Advocates Rebuffed
Dr. Unger nixes advocate hopes of proving reduced exercise capacity exists in chronic fatigue syndrome
In July, eleven ME/CFS groups and thirty-one advocates requested the CDC use the two-exercise protocol in phase two of their multi-site study. Their letter stated:
The two-day CPET regimen known as the Stevens Protocol provides gas exchange and other objective and measurable results “which can’t be faked.” …Having CPET testing performed by trained personnel on subjects involved in the multi-site clinical assessment should be considered a TOP PRIORITY…
We cannot over-emphasize the importance of measuring and understanding post-exertional malaise (PEM) in this study. PEM is most often the largest obstacle to activities of daily living, gainful employment, exercise, and more.
During the CDC Conference Call on Tuesday, Sept 10, Dr. Unger nixed any chance of meaningfully measuring exercise capacity in this study by her decision to do the 1-day exercise test. A brief look at the results from latest two-day ME/CFS exercise study will illuminate what was lost.
The One-Day Two-Day Question
The first exercise test suggested the ME/CFS patients had the same capacity to do exercise as the healthy controls
After the first exercise test the ME/CFS patients looked as healthy as the healthy controls. The ME/CFS patients’ ability to produce energy (at ventilatory threshold) dropped a full forty percent during the second exercise test. The healthy but deconditioned controls maintained their energy production. These findings demolished the ideas that deconditioning and lack of effort played a role in ME/CFS patients’ ability to exercise, and pointed a dagger at their energy production system.
Workwell’s ability to accurately determine who was healthy and who had ME/CFS 95 percent of the time simply by looking at the difference in results between day 1 and day 2 suggested they’d found a diagnostic biomarker.
- Dig Deeper! Busted! Exercise Study Finds Energy Production System is Broken in Chronic Fatigue Syndrome
Eliminating that second day means deconditioning will remain on the table as a possible explanation for ME/CFS. The idea that metabolic dysfunction is involved in ME/CFS will take a hit. Getting at the cause of the exercise problems in ME/CFS has been sidelined. Instead, what we have is a study that will determine whether ME/CFS patients’ symptoms and cognitive functioning get worse after exercise.
Dr. Unger gave up a lot when she gave up that second day. Let’s see why she made that decision.
The CDC’s Reasons
Dr. Unger’s rationale for dumping the two-day test was surprising to me. Questions about expense, about different staff doing the tests correctly, whether the sites had access to the equipment and personnel needed to do the test, whether the ME/CFS centers wanted to do two day tests–all the seemingly tough stuff–disappeared. Here are the reasons she provided in a response to the advocates.
(1) The CDC wanted to measure “exercise capacity” in as many patients as possible.
But they’re not really measuring exercise capacity, are they? They’re measuring the ability of ME/CFS patients to exert themselves fully on one day, and that’s NOT exercise capacity. Exercise capacity is the ability to engage in exercise day after day after day.
The ME/CFS patients ability to exercise plummeted during the second exercise test; the deconditioned controls were able to exercise at their normal rates
The ability (or rather inability) to do that is what gives people with ME/CFS so much difficulty. The beauty of the two-day testing protocol is that it captures what happens to people with ME/CFS in real life.
This study won’t do that. It’s not measuring exercise capacity in a meaningful way.
We know from past studies that most people with ME/CFS blow through the first exercise test with flying colors. We know that the real metabolic abnormalities in ME/CFS don’t show up until the second day.
This study is not about measuring ‘exercise capacity’; it’s about determining what symptoms and cognitive problems occur as a result of exercise.
Unintended Consequences Could Spell Problems
We know researchers have used results from one-day exercise tests to assert there are no underlying metabolic problems in ME/CFS. We know that the two-day test was developed, in part, to counter those claims, which brings up the question whether this study might not do more harm than good?
A large study that finds no significant changes in exercise capacity could inadvertently provide ammunition to those who propose no metabolic issues exist in ME/CFS…
If past studies are any guide, this large study will almost surely conclude that most people with ME/CFS do not have significant problems with energy production. It will probably be published in a widely-read journal. It will certainly eclipse the smaller efforts, published in more obscure journals, that found significant metabolic issues using two-day exercise tests.
After this study if your doctor knows anything about energy production in ME/CFS, he will know that it’s probably not the issue.
The two day test-retest studies suggest otherwise, but the lack of traction given them concerned ME/CFS advocates enough that they produced a major lobbying campaign to get them included in the CDC’s study. The advocates don’t necessarily believe the test-retest results are clear, but they do believe they’re clear enough to warrant significantly more study. This large study appeared to be a perfect launchpad for more extensive research into this area.
Unfortunately, it could do the opposite.
(2) Doing the two-day test would cause people who are travelling long distances to stay an extra night, causing additional costs that might cause them to not participate in the study.
What??? The study centers exist in major metropolitan areas. It’s not clear why many people would a) need to travel long distances to get to them, or b) if they are willing to do that, why they wouldn’t be willing to stay an extra day, and c) what proportion of the total study population this problem would affect anyway.
Four hundred and thirty-five people participated in the study. Even if you cut that number down dramatically you’d still have the biggest exercise study ever done in ME/CFS.
But there’s no reason to cut the study down dramatically. Let’s say 10% of the study participants have to fly in. Let’s say 25% of them decide not to participate because they don’t want to pay for another night. That would mean one-fourth of that 10%, or 2.5% of all study participants, would be dropped from the second test. But 97.5% would remain!
The two-day study would exclude the most severely affected.
Of course it would, but only from participating in the second test. Since the most severely affected will probably show metabolic dysfunction on the first exercise day, they don’t need to do the second test. Adding the second exercise test doesn’t exclude the more severely affected it simply includes include the less severely affected.
Conclusion
The weak reasons given for not doing the test-retest protocol suggests Dr. Unger and/or the centers in the study, simply didn’t want to do a two-day exercise test, and that we still don’t really know the reason(s) why.
In fact, Dr. Unger’s decision not to consult the experts in the field until after the study design was finished suggests that two-day exercise testing was never on the table.
CDC Choses Not to Use the Experts in the Field.
Dr. Unger’s discussion with Dr. Snell, a published expert on exercise testing in chronic fatigue syndrome, took place only after eleven organizations and thirty advocates implored the CDC to do the two-day exercise tests. It took place months after Dr. Unger, at the FDA Workshop, stated two day testing was not on the agenda. It took place well after the study design had been decided. It was a sop to ME/CFS advocates.
Two of Workwell’s PhDs, Snell and Van Ness of Workwelll, have published extensively on exercise in ME/CFS. Staci Stevens developed the two-day exercise protocol for ME/CFS. When Stanford’s Dr. Montoya needed to ensure that his exercise studies were done correctly, he went to Workwell. They would seem to be the natural consultants for a study on ‘exercise capacity.’
When Dr. Unger needed advice on exercise testing, she went to Connie Sol, a fine exercise physiologist, but who is not a PhD and has no long record of research (1 study). It turned out, though, that Connie was perfectly adequate to this task because it appears that the CDC had no intention of understanding exercise capacity or examining energy production issues in ME/CFS.
This study has always been about measuring symptom exacerbations and cognitive declines after exercise.
A Difference of Opinion
In my opinion we’re simply dealing with a difference in opinion. Dr. Unger clearly has reservations about doing two-day exercise tests. She believes different kinds of testing are more valuable.
ME/CFS advocates are baffled why the test-retest strategy was not used in this study
ME/CFS advocates, on the other hand, believe the two-day tests could be a game-changer. They recognize there are issues, but the possibilities presented are too significant not to pursue them further. The two-day exercise tests are a priority for them.
They’re completely baffled as to why the CDC (or other researchers) doesn’t see it the way they do. They just don’t get it. Dr. Unger’s explanation is so weak that some are beginning to think diabolical motives are in play.
Once again the CDC, which has done so much under Dr. Unger to allay fears and repair bridges, is under attack. That’s unfortunate, but she has to bear some responsibility for that; the explanation she gave simply didn’t help.
Game-Changers Needed
The chronic fatigue syndrome research field needs game-changers. It needs results that smack researchers between the eyes so hard that they finally sit up and take notice. Any study that eats up a year of one of our largest research effort’s budgets should be focused on possible game-changers. Let’s look at this study and see if it provides any.
The ME/CFS field needs game-changers but nothing in this large study, almost two years in planning, suggests it will produce a game-changer for the ME/CFS Community.
Before we start let’s note that Dr. Unger’s explanation of the study is very confusing. In it she states that the study will
- “Enroll patient for the protocol on combined cognition and cardio-pulmonary exercise testing (CPET), with 48 hour follow-up of cognition, pain and symptom measures to identify post-exertional changes.”
A bullet point she includes below that says ‘blood sampling for gene expression changes’ suggests gene expression changes are going to included–somewhere. In the header, though, she states the 48-hour post-exercise follow-up tests will include cognition tests and symptom measures. That suggests gene expression change tests are not part of the 48 hour post-exercise period.
Cognition
The study will attempt to identify cognitive declines in patients after exercise. Let’s be clear about one thing: as distressing as the cognitive declines are for ME/CFS personally, no-one in the research world is grasping just how horrible the cognitive declines are in ME/CFS. This is because they appear to be fairly mild relative to disorders known to produce significant cognitive problems. It’s possible that one fifteen minute exercise period to exhaustion will produce off-the-charts cognitive dsyfunction in ME/CFS over two days, but I doubt it.
My guess is that reading the results will not cause outside researchers to gasp, clean their glasses, and then read the study again to make sure they got it right.
Besides the cognitive tests, the CDC will examine pain and symptoms. Increases in these after exercise have been abundantly documented by other groups.
That’s it! Unless the description of the study is sloppily written, other testing is not going to be done in the 48 hour post-exertional testing period.
Gene Expression (?)
If gene expression studies are being done in the 48 hour post-exercise period, then validating Dr. Klimas’s unpublished results suggesting autonomic nervous system changes trigger an immune cascade, or Dr. Light’s results, would be a major step forward. Identifying any subgroups based on gene expression would be a step forward.
Gene expression is a hot but complex topic with a mixed record of success in the ME/CFS field
My guess is that gene expression has great value but that it’s going to take years to come to fruition. The last six gene expression studies have found increased sensory, adrenergic, etc. gene expression, nothing, increased GRK2 and NPAS2 (in subgroups), increased sensory, adrenergic, etc. gene expression, increased WASF3 and HDAC7A, concluded that misclassification of genes meant gene expression could not be used as a diagnostic tool, and one that talked about hundreds of upregulated genes.
The last Kerr gene expression study blew the results of his two previously positive studies out of the water which meant the ruin of years of work, and Kerr left the field shortly afterwards. The Light gene expression studies have been the most successful, but even there gene expression varies remarkably from individual to individual. Disentangling those complex but encouraging results to provide treatment options for ME/CFS is going to take work and time. (Dr. Vollmer-Conna of the Dubbo group in Australia recently told me they’ve been unable to duplicate the Light gene expression study results.)
Gene expression studies, for all their promise, are a gamble at this point.
For me, the choice between a possibly difficult to interpret gene expression result and clear evidence of metabolic dysfunction using exercise technology that’s been with us for decades, and has a good track record in ME/CFS, is an easy one.
Natural Killer Cell Dysfunction/Morning Cortisol
It appears that NK cell function tests and morning cortisol tests are not part of the exercise study, but part of the larger study. We know cortisol levels are mildly reduced in this disorder–particularly in the morning–but it’s hard to see how another low cortisol finding, particularly another mildly low cortisol finding, is going do anything significant for ME/CFS.
Natural killer cell dysfunction is clearly an important facet of ME/CFS, yet we might ask here too what finding more NK cell dysfunction will do that hasn’t been done already. Yes, it highlights a major issue in ME/CFS. Hopefully it will point to more immune research, but will another NK cell dysfunction finding be a game changer? My guess is no.
Conclusions
Demonstrating that ME/CFS patients’ ability to produce energy declines during a second bout of exercise is an eye-opener for me. It comports with my experience. It’s easily understandable. It doesn’t require complicated programs to understand it. It’s like being hit with a mallet over the head. It has the possibility of being an immediate game-changer for this disease. Nothing else in this study provides that kind of possibility that I can see.
Little in this study appears to be novel. The idea to study ME/CFS patients who see expert ME/CFS practitioners was a good one, but I believe the CDC is missing an opportunity.
- Next Up – We talk to exercise physiologist Betsy Keller about her experiences with two-day exercise testing in ME/CFS
Excellent explanation, as always.
You and your readers might be interested in the poll I just created on your original site, Phoenix Rising. The poll question is: “IF you were a CDC Multi-Site Study participant, would you agree to do the *2-day* CPET?”
http://forums.phoenixrising.me/index.php?threads/cdc-conf-call-follow-up-poll-would-you-do-2-day-cpet-if-in-cdc-multi-site-study.25286/
Great idea on the poll 🙂
Would it be possible to organize patients to sabotage the research by refusing to participate?
It seems this research will do more harm to us than good.
I understand where you’re coming from but I wouldn’t do that.
The study will do some good. If it was to show that cognition worsened after exercise that would be really good; it’s just not the breakthough I believe is possible by demonstrating that metabolic problems hamper exercise in ME?CFS….Ditto with the gene expression stuff (if it is being done after the exercise/)
I’m not so worried about the research community not getting the difference between the 2-day and 1-day exercise tests; it’s the doctors and people like that who are not closely following the research who I’m sure will miss the 2-day test results.
Dr. Keller is publishing a paper on the 2-day tests and I think another researcher is including it in a study. I think this stuff will keep coming out but the latest study – in a Physical Therapy journal – didn’t make any waves….It has to get into bigger journals in order to get traction…
For me I would register my disappointment that these tests are not being done.
I have a friend that has POTS and she had the two day test done. She did better on the first day – her threshold was very low. But, the second day was the tell all. Her fatigue was greatly increased and her endurance greatly diminished from the first day. A lot would have been missed if they had only done the one day test on her.
Issie
This is a good article, Cort.
Here is some further reading about a study in which mice that were poisoned with trichothecenes (the sort of mold poison made by the infamous Stachybotrys or “black mold”) display exercise intolerance.
http://www.ncbi.nlm.nih.gov/pubmed/18958698
The pieces are all falling into place, bit by bit. 🙂
Best,
Lisa
How peculiar that the comment form includes a space for my website address but then does not publish it.
Here it is:
http://www.paradigmchange.me
Best,
Lisa Petrison, Ph.D.
Executive Director
Paradigm Change
I’m not speaking for Cort, but just to point out that your name is a link to that website.
That’s standard practice on blogs Lisa – not sure why that is but it’s the default setting for WordPress
It does have a mind of its own, doesn’t it? 🙂
I fear that this ties in with the recent debacle of the farming out of the job of creating a new definition of ME/CFS (why another one now? because the CC and IC documents were produced by doctors in the field) to a non-medical company in illustrating both the profound distrust that medical bureaucracies have of doctor/researchers who actually have contact with patients. There is an appalling story in “Osler’s Web” of Paul Cheney’s meeting with a committee from the CDC, to which he brought both a video of severely ill patients and a beautiful young and severely ill patient; the committee literally walked out on him, and later commented that they thought the young woman was “hysterical” (she died two years later) and that Cheney was “depressed”–doubtless true, and I would imagine angry as hell. I realize that Dr. Unger is a virologist, but here she is acting as a medical bureaucrat.
The two actions together strongly suggest a conspiracy–the medical bureaucracies point blank are not going to do anything useful for us, and will probably fall back on CBT and GE as the only recommended therapies. It will take a major finding to dislodge this attitude, I fear.
If the results of a single day study are so potentially damaging if published in a major journal when the only 2 day studies are published in lesser known journals. It might make sense for patients to boycott the single day exercise study. They may lose more patients for the study via this than through any of the other mentioned reasons.
I think ut’s better to push for more 2-day test-retest studies. I’m not worried about the researchers – I’m more worried about doctors who aren’t following the research. I think the test-retest studies will continue to dribble out as long as they’re successful.
I would also note that better minds than mine; namely Dr. Klimas, Dr. Peterson, Dr. Lapp, etc. are on board for this study. Overall its surely a good thing.
If Dr. Unger doesn’t include a comprehensive blood analysis after even a 1-day exercise challenge and instead only does some bullshit ‘symptom profile’ questionnaire crap then that in itself is completely fucked up. The CDC should go through the literature and look for all the studies which have found abnormalities in ME/CFS patients following exercise challenge and see which of these would be the most feasible to try and replicate (even the CDC’s own goddamn studies which they still haven’t attempted to replicate!). I agree though, if they’re already going to do a 1-day exercise study then it seems like a pretty huge waste of resources and patients’ well-being to not go ahead and throw a second day in.
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1. Differential heat shock protein responses to strenuous standardized exercise in chronic fatigue syndrome patients and matched healthy controls. Thambirajah AA, Sleigh K, Stiver HG, Chow AW Clin Invest Med. 2008 Dec 1;31(6):E319-27
http://www.ncbi.nlm.nih.gov/pubmed/19032901
“Since physical exertion is known to exacerbate the symptoms of chronic fatigue syndrome (CFS) and metabolic changes and including oxidative stress can modulate heat shock protein (HSP) expression responses, we sought to determine whether HSP expression is altered in CFS patients before and after exercise. Heat shock proteins (HSPs) in peripheral blood mononuclear cells (PBMC) were examined from 6 chronic fatigue syndrome (CFS) patients and 7 controls before and after a standardized treadmill exercise. Basal hsp27 was significantly higher among CFS patients compared to controls, and decreased immediately post-exercise, remaining below basal levels even at 7 days. A similar pattern was observed for HSP60, which gradually decreased in CFS patients but increased in controls post-exercise. These findings suggest an abnormal adaptive response to oxidative stress in CFS, and raise the possibility that HSP profiling may provide a more objective biologic marker for this illness.
METHODS: HSP27, HSP60, HSP70 and HSP90 expression from 6 CFS patients and 7 age- and sex-matched controls were examined by western blot analysis of peripheral blood mononuclear cells immediately before, after, and at 1 day and 7 days following a standardized treadmill exercise.
RESULTS: Basal HSP27 was higher among CFS patients than in controls (0.54 +/- 0.13 vs. 0.19 +/- 0.06, mean +/- SEM; P < 0.01). In addition, these levels in CFS patients decreased immediately post-exercise (0.25 +/- 0.09; P < 0.05) and remained below basal levels at day 1 post-exercises (0.18 +/- 0.05; P < 0.05). P < 0.05). This declining expression of HSP27 during the post-exercise period among CFS patients was confirmed by one-way ANOVA analysis with repeated measures (P < 0.05). In contrast, HSP27 levels remained relatively constant following exercise among control subjects. Similar patterns of declining HSP levels in CFS patients were also observed for HSP60 (0.94 +/- 0.40 vs. 1.32 +/- 0.46; P < 0.05), and for HSP90 (0.34 +/- 0.09 vs. 0.49 +/- 0.10; P < 0.05) at day 7 post-exercise compared with basal levels, respectively. In contrast, HSP60 levels in control subjects increased at day 1 (1.09 +/- 0.27) and day 7 (1.24 +/- 0.50) post-exercise compared to corresponding levels immediately post-exercise (0.55 +/- 0.06) (P < 0.05, respectively).
CONCLUSION: These preliminary findings suggest an abnormal or defective adaptive response to oxidative stress in CFS, and raise the possibility that HSP profiling may provide a more objective biologic marker for this illness.”
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2. Complement activation in a model of chronic fatigue syndrome. Sorensen B, Streib JE, Strand M, Make B, Giclas PC, Fleshner M, et al. J Allerg Clin Immunol 2003; 112: 397–403.
http://linkinghub.elsevier.com/retrieve/pii/S009167490301546X
“Exercise challenge induced significant increases of the complement split product C4a, but not C3a or C5a, at 6 hours after exercise only in the CFS group (P < .01), regardless of allergy status. Mean symptom scores were significantly increased after exercise through the use of a daily diary (P < .03) and a weekly diary (P < .01) for the CFS group only. Mean scores for the Multidimensional Fatigue Inventory categories “reduced activity” and “mental fatigue” were significantly increased in the CFS group only (P < .04 and P < .02, respectively).”
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3. Chronic Fatigue Syndrome: Exercise Performance Related to Immune Dysfunction. Nijs, Jo; Meeus, Mira; McGregor, Neil R.; Meeusen, Romain; De Schutter, Guy; Van Hoof, Elke; De Meirleir, Kenny Medicine & Science in Sports & Exercise:Volume 37(10)October 2005pp 1647-1654
http://www.acsm-msse.org/pt/re/msse/abstract.00005768-200510000-00001.htm;jsessionid=JbSX8HTkTz9pksQG6Z2JQp1qQSPQmZyYbfspfMqYzm1byTqwFHVv2852599181811956288091-1
“Conclusion: These data provide evidence for an association between intracellular immune deregulation and exercise performance in patients with CFS.”
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4. Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise. Jammes Y, Steinberg JG, Mambrini O, Bregeon F, Delliaux S Journal of Internal Medicine:Volume 257(3)March 2005p 299-310
http://pt.wkhealth.com/pt/re/jimd/abstract.00004777-200503000-00010.htm;jsessionid=JbfTvF2Jd3jQVyrVTtTdRqTfwhyvsvTYxhQL9BrQ5k5r1Tnjysrb2852599181811956288091-1
“Conclusions The response of CFS patients to incremental exercise associates a lengthened and accentuated oxidative stress together with marked alterations of the muscle membrane excitability. These two objective signs of muscle dysfunction are sufficient to explain muscle pain and postexertional malaise reported by our patients.”
Note- Further discussion by MERUK- http://www.meresearch.org.uk/archive/muscle.html
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5. Exercise responsive genes measured in peripheral blood of women with Chronic Fatigue Syndrome and matched control subjects. T Whistler, JF Jones, ER Unger, SD Vernon BMC Physiol, 2005
http://www.biomedcentral.com/1472-6793/5/5
“CFS is defined by a post-exertional fatigue that does not subside 24 hours following physical stress. In contrast, exercise in healthy, untrained people induces changes in cellular homeostasis in 1 to 4 hours and a return to basal levels within 24 hours, as measured in muscle. Analysis of peripheral blood gene expression in the healthy control subjects confirmed this observation since the majority of gene expression levels were the same before and 24 hours following exercise challenge. This implied that expression either returned to basal levels or was unchanged as a result of the exercise challenge. And indeed, many of the 21 exercise-induced, differentially expressed genes in control subjects were characterized by gene ontologies(GO) that reflect a diverse set of molecular functions necessary for cell function and viability. (These ontologies overlapped with those identified in the GO comparison analysis given in Figure 2a). Figure 1 clearly illustrates the reciprocal pattern of gene expression in the 21 genes for most of the control subjects. In contrast, 11 of the genes were unchanged in CFS subjects before and after exercise; with 5 being classified in a transport-related ontology. Because this difference in gene expression is so dramatic, it implicates a fundamental perturbation in the biochemical activity of lymphocyte and monocyte peripheral blood fractions from CFS subjects compared with control subjects that does not affect classical immunologic markers (i.e, CD45) that have been shown to be unaffected in CFS patients. Rather, low expression of these genes may have subtle effects on immune function. Immune dysfunction has been inconsistently implicated in CFS pathogenesis.
It is evident that ion transport and ion channel activity segregate cases from controls and that exercise seems to intensify these differences. Several other conditions have been reported in which fluctuating fatigue occurs that are known to be caused by abnormal ion channels. These conditions include genetically determined channelopathies and acquired conditions such as neuromyotonia, myasthenic syndromes, multiple sclerosis, and polyneuropathies. There are other transmembrane functions associated with differences between controls and CFS patients, including signal transducer activity through receptor binding/activity (Figure 3a). Signal transduction of transmembrane receptors occurs by a number of mechanisms, including structural changes, ion channels, and changes of transmembrane potentials. The G-protein-coupled receptors play an important role in the membrane trafficking machinery. The most obvious exercise-induced changes in CFS cases pertain to gene regulation at the point of chromatin structure; whether these changes reflect the differences seen in the mRNA transcripts relating to membrane trafficking differences between cases and controls has not yet been determined.”
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6. Prefrontal cortex oxygenation during incremental exercise in chronic fatigue syndrome. J. Patrick Neary, Andy D. W. Roberts, Nina Leavins, Michael F. Harrison, James C. Croll and James R. Sexsmith Clin Physiol Funct Imaging (2008)
http://pt.wkhealth.com/pt/re/clph/abstract.00134502-200811000-00035.htm;jsessionid=JbgJvg15mSXPDV7F0gnrX6zB2vT83q24KcGTcRyJvpDR4vHj92hZ2852599181811956288091-1
“In this study, there was a 3-8% decrease in TOI in the CON group, in comparison with only 1-3% decrease in the CFS group during the exercise period (Fig. 4). This equates to a 64-5% difference in the amount of O2 extraction between the two groups.”
“Research has shown that cerebral blood flow is reduced in subjects with CFS when using transcranial Doppler sonography (Ichise et al., 1992; Yoshiuchi et al., 2006). In particular, Ichise et al. (1992) showed a significant blood-flow reduction in multiple regions of the brain of CFS subjects, including the prefrontal cortex. Some have suggested that this reduction in blood flow is related to an autonomic (cerebral autoregulation) dysregulation also noted in subjects exhibiting neurally medicated syncope under a number of different experimental conditions (Stewart et al., 1998; Yamamoto et al., 2003). Because cerebral autoregulation, metabolic regulation of O2 and CO2-mediated vasodilation are the most important mechanisms to ensure cerebral blood flow (Nybo & Rasmussen, 2007), our results would support the premise that the central nervous system of CFS subjects is somehow altered, and support previous research that suggests a CNS mechanism(s) is implicated in the pathogenesis of CFS (Georgiades et al., 2003; Chaudhuri & Behan, 2004; Siemionow et al., 2004b)”
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7. Chronic fatigue syndrome: characteristics and possible causes for its pathogenesis. Bassi N, Amital D, Amital H, Doria A, Shoenfeld Y. Isr Med Assoc J. 2008 Jan;10(1):79-82. Review.
http://www.ima.org.il/imaj/ar08jan-21.pdf
Patarka [19] demonstrated higher serum levels of interleukin-4 and interferon-gamma and lower levels of TGFß. Fulle and co-authors [20] showed a dysregulation of the Na+/K+ and Ca2+-ATPase pumps and alterations in ryanodine channels in sarcoplasmic reticulum membranes in CFS patients. Extracellular K+ accumulation can induce a negative feedback signal for sarcolemma excitability [21], and dysregulation of the pump activities can cause increased sarcoplasmic reticulum membrane fluidity [20], leading to the formation of lipid hydroperoxides[22]. All these alterations in muscle excitability can cause post-exercise oxidative stress, explaining muscle pain and post-exertional malaise reported by the patients [23]. The oxidative stress can be generated by a lower maximal aerobic capacity and by a reduced baseline oxygen uptake by tissues that occurs in CFS patients [23].
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8. White et al. Immunological Changes After Both Exercise and Activity in Chronic Fatigue Syndrome: A Pilot Study
Journal of Chronic Fatigue Syndrome, Vol. 12(2) 2004
“The main finding of this pilot study was the elevated median concentration of transforming growth factor beta, which seemed to be related to activity. We also found significantly fewer CD3+ and CD4+ lymphocytes and fewer expressing HLA DR, but there was no difference between groups in response to exercise, but no importance should be attached to this in view of the small numbers of subjects in this study. Finally, we found that exercise induced a sustained elevation in the concentration of TNF-a, which was still present three days later, and this only occurred in CFS patients.”
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9. VanNess et al. Diminished Cardiopulmonary Capacity During Post-Exertional Malaise Journal of Chronic Fatigue Syndrome, Vol. 14(2) 2007
“Results: Multivariate analysis showed no significant differences between control and CFS, respectively, for test 1: VO2 peak (28.4 ± 7.2 ml/kg/min; 26.2 ± 4.9 ml/kg/min), AT (17.5 ± 4.8 ml/kg/min; 15.0 ± 4.9 ml/kg/min) or HR% (87.0 ± 25.4%; 94.8 ± 8.8%). However, for test 2 the CFS patients achieved significantly lower values for both VO2peak (28.9 ± 8.0 ml/kg/min; 20.5 ± 1.8 ml/kg/min, p = 0.031) and AT (18.0 ±5.2 ml/kg/min; 11.0 ± 3.4 ml/kg/min, p = 0.021). HR% was not significantly different (97.6 ± 27.2%; 87.8 ± 9.3%, p = 0.07). A follow-up classification analysis differentiated between CFS patients and controls with an overall accuracy of 92%.
Conclusion: In the absence of a second exercise test, the lack of any significant differences for the first test would appear to suggest no functional impairment in CFS patients. However, the results from the second test indicate the presence of a CFS related post-exertional malaise. It might be concluded then that a single exercise test is insufficient to demonstrate functional impairment in CFS patients. A second test may be necessary to document the atypical recovery response and protracted malaise unique to CFS.”
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10. Discriminative Validity of Metabolic and Workload Measurements to Identify Individuals With Chronic Fatigue Syndrome
Christopher R. Snell, Staci R. Stevens, Todd E. Davenport and J. Mark Van Ness
http://ptjournal.apta.org/content/early/2013/06/26/ptj.20110368.abstract
“Results- Multivariate analysis showed no significant differences between controls and CFS for Test 1. However, for Test 2 the individuals with CFS achieved significantly lower values for oxygen consumption and workload at peak exercise and at the ventilatory/anaerobic threshold. Follow-up classification analysis differentiated between groups with an overall accuracy of 95.1%.
Conclusions- The lack of any significant differences between groups for the first exercise test would appear to support a deconditioning hypothesis for CFS symptoms. However, results from the second test indicate the presence of a CFS related post-exertional fatigue. It might be concluded that a single exercise test is insufficient to reliably demonstrate functional impairment in individuals with CFS. A second test may be necessary to document the atypical recovery response and protracted fatigue possibly unique to CFS, which can severely limit productivity in the home and workplace.”
———————————————————–
Findings from the 2009 IACFS/ME Conference-
1. A diagnostic test for the identification of metabolic dysfunction was discussed by J.Mark VanNess (Stockton,USA). Two graded exercise tests with cardio-pulmonary analysis were performed within 24 hours of each other. There was a “fatigue effect” of prior physical activity not characteristic of other illnesses. There was reduction of peak oxygen consumption and/or oxygen consumption at anaerobic threshold in CFS patients and in particular those with a high viral load. This provides evidence of metabolic dysfunction.
2.Patients with fibromyalgia and/or CFS demonstrate sustained increases in gene expression for metabolite sensing receptors and $adrenergic receptors on leucocytes from 0.5 to 48 hours after exercise. This is the time when pain and fatigue worsen, even when muscles are inactive. This study by Alan Light (Utah, USA) suggests a predisposition for these receptors to increase dramatically after exercise, stress and infection. There is potential for the increases in gene expression to provide biomarkers.
3. Gordon Broderick (Edmonton, Canada) found that subjects with Gulf War Illness (GWI) can be discriminated by demonstrating significantly different neuro-endocrine-immune dynamics in response to exercise. Changes in cytokines, NPY and cortisol are evident both at rest and much more so under challenge, and could separate subjects completely from the control group.
4. Remodeling of lymphocyte-cytokine networks in GWI under challenge – Gordon Broderick (Edmonton,Canada) – Characteristic immune responses occur spontaneously in these patients after exercise challenge, and resolve once the challenge is removed. Results suggest a potential shift in the regulation of body fat and energy metabolism in GWI and a bias toward Th2 mediated humoral immune response.
5. Toni Whistler (Atlanta,USA) used gene arrays to look at the mediators of NK cell function. She found that there was decreased functional capacity of NK cells in Gulf War Illness. There was impaired immune function involving Th2 and proinflammatory cytokines, cytokines, cytotoxic NK cells and T cells, and dysregulated mediators of the stress response such as salivary cortisol. These differences were augmented by exercise challenge. Laboratory diagnostic tests maybe developed as a result of this research.
Thanks, John for demonstrating a list of candidates for further exploration. I do find it hard to believe that all they’re going to do is symptom and cognition testing. The first phase of the study has been done for quite a while. The second phase won’t start until mid-2014 I believe. It’s a long time to wait for an exercise study on cognition and symptom exacerbation…I’m hoping that other tests are being done; the outline of the study was rather confusing.
Can’t we sue the CDC for decades of mistreatment of the CFS community?
I believe the test should go on as described with 1 caveat: All participants must undergo what they would consider a strenuous day of exercise the day before the test. For each it will be different, but it will still be as close to the first day as we’re going to get under Unger.
This may mean the participants will need companions, but then just state they had a normal day the day before.
Greg
🙂
I had that idea as well. It would mess with the results of former exercise studies – though…
I love both the boycott idea and the “exercise like hell the day before the exercise test”! Yes, as a community, we need to take this matter into our own hands. (Damnit!)
I think the real question is: what does the CDC/Big Pharma have to lose, if ME/CFS is bio-markered? No doubt it is a big money issue.
It seems the medical INDUSTRY is afraid they will lose substantially if CHRONIC FATIGUE is effectively addressed. RP
Dr. Unger clearly does not have a good understanding of the pathophysiology of CFS/ME…not surprising given how the CDC time and again seems to botch important scientific inquiries, using vaccines as another prime example. There are already studies that are suggestive of the second day being of crucial importance in differentiating between CFS and deconditioning.
A comment above mentioned would people participate in a 2 day study…I recently participated in a one day study and it near killed me…however, if it were to help the cause, I would gladly sacrifice a few of my remaining mitochondria to participate. This is too important!
”Let’s say 10% of the study participants have to fly in. Let’s say 25% of them decide not to participate because they don’t want to pay for another night. That would mean one-fourth of that 10%, or 2.5% of all study participants, would be dropped from the second test. But 97.5% would remain!”
Why would you write this in a article when you are trying to prove science? This is a conjecture,a guess, a speculation and has no place in this article. It makes me suspicious about veracity and influence.
We have enough loose statistics floating around the ME/CFS world. Sticks to the facts.
It’s not supposed to be science, Karen, As you note it’s conjecture, a guess, speculation. You should be suspicious about it if it was posed as a fact but it was meant as conjecture; hopefully you can take it as such and not confuse it with fact. When no facts are available I think its OK to speculate.
It’s really not surprising. Everyone is familiar with the CDC’s history. Unger is a bureaucrat with a PhD. The admin of the CAA earn more than she does. Those who do do those don’t work at the CDC where they earn an okay salary with excellent benefits.
I think the real issue is there is tremendous benefit in maintaining a waste bin diagnosis for Neuro-Immune diseases. Great for doctors, insurance companies and governments to dump difficult to treat patients into a nebulous hell hole.
Hi Cort,
Very helpful blog thank you.
In your blog, you provide a link to Beth Unger’s letter:
http://www.cortjohnson.org/wp-content/uploads/2013/09/Response-to-July-22-letter1.pdf
In the letter, she says “Our plans for the next stages of the study are briefly outlined in a separate page (attached).”
Do you know if there is anywhere I can read a copy of that separate page?
I’d really like to read the exact details of the next stage of the study, if possible.
Thanku,
Bob
Thanks cort. One of your best articles to date. I could not agree more. Having only a one day exercise test is useless and possibly very harmful.
Cort,
Thank you for this excellent blog; even though I’ve been talking about PEM and noticing my own inability to maintain exercise that goes on for more than a day or two, I wasn’t really understanding the problem until I read this blog. I would go to my PT and use the heart rate monitor during my weekly session and think, wow, I’m really doing pretty well, maybe I’m not having this problem. Maybe it’s all in my head. But then I’d get going on a routine and two or three days into it, I’d launch into a crash that took me back past square one into the negative zone. Now it starts to make sense.
I really like the idea of patients in the studies taking control and doing the second day of exercise first. Is there a way they could be tested by their physicians after that “first day” and that the data could be made available to the researchers even if it wasn’t part of the study protocol. I know, someone would have to pay for it, but what if exercise physiologists, and the docs got behind this effort and donated their services for just one day? I’m sure most patients would gladly pay a portion—hell, we’re all paying for a lot of tests and expensive medications anyway.
Failing this, what if we all do our own informal studies, measuring what we can and providing anecdotal information to a poll that you or Phoenix Rising publishes. Couldn’t there be some traction gained by a large cohort of patients demonstrating both their willingness to do the two-day test and the results?
Again, thank you for this and all of the Health Rising articles. It really does seem that there is a ground-swell of energy (!-as much as we can muster) from the ME population that will help us help ourselves.
The CDC have no intention to prove that ME/CFS is a real disease with metabolic problems. Teh CDC will prove with a singel CPET test that ME/CFS patients are deconditioned. If they prove that this is not the case with a 24 or 48 hours repeated CPET test it will cost money for insurrance. The CDC is a ‘corrupt’ organisation with ‘bad’ intensions.
I agree. One option is to put pressure on everyone to marginalize the CDC as much as possible – ie refuse to participate in CDC testing, get top “ME” docs to not work with them, etc. Their history is absolutely abominable. There is no reason to think it’s ever going to change. If we rely on the CDC to create a new definition there is a 100% chance it’s going to be detrimental.
The “use of bicycle ergometry to accurately measure work output” is completely inappropriate ,would be extremely dangerous – is an impossible demand ,for people with Severe ME. With the greatest possible respect, I am surprised and disturbed you should suggest even one day of it Cort.
That test shows little awareness of the potential harm that can be done. Two days of tests, plus riding a bike(to prove you are ill). Imagine if ATOS here in the UK thought that was a bright idea ! What genuine ME patient would dare put themselves through it ?
The risk is incomprehensible – what a way to push someone moderately affected into Severe ME !
I am increasingly concerned about the apparent ignorance of researchers.
I agree that the really severely ill cannot participate but these tests have been done for disability and other studies without harming patients long term. I wish there was an easier way but I view these kinds of tests as the best possible way to get at the heart of ME/CFS.
Closely studying what happens during exercise should ultimately lead to biomarkers that can be found without patients going through the rigors of an exercise test. I think that’s everybody’s ultimate goal.
From what I understand of the multi-center study it’s not meant to be a “game changer” in terms of discovering anything (that’s for the Lipkins and Montoyas), but rather designed to tell clinicians how to diagnose the disease with what tests. The purpose of the NK cell and cortisol tests (and all the other tests) is to see if they are applicable to a wide enough breadth of the patient population to make them clinically valid to define/diagnose ME/CFS — something these tests currently cannot do because all of the research on them is made up of studies with tiny cohorts.
Moreover I think that rather than understanding precisely what happens during PEM, the CDC study is more concerned with establishing that PEM is indeed universal among patients, thus making it mandatory for a diagnosis of ME/CFS — something, of course, the current CDC/Fukuda criteria do not require. A one day CPET will most definitely show that yes, everybody in this study gets PEM (or, at least, I feel pretty confident it will given the doctors choosing the patients for this study!). In many ways, I would imagine that this CDC study is trying to validate the Canadian/ICC criteria, which all the clinicians involved in this study were apart of creating but simply didn’t have the resources or the stature of the CDC to accomplish.
To be sure, I would LOVE to see the 2-day CPET protocol validated. I would love to see more than yet another n= study that may or may not be able to replicate the results. And I too am concerned that expense is being used yet again by CDC to avoid doing a thorough job investigating what could be a vital means of diagnosing this disease. They should simply put these patients in hospital to conduct the 2-day CPET — and all the rest of the testing — given just what a gauntlet these heroic patients are being put through. And I would really, really like to see Connie Sol publish whatever it is she’s doing. I’m concerned that we’re basing a lot of exercise advice (both for and against) on the anecdotal experience of a handful of people that may not reflect the sheer heterogeneity of this disease(s) (the Lenny Jason study you reported on awhile back suggests that may be as much as 40% of the ME/CFS patient population).
But…if I might play devil’s advocate for a moment, there are reasons to be cautious about the 2-day CPET. The problem for it is that, unlike NK cell, cortisol studies, SPECT scans (are they doing SPECT scans?) and even gene expression (yes that can be bit of a dog’s breakfast), the 2-day CPET with ME/CFS is still extremely experimental with only 2 published studies from the Workwell/UofPacific group (n=6 and n=50, respectively) and another study replicating their work in 15 patients. That’s it. Which means we have less than 100 patients upon which to base the long-term safety of this test. There have apparently been many more who have had the test for disability and/or rehabilitative purposes, but as none of that has been put through the rigors of the peer-review process (or an ethics committee process for reporting harms), we can only guess that there haven’t been long-term safety issues based on the lack of anecdotal evidence. And short-term, it’s one hell of a diagnostic test to put sick people through! Which makes one wonder at the ethics of causing such severe pain and debility for weeks on end just to diagnose a disease.
I actually blame NIH for this more than CDC. If NIH would have funded the grant application the then-UofPacific group submitted years ago to try and replicate their initial n=6 study, the field of CPET and ME/CFS would probably be much further along by now (or, at least, one could hope it would have been; given the way promising ME/CFS research so often never moves beyond it’s initial research group, it’s always difficult to say). Hell, if NIH would have funded this disease more period then the CDC’s job at this point would be a lot easier.
All is not lost, however. Assuming that this CDC study is going to “conclude that most people with ME/CFS do not have significant problems with energy production” is both unlikely, since they are not necessarily trying to answer that question in the first place, and too pessimistic. Even if it’s not included in the CDC diagnostic study, the question of exercise capacity/CPET is sure to be revisited a great deal over the coming years thanks to the demands of patients and a growing number of clinicians (perhaps even Peter White himself may wonder about it — albeit ever so privately — after the anemic results of the PACE trial). In the meantime, I hope CDC can finally give our doctors a way to properly diagnose this disease without making patients bedridden for weeks on end.
P.S. I agree with Karen above that you play to your strength when you examine issues and research in a more dispassionate manner.
Thanks, Michelle –
I think Dr. Unger would have better served if she had brought up your points 🙂
I appreciate your important note that the CDC study is attempting to improve diagnosis and not to establish the cause of ME/CFS. I think mine and other patients frustration is the lack of progress on finding the cause of ME/CFS, and honestly, to see this very large study – which is apparently going to consume a significant portion of the CDC’s time over the next two years (it starts in mid-2014) – focus on symptoms and cognitive functioning (it appears) is frustrating.
Cortisol has been studied many times in ME/CFS; the consensus is that it’s mildly low in ME/CFS and is not low in a number of patients, and I would be surprised if a focus on AM salivary cortisol would change much of that. It’s possible they will find subsets, though, and that will be helpful.
Natural killer dysfunction is a good diagnostic tool and I imagine they will find subsets – so that’s good.
I would be surprised if cognitive testing is going to used as a diagnostic tool. I would be surprised, in fact, if any diagnostic tool using a exercise test to exhaustion will ever be implemented in ME/CFS. Can you imagine doctors patients on a bike, exercising them to exhaustion and then having them do cognitive tests or taking blood samples. I suppose it could happen but I would be surprised if it was. It could validate PEM thought.
The gene expression tests are so all over the map that I can’t imagine they could be diagnostic tools.
I agree, though, that the test-retest protocol is a very difficult biomarker to use; it’s costly and difficult for patients. I don’t see it ever being used regularly for diagnostic purposes.
I agree that the published evidence of the test-retest efficacy is fairly sparse (I come up with 71 patients and 102 total participants). I’m basically backing on the Workwell Foundations researchers experience dating back over 10 years. Betsy Keller of Ithaca has also validated those findings in her patients. (A paper is due.) I imagine a good segment (1/3rd???, 40%?) of the community will not have this problem but that’s still 60 or 70% that do. Only large studies will tell us.
It’s the kind of piddly studies that have come out, against a background strong anecdotal reports, that make the progress is this facet of ME/CFS so frustrating. I share your frustration regarding the NIH.
If the CDC had concerns about validating the 2-day test they could have done as they’re doing with cognitive testing, using one center as a test site and, if it was successful, used it in the rest of the centers.
The best way to get a diagnostic tool is, I think – to differentiate select groups of patients (energy challenged, orthostatic intolerant, etc.),dig into their pathophysiology, and then come up with something that can measured in a doctors office.
Of all the subjects in ME/CFS I may be the most passionate about exercise testing probably because my response to exercise is so definitive for me……It’s the hallmark of my disorder. Nothing else comes close and I’m frustrated this avenue has gotten so little attention. This is one subject I can hardly contain myself on :)….(I think every study should include exercise in it. It’s good that the CDC is provoking their participants with exercise – good for them; that’s a good step. If they had taken it one step further that would have been dynamite.)
By the way, I did not include some rather negative comments about the CDC program in the blog that mirrored your statement about who’s going to produce breakthroughs in ME/CFS. But why should the CDC, one of our biggest research programs, not be producing the breakthroughs in ME/CFS. Why should we rely on Lipkin or Montoya? The CDC should be in that conversation as well.
I agree that not all is lost and that researchers will continue to push out 2-day test results and that sooner or later we’ll get to the bottom of this.
Thanks for taking the time to spell out your concerns. 🙂
The 2-day CPET is also used to identify your personal heart rate at the anaerobic threshold. This is the HR number that you set your heart rate monitor alarm to, so that it beeps when your heart rate goes beyond this #. The CPET is the only way to definitively provide this #. And for ME patients (uniquely so far), since the # can drop significantly on day 2, the 2-day test is required to get this #.
So, in addition to diagnosis, this 2-day test provides practical advice you can use continuously to pace your activity and avoid PEM.
Im so angry, Dr. Ungers decision is NEGLIGENT. She needs to be FIRED, AND SUED. Listen people, this person is NOT ON OUR SIDE. For a physician not to order a diagnostic test this critical is negligent at the very least or its personal, political, shes being paid off, or she knows what this disease is and doesnt want it found out, or fill in the blank, nothing else makes sense. Its time to organize. We need to start emailing, calling, writing, every day, until shes fired. Its clear they are not going to move forward unless forced to, they work for us, and its been over a decade with NOTHING! If this committee was a business it would be bankrupt!
Excellent essay, Cort.
After years of faithfully attending the CFSCC meetings in the 1990s, then the CFSAC meetings after 2003, I think I have a pretty good view of what is gong on here – what a coincidence that none of us will be allowed to attend the next CFSAC meeting in person!
The only time I ever saw Dr. Unger get really angry was when we asked CDC to stop emphasizing “Cognitive Behavior Therapy” and “Graded Exercise” as the main treatments for CFS. We also asked that she quit using the website to promote the views of the psychiatric clinic in London run by a regular consultant to CDC – who is also Chief Medical Officer of two insurance companies! She said that both treatments were supported by research and the emphasis on them – including graded exercise – on CDC’s website was “non-negotiable.” Ironically, Dr. Chris Snell – who worked with Staci Stevens on the two-day exercise protocol, was CHAIR of CFSAC at the time, and she would not even consider listening to what his research had shown.
When it comes to scholarship, “difference of opinion” is not enough to warrant such blatant prejudice against other scholars’ work. You have to address the SCIENCE in the study, not whether it is “convenient”. [For the record, Chris Snell has remarked on several occasions at how much ME/CFS patients were willing to endure for the sake of science.]. CDC has always refused to admit the existence of published peer-reviewed scientific research that might cast doubt on their own decisions.
To those asked to participate in this study – please DO NOT boycott it. But the recommendation to work out the day before is an excellent one. After all, this will be used to say whether or not we can perform daily like normal people do. So try to be a normal person the day before.
The speed with which CFSAC has gone from patient-friendly to patient-hostile has me personally stunned.
Who benefits from this? Obviously not the patients. But not medical science, either – a study does no good if it does not include information we have already gained from prior studies.
It is the insurance companies, and penurious governments internationally, who stand to gain the most.
At what cost? Many patients will be harmed if the drumbeat of “exercise! exercise!” continues to emanate from CDC. The teenager forced to work out in gym class who ratchets down from being able to attend school to being partially paralyzed, left bedridden at home. The patient who dies at the age of 50 from a heart attack after being forced into continual anaerobic exercise through ignorance. And the 850,000 patients out there whom CDC has admitted they can’t find.
Go to our Congressional representatives with the results of the Stevens protocol and ask that the CDC’s CFS program be stopped before it does more harm.
And send a copy of this essay to everyone you know.
Thanks.
I think it’s possible that Dr. Unger is worried that a test-retest study result would contradict GET but I think it would just modify GET. I think Staci Stevens would be up in arms over the idea that ME/CFS patients should not ‘exercise’. She strongly believes exercise should be done using HR monitors and the results if exercise testing. When that’s done correctly – many patients can improve…
I’m sure this study will show that exercise exacerbates symptoms – that’s been well studied – I hope it will show cognitive declines as well. Unfortunately it probably won’t get at the root of what’s going one.
I would say: boycot the single CPET test! Digging your own grave is ridiculous. But patients can do exercise the day before this test at home, like you said. That is a good idea for a fair change. Do not rest the day before!
Mary, just wanted to say thank you for your testimony at the last CFSIC meeting, you were awesome. I will be contacting my Congress people .
Mary Schweitzer said:
> …the recommendation to work out the day before is an excellent one. After all, this will be used to say whether or not we can perform daily like normal people do. So try to be a normal person the day before.
I think that I strongly disagree with this advice. Beth Unger is carrying out online cognitive tests (and some self-reported symptom assessments) for 48 hours after the official exercise session, in order to test for post-exertional symptomatic exacerbation. (I assume that a pre-exercise cognitive test will be carried out for comparison.) Even Dr Snell has indicated that there could be some value in this:
Quote:
> I do believe, for most patients, a single max test will elicit PEM which should affect the post-test cognitive scores and fatigue scale scores.
http://www.occupycfs.com/2013/09/10/opportunity-lost/
If participants are already exhausted (because they exhausted themselves prior to the official exercise test) then the study will not show any significant differences between the pre-exertion and post-exertion cognitive tests (because both will be post-exertion). Thus, the tests would wrongly demonstrate that we don’t experience post-exertional malaise. So if participants were to exercise the day before the official exercise test, then i think we’d be shooting ourselves in the foot, because no post-exercise differences would show up in the tests. So I think this is really bad advice, and could potentially do us all a massive disservice.
I suggest that participants should do the study as directed, and then let’s see the results and take it from there. The cognitive tests may turn out to be a very valuable demonstration of post-exertional symptomatic exacerbation. With time and further pressure/persuasion from our community, perhaps Unger will agree to include a two-day exercise test in the future. Dr Snell suggested that Unger has not ruled out including a two-day CPET test at some point:
Quote:
> On what may be a selfish note, I am disappointed that the study does nothing to validate the diagnostic value of repeated CPET testing for ME/CFS. It was briefly mentioned that this might be part of subsequent studies.
http://www.occupycfs.com/2013/09/10/opportunity-lost/
The details of the tests after exercise should be very closely monitored. It looks like a Cognitive Psych evaluation rather than any objective evaluation. Any time “symptoms” are highlighted look out for dumb, vague questionnaires favored by the Psychobabbling crowd.
Cognitive ‘tests’ are not questionnaires. I haven’t read any research about the value of online cognitive tests, so I don’t know much about them, but perhaps they are considered helpful objective measures of cognitive ability.
For example, I think that cognitive tests are considered useful tools to aid the diagnosis of Alzheimer’s and dementia:
http://www.ncbi.nlm.nih.gov/pubmed/11113213
Fatigue questionnaires are totally subjective, and a pretty useless measure of illness, in my opinion.
I disagree. Based on past history it’s easy to see conclusions being reached that poor cognitive performance is related to false beliefs about exercise causing “stress”.
I’ve taken several “neuro-psych” tests. If there is psychiatric bias, then that’s what you get. If the test is given by someone without the bias the test and results are much different. The CDC’s bias is on the psychiatric side so you do math on what the results are going to be.
It’s a matter of trust. The CDC has never shown any interest or evidence in anything but a mental explanation so why does anyone think that will change?
Thank you Cort for writing this article and keeping me informed!! Thank you for the time you spend to keep us all informed.
My opinion is that Dr. Unger and the CDC are afraid of the out come of a two day study. That it would show the truth of our inability to function after the second day. That we would use this study to go after Disability. If a study by the CDC proved that after two days we were worse and couldn’t function, than Lawyers would use that study to go after disability. And that is the last thing that the CDC or any part of our government wants, more money going out to pay for long term disability.
I’m sure Dr. Unger is being advised by someone in the CDC to be careful of what she says or what see writes in any emails that she sends out.
I think we need to send emails out to the CDC and others stating that we want the second day test. That way it will be documented that we don’t think one day is enough. I’m not good at writing letters if someone could put something together we could copy and paste and also a list of emails to send the letter to.
Thanks,
Readyforlife
I don’t recommend sabotaging or not participating in the study. My main disagreement is with what it’s not doing. The study will do some quite valuable things that were lost in my dismay about what they’re not doing.
Dr. Kogelnik, Dr. Peterson, Dr. Klimas, Dr. Lapp, Dr. Bateman have all agreed to participate – they wouldn’t have done that if they didn’t feel the benefits outweighed the risks.
Unfortunately the study won’t be able to associate any of their findings with energy production issues because they probably won’t show up. It will also, to the uninformed, obscure the problems with energy production and give some a plank to say there are none. That’s unfortunate, and it was very frustrating to get so close to exploring exercise capacity on a large scale, and then miss out.
Overall, though, I think Dr. Unger has done a good job during her time at the CDC. I don’t think she’s been completely forthcoming with this study but she’s magnitudes better than Dr. Reeves, and probably better than anyone else we could expect from the CDC.
I propose that we keep pushing for more funding to explore exercise capacity problems in ME/CFS.
“it appears that the CDC had no intention of understanding exercise capacity or examining energy production issues in ME/CFS.”
Finally you’re getting it! This is what Unger/CDC is all about, all the time. Looking like they are doing something while doing nothing or something that will have a negative impact on patients.
Unger/CDC is not looking out for patients.
Thanks for having the balls to say it in print!!!
I agree. The CPET test can validate your capacity objectively and this is a big problem for insurance companies. This test can stand in court. Unger knows that. I think Cort is too optimistic.
Cort,
well written and persuasive.
For me, the most persuasive point was that the two day exercise test is a 95% Accurate diagnostic test. i was just thinking how much clout the 2 day test would have if the CDC just went and tried to replicate the Workwell study.
Good point. That amazing thing about that number (and we should note that there were only 10 controls – although there were I think 50 ME/CFS patients) is that the ME/CFS were not cherry-picked; there were patients with recent onset and later onset and the test accurately identified every ME/CFS patient. It only missed on one healthy control.
That’s an amazing achievement and it speaks to how unusual the exercise problems are. Those healthy controls, by the way, were in the bottom 10% in fitness in the population – they were in horrible shape aerobically.
The two day stress test would take GET, and CBT off the table instantly! Proof that its not in our heads, AND we should NOT exercise. It makes no sense. Unger is not for us. Dr. Unger first rule as a physician is TO DO NO HARM! The absence of the second day test does harm to the patients. The lack of information about this illness to the medical professional community will ripple bad diagnosis, mistreatment, prejudices, undertreatment, and misdiagnosis!!! And above all it will CAUSE HARM! This is the best diagnostic tool we have had, and a huge biomarker for this illness!!
Timv’s comment demonstrates how powerful a diagnostic tool this test appears to be…..It needs more study!
Thanks Cort for all you do.
Thanks Cort!
You have helped my brain grasp this study more, much appreciated.
I may have missed something, but do you or anybody else know if there will be baseline cognitive testing done pre exercise and if the cognitive testing will be done again the day after the exercise or straight after the exercise?. I feel these are important factors also.
It would also be interesting to know what cognitive testing they will be performing actually.
I know for sure in my own case that I would completely bomb in cognitive testing on behavioural working memory/sequencing.
Just interested, but thanks again Cort I thoroughly enjoy your work.
Follow up: I sent the results of the poll on Phoenix Rising to HHS and CDC, as accessed on Wednesday ..93.3% of voting members said “yes”. Snce then there are a few more “yes” votes. The text of the email I sent is here (post #34):
http://forums.phoenixrising.me/index.php?threads/cdc-conf-call-follow-up-poll-would-you-do-2-day-cpet-if-in-cdc-multi-site-study.25286/page-2#post-390572