged fatigue and 33% with chronic fatigue (but not CFS) reported unusual fatigue after exercise but from there it jumped up markedly; 77 and 74% of CFS-like and CFS patients reported this symptom. This suggests that with regard to this symptom there is a big difference between patients with chronic fatigue and CFS patients (defined by the Fukuda definition.). An even larger split would of course occur if CFS was defined using the Canadian Consensus Definition. 

Similarly CDC studies exploring the question of subsets in this same group of CFS and CFS-like patients (Conna et. al. 2006, Aslakson et. al. 2006) found that post-exertional fatigue – was the first and third most important differentiating variable in the PCA and Latent Class Analyses. Its discriminatory prowess was highlighted by the fact that it and concentration difficulties were the only variables not found at all in the Well Group. The very high levels of post exertional fatigue (78-91%) in the three classes dominated by CFS patients and the low to moderate levels of it (33-41%) in the classes dominated by idiopathic fatigue patients  suggest that this symptom plays a special role in CFS.

The importance of post-exertional malaise in the Empirical Definition is diluted to such an extent that it plays little role in differentiating CFS from non-CFS patients. Interestingly just as PEM has completely disappeared from CDC’s sight studies reported at the 2007 IACFS conference by the Pacific Fatigue lab suggest that it is an integral part of CFS. These studies indicate that, in contrast to healthy people, as CFS patients engage in aerobic exercise over time their maximum oxygen uptake levels fall and their symptoms increase.

Other findings that CFS patients must recruit more areas of their brain to carry out mental tasks could explain the post (mental) exertional fatigue reported in CFS/ME. It’s interesting that more central nervous system abnormalities have been found in CFS/ME patients without emotional distress (depression) than in those with emotional distress. These findings suggest that PEM is an important part of CFS/ME.  

Will the same findings show up in the Empirical Definition CFS patients? Only time and rigorous study will tell.