Just about everyone with chronic fatigue syndrome (ME/CFS) has the sense that the disease has an astonishing ability to fall through the cracks. It’s a major disease that affects around a million people in the U.S. yet gets very little funding. It has no home at the NIH; it doesn’t fit it in any medical specialty (other than its own); patients can get astonishingly, jaw-droppingly ill; their functionality is far lower than in many other serious diseases, and patients often present with weird findings which doctors tell them they’ve never seen before.
The biggest crack of all, though, may be the strange pattern of exercise intolerance found in the disease. Exercise, after all, is almost like a universal medicine. Moderate levels of exercise are recommended for just about every person and every chronic disease. Studies indicate that even “frail and very old adults” can benefit from exercise.
Research has demonstrated that virtually all individuals can benefit from regular physical activity, whether they participate in vigorous exercise or some type of moderate health-enhancing physical activity. Even among frail and very old adults, mobility and functioning can be improved through physical activity. U.S. Dept of Health and Human Services
Plus, stop exercising and you open yourself up to all sorts of problems. In fact, one study suggested that inactivity was as harmful as smoking. It’s no wonder that doctors just don’t get ME/CFS. The exercise problem flies in the face of just about everything they know and have experienced.
It flies in the face of what we know as well. I spent years trying again and again to vigorously exercise. The fact that it never worked and made me worse hardly dissuaded me. I was going to find a way to exercise. That, unfortunately, never happened.
The two-day exercise test pioneered by the Workwell Foundation for ME/CFS proved a boon for ME/CFS patients in its ability to capture what every person with ME/CFS knows but which few doctors get: exercise, particularly strenuous exercise, makes us worse.
Check out Health Rising’s first blog on Workwell’s findings – the 2009 “A Crack in the Foundation”
A big question confronting our disease is just how unique it is. Are we true outliers in the medical world? Or are there some exercise intolerant compadres out there that we can share our woes, or even better, our findings with?
Past studies indicate that people with heart failure, pulmonary hypertension, end-stage renal disease, cystic fibrosis, mild-moderate COPD, and stroke can all jump on a bike and exercise to exhaustion one day and then hop on the bike again the next day and generate the same amount of energy. It’s a remarkable thing, indeed, that even severely ill people can hammer themselves with exercise one day and then do the same the next day – with no diminishment in their ability to produce energy.
Take pulmonary hypertension (PH), a very, very serious disease (about 50% of patients die within five years) known to cause exercise intolerance. By narrowing the blood vessels in the lungs, PH makes it difficult to get oxygen to the tissues. The disease seems the very definition of exercise intolerance, yet, in contrast to ME/CFS, exercise itself does not damage people with PH. People with PH can exercise to exhaustion one day and then do the same the next day without impairment.
These findings, indicating that even people with severe diseases can reproduce their energy production results on the second day of a maximal exercise test, are so consistent that, outside of ME/CFS, two-day exercise studies appear to have been largely abandoned. The last non-ME/CFS two-day exercise study appears to have been done in 2004, and most date from the 80’s and 90’s.
They were relics of the past until Workwell brought them back into the medical field with their ME/CFS studies about ten years ago. Since then, Workwell in California, Betsy Keller at Cornell, Katrina Lien in Norway, David Patrick in British Columbia, Lynette Hodges in New Zealand and others have been conducting 2-day CPET studies in ME/CFS. Maureen Hanson at Cornell is currently including a 2-day maximal exercise test in her NIH-funded ME/CFS center work.
Most of the studies have examined the performance of ME/CFS patients vs. healthy controls, but two small studies/case reports which included other fatiguing diseases have given us another look at the crucial question of how unique the exercise intolerance in ME/CFS is.
The most recent study is the Larson/Workwell case-series that compared the results of a two-day maximal CPET test in six women (matched for age and body mass index).
The Larson-Workwell Case Reports
The six women included a sedentary but healthy person without fatigue, an active person without fatigue, a person with multiple sclerosis (MS), a person with HIV, and two people with ME/CFS – a lower functioning person (low energy production; low VO2 max) and a higher functioning individual (higher energy production; high VO2 max).
Both the MS and HIV patients experienced high levels of fatigue, but both were able to duplicate their levels of energy production on the second exercise test. In fact, the active healthy person and the MS and HIV patients all significantly improved their ability to exercise on the second test (their energy consumption at anaerobic threshold increased).
Not so with the two ME/CFS patients. Exercise one day whacked their ability to exercise the next day.
The exercise tests revealed some interesting trends. The higher level of functioning in the one patient didn’t protect her at all, as both she and the lower functioning patient displayed “substantial decreases in every variable at anaerobic threshold” on their second CPET (ouch!).
This was despite the fact that she was truly much higher functioning than the lower functioning patient. Even on her second exercise test the higher functioning patient produced more energy (oxygen consumption – 14.6) – than the lower functioning patient produced on her first exercise test (8.8).
Despite her improved level of functioning, the higher functioning person with ME/CFS suffered an even greater drop in energy production on the second exercise test – a remarkable 30% – than did the lower functioning person (16%).That demonstrated how difficult it is for even a higher functioning person to estimate how big of a metabolic hit exercise may incur for them.
The exercise scores of the lower functioning patient suggested that any activity more intense than slow walking, standing while washing dishes, or playing a musical instrument was likely to “trigger excessive activation of (her) impaired oxidative metabolic pathway”.
All in all, while the MS and HIV patients and healthy controls adapted to the exercise and generally got stronger during the second exercise test, the ME/CFS patients significantly declined in just about every parameter.
Score one for a unique intolerance to exercise in ME/CFS.
The Hodges New Zealand Study
Remarkably – at least to me because I completely missed it – the 2017 Hodges New Zealand study was the first to explicitly assess whether the exercise intolerance and post-exertional malaise in ME/CFS is unique. Past studies certainly suggest that exercise uniquely whacks the energy production systems in ME/CFS, but as noted above, most of the 2-day exercise studies in other diseases are quite old. Plus, none of them pitted people with ME/CFS against people with other fatiguing diseases. That’s a critical need – and that’s what Hodges did.
The Hodges study put people with ME/CFS (n=10), people with multiple sclerosis (n=7) and healthy controls (n=17) through a 2-day exercise study.
The small Hodges study found a significantly lower workload at anaerobic threshold in the ME/CFS patients compared to the healthy controls on day 2. The MS patients, on the other hand, were able to meet the same workload during the second exercise test as they did during the first exercise test.
Workload refers to the amount of power the participants can put out. As the exercise test proceeds, the resistance at the pedals is increased, requiring the participants to exert more and more force to move them. The significantly reduced workload in the ME/CFS group at anaerobic threshold on the second exercise day indicated that the first exercise test had significantly impaired their ability to produce force the next day.
Put another way, if this were a weight-lifting contest, the ME/CFS group would have been able to lift considerably less weight the second day.
The study, interestingly, did not find a decrease in energy production (oxygen consumption) at anaerobic threshold in the ME/CFS group on day 2. That brought up the interesting conclusion that the ME/CFS patients were using as much oxygen on the second day, but the oxygen they were using was less effectively used, as they were unable to produce the same amount of force.
Several studies suggest that workload, or the ability to produce force – a seemingly more direct measurement of functioning – may by more impaired by exercise than oxygen consumption (energy production) in ME/CFS.
We shouldn’t get hung up on individual measurements – particularly in small studies like this. It’s clear that exercise affects people with ME/CFS differently. I know of an ME/CFS patient who exhibits significantly reduced oxygen consumption and ventilation at anaerobic threshold on the second day but no drop in workload. (Their workload was abnormally low at anaerobic threshold on both days but did not drop on the second day.)
Exercise, then, can impair oxygen consumption or workload and/or ventilation in ME/CFS. The key is that each two-day exercise study thus far has found significant reduction in some important factor at anaerobic threshold – the point at which the clean aerobic energy production system declines dramatically and the more inefficient and toxic anaerobic energy production system takes over – and exercise becomes dramatically more difficult.
Fatigue vs PEM (Post-Exertional Malaise)
Larson suggested that the type of fatigue found in MS – which they suggested was neurogenic – differed from the kind of metabolic fatigue found in ME/CFS. They’re not the first to suggest this.
Alan Light’s ME/CFS and MS exercise study suggested there’s fatigue and there’s post-exertional malaise – and the two are different. The MS patients actually reported more fatigue – twice as much fatigue, in fact, as the people with ME/CFS (MS – 72-ME/CFS – 35).
The MS patients’ physical and mental fatigue did rise 8 hours after exercise, but both were back to baseline within 24 hours. At no point did the exercise bout increase their pain levels.
The ME/CFS patients, on the other hand, immediately experienced increased levels of physical and mental fatigue and pain after exercise that were still present 8, 24 and even 48 hours later. Plus, exercise evoked different patterns of gene expression.
Light’s results were partially echoed by a 2014 study that examined symptom levels following a moderate exercise session in MS and ME/CFS patients. It found a trend toward increased pain in both groups (but not a significant increase) and a significant decrease in fatigue in the MS group. The ME/CFS group, however, experienced a significant increase in fatigue.
In their conclusions, though, the authors – who clearly wanted to buck up the idea of exercise in ME/CFS – simply ignored the significant increase in fatigue in the ME/CFS group and simply declared that, “exercise provides many benefits for those with MS or ME/CFS,” and that moderate exercise, “may not exacerbate pain or function” in either disease.
ME/CFS received a different fate in a review of the cause of the fatigue in Parkinson’s disease and other disorders – it simply disappeard. Fatigue is one of the first symptoms to appear in Parkinson’s disease, and is such an issue in it that Simon Wessely even developed a fatigue scale specifically for it.
It was remarkable, given all the exercise studies and other studies that have attempted to understand the fatigue in “chronic fatigue syndrome”, to see ME/CFS completely ignored in an overview of fatigue in Parkinson’s and other diseases (including cancer fatigue).
Face-to-face exercise studies (involving ME/CFS and other fatiguing diseases) unfortunately are still quite limited, but thus far, these and past studies of other diseases suggest that the exercise intolerance in ME/CFS may be unique. Larger studies are clearly needed to clarify whether the fatigue and the post-exertional malaise ME/CFS is so well known for are unique, and if they are, how so. My guess is that some people with mitochondrial diseases and disorders of inborn errors of metabolism (a blog from Brian is coming up) could exhibit the same kind of exercise intolerance found in ME/CFS.
Fibromyalgia, with its more limited exertion problems, is a huge question mark for ME/CFS. (Workwell hopes to have papers out on the exercise intolerance in people with comorbid fibromyalgia and Lyme disease by this summer.)
Meanwhile, David Systrom recently published a kind of magnum opus – a 300 ME/CFS plus invasive CPET study – that digs deeper than ever into the exercise problems found in this disease. A blog on that is coming up.
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