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Damaged Small Nerve Fibers May be Causing Energy Problems in Chronic Fatigue Syndrome (ME/CFS)

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Reprinted with the kind permission of Cort Johnson and Health Rising

David Systrom, the Harvard pulmonologist, is digging ever deeper into his ME/CFS patients. Systrom and his invasive exercise tests have broken open our understanding of what’s going on during exercise. Through Systrom’s work, we now know much more about what’s going on, metabolically, during exercise.

In “Insights From Invasive Cardiopulmonary Exercise Testing of Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome,” Systrom and company assessed the records of 160 people retrospectively diagnosed with ME/CFS. This study is the first to assess small fiber neuropathy (SFN) in ME/CFS.

The first major finding was that mean peak V02 – the highest level of oxygen extraction that occurred during the exercise – was significantly lower in ME/CFS. Since energy is mostly a function of oxygen extraction, this indicated the ME/CFS patients were unable to produce as much energy as the healthy controls. Under that broad brush, though, several subsets were about to pop out.

Joseph and Systrom uncovered two radically different kinds of ME/CFS. One set of patients has high cardiac output (high-flow) during exercise – their hearts are pumping out a lot of blood; the other has low cardiac output (low-flow) – their hearts aren’t pumping out much.

  • Low-Flow – The hearts of the low-flow group are not pumping out as much blood. Reduced cardiac output is usually due to problems of the heart itself (heart failure) or the lungs (pulmonary hypertension), but neither of these are happening in the low-flow group. Their heart output is reduced because their hearts don’t have enough blood to pump out in the first place. Studies of this group in POTS indicate they have high vascular resistance; i.e., narrowed down blood vessels that impede blood flows.
  • High-Flow – Despite the plentiful blood flows, the high-flow group had the lowest oxygen extraction of the group. They also had the highest venous oxygen tension (vPO2); i.e., higher levels of oxygen were left in the venous blood. (Oxygenated blood flows from the hearts to the arteries, into the muscles, then out of the muscles into the veins, where it returns to the heart.) In short, this was the impaired oxygen extraction group. The authors proposed that either blood is being shunted away from the muscles and/or a mitochondrial problem is present.  Systrom noted that this kind of shunting has been associated with small fiber neuropathy before.

Small Fiber Neuropathy (SFN) (Finally) Found in Chronic Fatigue Syndrome (ME/CFS)

It was good to see, 8 years after the first fibromyalgia (FM) SFN study and dozens of FM SFN studies later, SFN FINALLY getting assessed in ME/CFS. For one thing, it will help people with ME/CFS get their doctors to assess them for this condition if that’s something they want to do.

About a third of the ME/CFS patients – just a bit below the 40% generally seen in FM studies – had small fiber neuropathy (SFN) in their skin. SFN occurs when the very small autonomic/sensory nerve fibers in the skin or elsewhere have become damaged. Studies have also found SFN in the corneas of the eyes of fibromyalgia patients and in POTS. Both Systrom and Oaklander have proposed that small nerve fibers may be damaged elsewhere, such as the blood vessels or the gut.

SFN was found in both low-flow and high-flow ME/CFS patients. The authors speculated how SFN might be causing problems in either group.

  • Low-Flow SFN – The authors proposed that after the blood reached the muscles, small nerve fiber problems were impairing the veins from constricting properly – resulting in blood pooling and blood loss. The resulting reduced blood flows to the heart caused reduced preload and low heart blood flows.
  • High-Flow SFN – The authors proposed that small nerve fiber problems were causing blood to be shunted away from the muscles prior to reaching them. Because less blood was reaching the muscles, less oxygen was being consumed and less energy was being produced aerobically, causing the muscles to produce energy anaerobically, resulting in pain, fatigue, etc. The authors suggested that the loss of small nerve fibers in the gut in this group may be affecting gut motility, discomfort following meals and nausea.


Ron Tompkins of the Open Medicine Funded Harvard ME/CFS Collaborative Research Center is collaborating with David Systrom to dig deeper into what’s happening during exercise. Tompkins is doing the first ever “omics’ analysis of ME/CFS patients’ blood before it gets to the muscles (where all sorts of havoc may be happening) and after it’s passed through them during exercise. Tompkins will be analyzing cytokines and doing metabolomics (metabolism) and proteomic (proteins) in three time points (before, during and after exercise) over 100 patients and healthy controls.

Tompkins recently reported that significantly higher levels of multiple cytokines have been found this far in the ME/CFS patients. That would fit well with Dr. Klimas’s findings suggesting that exercise triggers a burst of inflammation in people with ME/CFS. To cap the Systrom study off, Tompkins will also be taking muscle biopsies and creating metabolic models.

Deconditioning Hypothesis Gets Another Body Blow 

If the deconditioning angle didn’t get destroyed by Visser’s recent study (and the two-day studies), it will hopefully be obliterated by this one. It’s not that deconditioning is not present in ME/CFS – it is. The question is whether deconditioning is causing these abnormal exercise results – it isn’t.

It’s a crucial question. If deconditioning is actually causing these abnormal exercise findings, then all a person with ME/CFS should need to do is exercise to overcome. If it’s not – if there are core problems with generating energy – then too much “exercise” might make the situation worse.

It must be a tough time for the proponents of the deconditioning hypothesis. It’s not that these studies aren’t finding evidence that deconditioning is playing a role – the results they’re getting are actually opposite to those expected if deconditioning was whacking ME/CFS patients’ energy production systems.

The authors reported that the study “definitively eliminates (the) possibility” that deconditioning is causing the exercise abnormalities “because the hallmark of deconditioning is low peak exercise cardiac output” rather than the increased output they found. Plus, instead of the high heart filling pressures seen in deconditioning, they found the opposite – low filling pressures. Plus, they noted that deconditioning doesn’t have any effect on oxygen extraction, which was low in the low-flow patients.

The ME/CFS/POTS/Fibromyalgia/Long-Hauler Mega Group

Postural orthostatic tachycardia syndrome (high heart rates, increased symptoms upon standing) and ME/CFS were linked ever closer together with the authors noting that both the low-flow and high-flow subsets found in ME/CFS are also found in POTS.

Visser’s seminal brain blood flow study, which showed virtually every person with ME/CFS has reduced blood flows to the brain (the very definition of orthostatic intolerance), more closely links ME/CFS, orthostatic intolerance and POTS. Given enough study – and quite a bit has already been done – fibromyalgia will likely fit in there as well. With POTS and dysautonomia showing up in long COVID patients, they are joining the club as well.

A suite of factors – dysautonomia, orthostatic intolerance, exertion problems, metabolic and mitochondrial problems – are showing up in different degrees in all these conditions. At some point, this will all hopefully merge together.

Assessing ME/CFS from a whole body perspective, Systrom is finding problems with foundational factors such as oxygen consumption, blood flows, and gas levels. Systrom’s invasive tests are so effective and illuminating because he’s able to measure how these factors change before and after the blood feeds the muscles. Workwell’s two-day exercise test (CPET) and Avindra Nath’s metabolic chambers are other ways of assessing energy production from a more macro perspective.

Muscle studies and cellular energy production studies, on the other hand, examine energy production from a more micro perspective. While the results have varied from study to study, in general, the two approaches seem to be validating each other: both the more macro and the more micro studies are finding evidence of energy production problems. The key will be in linking them together.

About the Author: ProHealth is pleased to share information from Cort Johnson.  Cort has had myalgic encephalomyelitis /chronic fatigue syndrome for over 30 years. The founder of Phoenix Rising and Health Rising, he has contributed hundreds of blogs on chronic fatigue syndrome, fibromyalgia and their allied disorders over the past 10 years. Find more of Cort’s and other bloggers’ work at Health Rising.

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