Category: Pathophysiology

The Glymphatic–Meningeal Lymphatic System and Autophagy in ME/CFS and Long COVID: A Mechanistic Perspective

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Post-Acute Sequelae of SARS-CoV-2 infection (Long COVID) are complex multisystem disorders affecting 60–400 million individuals globally. They are considered post-infectious illnesses and share similar biological mechanisms, including immune dysregulation, orthostatic intolerance and cognitive dysfunction, highlighting a substantial overlap between the two conditions. Persistent fatigue, sleep dysfunction, post-exertional malaise and brain fog are among some of their most common and debilitating symptoms.
Despite extensive research, they remain incurable, with no effective treatments, or simple diagnostic tests. They are increasingly understood as heterogeneous, multisystem diseases, involving neurological symptoms, with varying severities and diverse underlying biological abnormalities. More recently, the possibility of glymphatic dysfunction and autophagy impairment have been proposed as parts of the mechanistic features of the pathophysiology of these conditions, which are discussed more fully in the present perspective.
With the glymphatic and meningeal lymphatic systems being operationally integrated, we will try to delineate how the metabolic waste removal mechanism afforded by this system may work together with autophagy to maintain brain homeostasis. We will provide some of the established mechanistic features of toxicity of misfolded proteins, explore their role in causing glymphatic dysfunction and impairing autophagy, and discuss the potential for therapeutic interventions.
Source: Nemat-Gorgani M, Jensen MA, Davis RW. The Glymphatic–Meningeal Lymphatic System and Autophagy in ME/CFS and Long COVID: A Mechanistic Perspective. International Journal of Molecular Sciences. 2026; 27(20):9351. https://doi.org/10.3390/ijms27209351 https://www.mdpi.com/1422-0067/27/20/9351 (Full text)

Natural Strategies for Stopping a Common Energy Drain in ME/CFS and Fibromyalgia

By Jacob Teitelbaum, MD

www.ProHealth.com • October 12, 2011

Dr. Teitelbaum, a well-known fatigue and pain specialist who contracted CFS as a medical student, has researched ME/CFS/FM patients’ nutritional and therapeutic needs for more than 20 years. This article is reproduced with kind permission* from his educational web site at https://www.vitality101.com/

Reprinted with the kind permission of ProHealth: 10/12/11

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Treating Low Blood Volume & Decreased Heart Function in CFS & FM

In this important article we will discuss a critical but usually overlooked part of treating Chronic Fatigue Syndrome and fibromyalgia effectively. It can be relatively easy to treat, but is not very glamorous, and is therefore often forgotten.

We will focus on research by Dr. Barry Hurwitz and a team of University of Miami researchers, including Dr. Nancy Klimas, who is wonderful and one of my favorite people in the CFS community… Their [2009] study shows that patients with CFS have:

1. A lower blood volume (basically are dehydrated).

2. Fewer red blood cells to carry oxygen and nutrients (basically anemia, despite normal blood tests).

The study also discusses that although the heart may be smaller in CFS and beats less efficiently, this is likely caused by the dehydration and low blood volume, as opposed to primarily being a heart problem. (More on the details later.)

The good news is that all of these issues can be effectively treated and optimized naturally – which can leave you feeling much better!

THE BOTTOM LINE FIRST

There are several key things that you can do to treat the low blood volume and low blood cell levels that will leave you feeling better:

1. Treat the Dehydration.

Despite your increased thirst and drinking a lot (“like a fish”), most of you are still dehydrated because you’re urinating even more. This occurs for several reasons, including underactive adrenal function and a decrease in antidiuretic hormone (“anti-peeing hormone”), both of which are routinely present in CFS because of the hypothalamic dysfunction (“blowing a fuse”) that we often discuss….

Quick Fixes:

a. Drink more water! Instead of counting glasses of water (an annoying way to spend the rest of your life), check your mouth and lips to see if they are dry. If they are, drink!

b. Eat more salt. Unless you have high blood pressure or heart failure, you need more salt than most people. In fact, many studies have shown that the more salt people eat the longer they live [see sidebar at end of article, “High Salt Intake is Associated with BETTER Health”], and for most people the need to avoid salt has been a problematic medical myth (see six dangerous “Medical Myths“). Use an iodized salt or better yet sea salts… Enjoy salty foods as well.

c. Improve adrenal function. This is discussed at more length in “The Adrenal Gland, and Symptoms of Adrenal Insufficiency,” but a simple way to do this is with an excellent product called Adrenal Stress End.

d. Saline IVs. Clinical experience has also shown that salt water (saline) IVs can be very helpful. The effects are transient though, unless other nutrients are added  – e.g., the Myers’ Cocktails [which are IV vitamin and mineral therapies first conceived in the 1970s by the late John Myers, MD, at Johns Hopkins] administered at holistic physicians’ offices [such as] the Fibromyalgia and Fatigue Centers.

2. Increase Your Body’s Production of Red Blood Cells.

Although treating the infections and hormonal problems we discuss overall in the SHINE Protocol will do this (addressing possible problems with Sleep, Hormones, Infection, Nutrition, and Exercise), below are key things that will help.

a. Treat for low iron – even if your blood tests are normal but modestly low. The best blood test is called a “ferritin” level. Your doctor will say it is normal if it is over 12, but research has shown(2) that in people with chronic fatigue, iron supplementation increased energy dramatically in people with a ferritin under 50 (see Iron Helps Fatigue – Even with Normal Iron Levels and No Anemia) who were not anemic. If the ferritin blood test is under 50, or the iron percent saturation blood test is under 25%, take 1-2 tablets of iron (29 mg with vitamin C) each afternoon or evening on an empty stomach for 4-6 months.

b. Treat for low testosterone and low thyroid levels – despite the normal blood tests. Both of these, especially the testosterone (use only the safe and natural bioidentical forms), increase red blood cell production.

3. Improve Your Heart Function

Though the study discussed in this article notes that the low blood volume and anemia are key, other studies and clinical experience show that nutrients that improve heart function also improve energy in CFS patients. These include:

a. Ribose (Corvalen) 5 gm (1 scoop) 3x day for 3 weeks, then twice a day.

b. Acetyl L-carnitine 500 mg 2x day. [See for example “Long-chain acylcarnitine deficiency in patients with Chronic Fatigue Syndrome,” Journal of Internal Medicine, Jul 2011].

c. The Energy Revitalization System vitamin powder (contains 50 nutrients including B vitamins and magnesium).

d. Coenzyme Q10 at 200 mg daily.

Give the above treatments 6-12 weeks to see the effect. But by one month, most of you will be feeling a lot better with these treatments. In addition, if you have not already done so, do the free Symptom Analysis Program to tailor an overall treatment protocol to your case. Although you do not need to have your blood tests results, if they are available the program will also analyze the more important tests.

WHAT THE UNIVERSITY OF MIAMI STUDY SHOWS

The study(1) looked at 146 people with chronic fatigue syndrome, 30 of whom were very severely affected. It compared them to healthy controls and then factored in how active or sedentary the people were.

People with CFS showed 25% lower heart contractility, so they pumped much less blood.

They then did specialized testing which showed what the person’s total blood volume was and also whether they had enough red blood cells, both of which have been shown to be low in the majority of those with severe CFS.

As all of the above problems have been shown to be common in CFS, the study explored whether there was predominantly a heart problem or whether all of these findings could be explained by dehydration and having too few red blood cells. I would note that, normally, having too few red blood cells would be called being anemic.

Unfortunately, the standard blood tests for anemia compare the amount of blood cells relative to the blood volume. As both are low, the blood count tests come back as normal despite CFS patients in reality being functionally very anemic.

As the study authors note, “The elevated prevalence of low red blood cell volume suggests that the CFS subjects may have an anemia type that goes undetected by standard hematologic evaluations.”

In other words, people with CFS are likely to be anemic despite normal testing (being 6% to 13% lower than optimal, depending on the severity of their CFS).

The role of decreased heart function in CFS has been a major focus of work by Dr. Paul Cheney, MD, PhD, a chronic fatigue syndrome expert who is intimately familiar with the effects of heart problems, as he needed a heart transplant himself. He theorizes (and I am markedly oversimplifying his theory) that heart function decreases as an adaptation to not being able to properly handle the oxygen needed to make energy in CFS.

Chronic disease in general can trigger dehydration and low red blood cell volume, so there are many possible reasons for these occurring in CFS. Deconditioning can also then decrease heart function.

This study was associated with another study looking at whether injections of a prescription blood cell stimulating hormone called
“erythropoietin” would be helpful in CFS, which would naturally lead to some focus towards interpreting the results as being associated with a deficiency of blood cells as opposed to a heart problem. The benefits of erythropoietin treatment were modest relative to the cost and hassle, though, and I think the researchers’ bias is fairly modest.

The authors conclude, “Given these findings, it may be prudent in the clinical setting to perform a direct examination of blood volume status in CFS patients and consider treatment for those with abnormal levels. A blood volume deficit may:

• Impact adversely oxygen delivery and nutrient supply,

• Impair hemodynamic regulation (e.g., blood pressure and heart function),

• And contribute to the exacerbation of fatigue and other CFS symptomatology.”

As their earlier study showed minimal benefit from only increasing the amount of red blood cells using erythropoietin, it again shows the need to use an overall treatment approach to treat all the problems present in CFS.

These include raising red blood cell mass and treating the dehydration, but also treating the underlying infections, adrenal under activity, and other problems that are at the root of these problems.

As we know that most people with CFS will have the dehydration and “anemia despite normal blood testing,” I do not think it is worth the cost of doing these expensive nuclear scans, but instead recommend the simple treatments discussed in the summary above, which we know are helpful in CFS. (Again, these are part of the SHINE Protocol.)

* * * *

SIDEBAR: High Salt Intake is Associated with BETTER Health
Re: “Sodium Intake & Mortality Follow-Up in the Third National Health and Nutrition Examination Survey – NHANES III.”

This study is a fascinating one. It is based on the NHANES data base, which is one of the most respected (if not the most respected) nutritional data bases in the country. What the study showed is the opposite of what we have been led to believe medically.

It showed that the lower the salt intake, the HIGHER the risk of death. Put differently, our advice to people to avoid salt is more likely to be harmful than helpful!

On the other hand, though there was no significant evidence that salt was harmful, the evidence for a low salt diet being harmful was modest, so if people want to avoid salt it probably won’t hurt them too much.

The possibility of a low salt diet being harmful was also likely affected by more people in the low salt diet group having high blood pressure, so it may have been the underlying high blood pressure which caused their higher death risk (i.e., people with high blood pressure were told by their doctors to be on low salt diets, and this could be a “confounding variable” that makes people misinterpret the data. The low salt didn’t kill them, but rather it was their earlier high blood pressure).

Bottom line – Enjoy yourself! Eat the amount of salt that your body wants and don’t worry about it (if you don’t have high blood pressure or heart failure).

The Abstract:
“Sodium Intake and Mortality Follow-Up in the Third National Health and Nutrition Examination Survey – NHANES III.” (The full text article is here – https://pmc.ncbi.nlm.nih.gov/articles/PMC2518033/)

Background: Sodium restriction is commonly recommended as a measure to lower blood pressure and thus reduce cardiovascular disease (CVD) and all cause mortality. However, some studies have observed higher mortality associated with lower sodium intake.

Objective: To test the hypothesis that lower sodium is associated with subsequent higher cardiovascular disease (CVD) and all cause mortality in the Third National Health and Nutrition Examination Survey (NHANES III).

Design: Observational cohort study of mortality subsequent to a baseline survey.

Participants: Representative sample (n=8,699) of non-institutionalized US adults age 30 and older, without history of CVD events, recruited between 1988-1994.

Measurements and Main Results: Dietary sodium and calorie intakes estimated from a single baseline 24-h dietary recall. Vital status and cause of death were obtained from the National Death Index through the year 2000.

Hazard ratio (HR) for CVD mortality of lowest to highest quartile of sodium, adjusted for calories and other CVD risk factors, in a Cox model, was 1.80 (95% CI 1.05, 3.08, p=0.03). [Note: an HR of 1.0 would represent no difference; so a ratio of 1.80 would indicate that individuals in the lowest sodium intake quartile were 80% more likely on average to die of a cardiovascular event than those in the highest sodium intake group.]

Non-significant trends of an inverse association of continuous sodium (per 1,000 mg) intake with CVD and all-cause mortality were observed with a 99% CI of 0.73, 1.06 (p=0.07) and 0.86, 1.04 (p=0.11), respectively, while trends for a direct association were not observed.

Conclusion: Observed associations of lower sodium with higher mortality [all causes] were modest and mostly not statistically significant. However, these findings also suggest that for the general US adult population, higher sodium is unlikely to be independently associated with higher CVD or all-cause mortality.

___

1. Low Blood Volume and Red Blood Cell Mass Study, Abstract: “Chronic fatigue syndrome: Illness severity, sedentary lifestyle, blood volume and evidence of diminished cardiac function,” Barry E. Hurwitz, Nancy G. Klimas, et al. Behavioral Medicine Research Center, University of Miami, Florida. Clinical Science (Lond), Oct 19, 2009.

2. Reference for Iron Study: “Iron supplementation for unexplained fatigue in non-anaemic women: Double blind randomised placebo controlled trial,” F Verdon, et al. BMJ, May 2003.

* Copyright © 2011 by The Annapolis Chronic Fatigue and Fibromyalgia Research Center for Effective CFS/FMS Therapies. All rights reserved.

Disclaimer: These statements have not been evaluated by the FDA. This information and the supplements discussed are not intended to diagnose, prevent, treat or cure any illness, condition or disease. It is very important that you make no change in your healthcare plan or health support regimen without researching and discussing it in collaboration with your professional healthcare team.

Epigenome-wide profiling identifies distinct DNA methylation architecture underlying ME/CFS and fibromyalgia symptom burden

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia are overlapping chronic disorders characterized by fatigue, pain, cognitive dysfunction, sleep disturbance, and multisystem symptoms. Whether peripheral blood DNA methylation reflects diagnostic categories, quantitative symptom burden, or both remains unclear. We aimed to identify DNA methylation axes associated with diagnosis, symptom dimensions, and clinical differences between these conditions.

Methods: This cross-sectional study included 188 women: 73 healthy controls, 71 with ME/CFS, and 44 with fibromyalgia. DNA methylation was profiled in peripheral blood mononuclear cells using the Illumina MethylationEPIC v2 array. Principal component analysis identified latent methylation axes. Linear models adjusted for age, body mass index, and estimated immune-cell composition tested associations with diagnostic group and clinical measures. Region-level methylation analyses, functional enrichment, bootstrap resampling, permutation testing, leave-one-out analyses, and medication/comorbidity sensitivity analyses were performed.

Results: Both patient groups had greater symptom burden than healthy controls but differed clinically. Fibromyalgia showed greater widespread pain, pain catastrophizing, central sensitization inventory scores, and temporal summation, whereas ME/CFS showed greater post-exertional malaise, cognitive symptoms, and lower physical activity. Two methylation axes showed clinically relevant associations. PC5 differentiated ME/CFS from fibromyalgia and healthy controls and was associated mainly with post-exertional malaise and cognitive symptoms. PC6 separated both patient groups from healthy controls but not from each other, and was associated with broader symptom burden, including widespread pain, pain impact, sleep disturbance, visceral symptoms, and temporal summation. The temporal summation association, together with higher widespread pain and temporal summation in fibromyalgia, suggests that PC6 includes a pain-related component extending to experimentally assessed nociceptive summation. Region-level analyses identified 591 PC5-associated and 54 PC6-associated high-confidence differentially methylated regions. Enrichment implicated neuroimmune, metabolic, cytokine, NF-κB, JAK-STAT, TGF-β, and immune-regulatory pathways. Sensitivity analyses supported the stability of the main associations.

Conclusions: Peripheral blood DNA methylation profiles identified partly distinct but overlapping DNA methylation axes in ME/CFS and fibromyalgia. PC5 was aligned with post-exertional malaise and cognitive symptoms, whereas PC6 was aligned with broader pain-related multisystem burden. Independent replication and longitudinal studies are needed to establish clinical utility.

Source: Polli A, Hendrix J, Wyns A, Van Campenhout J, Allard S, Aerts JL, Laeremans T, Xiong H, Buntinx Y, Michiels J, Ben Amar J, Godderis L, Thienpont B, Nijs J. Epigenome-wide profiling identifies distinct DNA methylation architecture underlying ME/CFS and fibromyalgia symptom burden. J Transl Med. 2026 Aug 22;24(1):1222. doi: 10.1186/s12967-026-08824-5. PMID: 42811334. https://link.springer.com/article/10.1186/s12967-026-08824-5 (Full text)

Muscle symptoms and a latent physiological symptom-dysregulation factor in ME/CFS: exploratory analyses by sex and age-defined menopausal-status proxy group

Abstract:

Background: Muscle-related symptoms are among the most disabling manifestations of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), yet their position within the broader symptom architecture of the disease remains unclear. We hypothesized that muscle symptoms may represent a candidate integrative symptom within a broader shared symptom-dysregulation structure and their symptom associations differ according to sex and menopausal status.

Methods: Cross-sectional data from 736 individuals with physician-diagnosed ME/CFS enrolled in the APAV-ME/CFS registry were analysed. Muscle problems served as the primary outcome variable. Associations with 14 symptom domains were examined using multivariable logistic regression. Pearson and tetrachoric correlations, exploratory factor analysis, and structural equation modeling (SEM) were used to identify latent symptom structures. Exploratory analyses were stratified by sex, menopausal status, and disease duration.

Results: In the full multivariable model (non-robust estimates), breathing problems (OR 2.49 [95% Conf. Interval: 1.42-4.38], p = 0.001), flu-like symptoms (OR 1.97 [1.14-3.42], p = 0.015), and temperature-regulation disorders (OR 1.97 [1.10-3.51], p = 0.021) independently predicted muscle problems. A reduced physiological model (not-robust estimates) additionally identified cardiovascular symptoms (OR 1.87 [1.09-3.24], p = 0.024) as a significant predictor. Tetrachoric correlations demonstrated substantial latent associations between muscle problems and breathing difficulties (ρ = 0.52), cardiovascular symptoms (ρ = 0.49), temperature-regulation disorders (ρ = 0.49), visual disturbances (ρ = 0.39), and flu-like symptoms (ρ = 0.39). Factor analysis and SEM supported a single latent physiological dysregulation factor with good model fit (RMSEA = 0.046, CFI = 0.971, TLI = 0.952, SRMR = 0.026).

The sex-stratified analyses revealed differences in the pattern of statistically significant symptom associations across the subgroups. However, the overall test of the symptom-by-sex interaction terms did not provide evidence for a statistically established difference in the symptom associations by sex. Thus, the subgroup-specific patterns should primarily be interpreted as descriptive and exploratory. At the individual symptom level, the association between breathing-related symptoms and muscle problems showed a statistically significant interaction with sex, suggesting that this association may differ between women and men. However, this finding should be interpreted cautiously given the non-significant overall interaction test and the wide confidence interval of the interaction estimate.

In women, all five physiological symptoms independently predicted muscle problems, whereas in men only breathing problems and temperature-regulation disorders remained significant. Women classified as premenopausal and postmenopausal based on an age-defined proxy showed different patterns of symptom associations with muscle problems in subgroup-specific analyses. Women in the premenopausal age-proxy group showed significant associations with cardiovascular symptoms, visual disturbances, and temperature-regulation disorders, whereas women classified as postmenopausal showed significant associations with breathing difficulties and flu-like symptoms. However, the overall menopausal-by-symptom interaction was not statistically significant (Wald χ2 (5)=5.96, p = 0.310).

The specified latent physiological factor showed statistical comparability across the cross-sectional disease-duration groups. Gastrointestinal complaints loaded substantially on the latent factor despite lacking an independent association with muscle problems in multivariable regression. Urogenital symptoms also showed a smaller but significant association with the latent factor and substantial item-specific variance.

Conclusions: Muscle symptoms may represent a candidate integrative symptom within a latent physiological symptom-dysregulation factor encompassing respiratory, cardiovascular, thermoregulatory, visual, and flu-like symptoms in this ME/CFS sample. Secondary analyses suggested that gastrointestinal complaints were also part of the broader physiological symptom pattern, although they were not independently associated with muscle problems. The specified latent physiological factor showed no overall statistical evidence of measurement differences across the cross-sectional disease-duration groups. However, subgroup-specific symptom patterns differed descriptively by sex and age-defined menopausal-status proxy group.

Women classified as premenopausal were characterized primarily by cardiovascular, visual, and thermoregulatory symptom associations, whereas women classified as postmenopausal and men showed greater prominence of breathing-related symptoms. Flu-like symptoms were independently associated with muscle problems in the postmenopausal subgroup but not in the premenopausal subgroup. Because the corresponding interaction term was not statistically significant, this subgroup contrast should be interpreted as an exploratory difference in association rather than as evidence of a menopause-specific effect. More broadly, the findings are compatible with the hypothesis that the latent symptom-dysregulation factor may reflect a chronic PEM-associated multisystem response.

Whether this symptom-dysregulation factor corresponds to interacting autonomic, vascular, immunological, and metabolic processes remains to be determined by longitudinal and biomarker-based studies. ME/CFS phenotyping may improve patient stratification and facilitate the development of mechanism-based therapeutic approaches.

Source: Habermann-Horstmeier L, Horstmeier LM. Muscle symptoms and a latent physiological symptom-dysregulation factor in ME/CFS: exploratory analyses by sex and age-defined menopausal-status proxy group. J Transl Med. 2026 Sep 28;24(1):1216. doi: 10.1186/s12967-026-09018-9. PMID: 42806383. https://link.springer.com/article/10.1186/s12967-026-09018-9 (Full text)

Hemodynamic Phenotyping in ME/CFS and ANOCA: Complementary Insights from Coronary Function Testing and Invasive Cardiopulmonary Exercise Testing

Abstract:

This single-center cohort study sought to evaluate the association between Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Angina with Non-Obstructive Coronary Arteries (ANOCA), by determining the observed frequency of ME/CFS among patients with ANOCA diagnosed by coronary function testing (CFT). Additionally, we performed an exploratory analysis of the diagnostic utility of invasive cardiopulmonary exercise testing (iCPET) in ME/CFS patients with CFT-confirmed ANOCA, with the aim of identifying the predominant physiological mechanism responsible for exertional limitation in this population.

Systematic medical record review of 261 patients with CFT-confirmed ANOCA was performed using standardized diagnostic criteria to identify concurrent ME/CFS diagnosis. ME/CFS was identified in 47 patients, representing an observed frequency of 18%. The only statistically significant difference between ANOCA patients with and without ME/CFS was a higher frequency of connective tissue disease in the ME/CFS group (p = 0.0221). In a separate cohort of 27 patients with ME/CFS who underwent iCPET, 24 patients (89%) had CFT-confirmed ANOCA.

The diagnosis of ANOCA by CFT prompted a change in medical management in 81% of patients in this cohort. iCPET revealed a primary peripheral limitation to exercise, characterized by impaired peak systemic oxygen extraction despite normal peak oxygen delivery. This study demonstrates a clinically significant association between ME/CFS and ANOCA.

These findings underscore the clinical value of CFT in patients with ME/CFS and exertional chest pain and highlight iCPET as a complementary tool for hemodynamic phenotyping in this population. Prospective studies incorporating simultaneous CFT and iCPET with molecular phenotyping are warranted.

Source: Mackay Z, Shah S, Villalobos JG, Latif N, Arun A, Joseph P, Heerdt P, Singh I. Hemodynamic Phenotyping in ME/CFS and ANOCA: Complementary Insights from Coronary Function Testing and Invasive Cardiopulmonary Exercise Testing. Am J Physiol Heart Circ Physiol. 2026 Sep 21. doi: 10.1152/ajpheart.90080.2026. Epub ahead of print. PMID: 42767811. https://journals.physiology.org/doi/abs/10.1152/ajpheart.90080.2026 (Full text available as PDF file)

Total blood volume and red blood cell volume are not associated with orthostatic intolerance in adults with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Orthostatic intolerance is common in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and may worsen daily functioning. Although hypovolemia has been proposed as a contributor, its relationship to objective orthostatic abnormalities remains uncertain. We examined whether measured blood-volume abnormalities were associated with standardized lean-test outcomes.

Adults meeting the 1994 ME/CFS criteria and reporting substantial post-exertional malaise underwent a 10-min lean test with capnography, followed 8 days later by total blood volume (TBV) measurement using the Daxor BVA-100. Supine hypocapnia was defined as baseline end-tidal CO2 (eTCO2) <34 mmHg; postural orthostatic syndrome of hypocapnia (POSH) as normal supine eTCO2 with any leaning value <34 mmHg; and postural orthostatic tachycardia syndrome (POTS) as a heart-rate increase ≥30 beats/min or absolute heart rate ≥120 beats/min.

Among 49 participants, TBV was hypovolemic in 35%, normovolemic in 43%, and hypervolemic in 22%; red blood cell volume was deficient in 49%. Overall, 55.1% had at least one lean-test abnormality, most commonly POSH (40.8%). Abnormalities did not differ by TBV or red blood cell volume category. Static blood-volume categories were not associated with lean-test-defined orthostatic abnormalities in ME/CFS, suggesting contributions from autonomic, vascular, respiratory, or cerebrovascular mechanisms.

Source: Yamazaki T, Mancini DM, Blate M, Quan P, Norweg A, Cook DB, Natelson BH. Total blood volume and red blood cell volume are not associated with orthostatic intolerance in adults with myalgic encephalomyelitis/chronic fatigue syndrome. Physiol Rep. 2026 Sep;14(17):e71087. doi: 10.14814/phy2.71087. PMID: 42717554. https://physoc.onlinelibrary.wiley.com/doi/10.14814/phy2.71087 (Full text)

Skeletal muscle properties in long COVID and ME/CFS differ from those induced by bed rest

Abstract:

Patients with long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) suffer from post-exertional malaise. The accompanying physical inactivity may contribute to a lower aerobic capacity and may explain skeletal muscle adaptations in these patients. Here, we compare whole-body exercise responses and skeletal muscle adaptations after strict 60-day bed rest in healthy people with those in long COVID and ME/CFS patients, and healthy age- and sex-matched controls.

Bed rest alters respiratory and cardiovascular responses to maximal exercise, which are dissimilar in patients. Bed rest causes muscle atrophy without altering fiber type. Both patient groups have more glycolytic fibers, and ME/CFS patients display type I-specific atrophy. Only after bed rest is oxidative phosphorylation capacity associated with maximal oxygen uptake.

As skeletal muscle characteristics differ between patients and healthy individuals after bed rest, physical inactivity cannot solely explain the lower exercise capacity and skeletal muscle adaptations in long COVID and ME/CFS patients.

Source: Charlton BT, Slaghekke A, Appelman B, Eggelbusch M, Huijts JY, Noort W, Hendrickse PW, Bloemers FW, Posthuma JJ, van Amstel P, Goulding RP, Degens H, Jaspers RT, van Vugt M, Wüst RCI. Skeletal muscle properties in long COVID and ME/CFS differ from those induced by bed rest. Nat Commun. 2026 Jul 28;17(1):9125. doi: 10.1038/s41467-026-75725-y. PMID: 42649155. https://www.nature.com/articles/s41467-026-75725-y (Full text)

A cardiometabolic perspective on post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID

Abstract:

Post-exertional malaise (PEM), the defining feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is increasingly recognized in individuals with Long COVID. Although traditionally viewed as symptom exacerbation and/or emergence of new symptoms following exertion, PEM may reflect disrupted coordination across interconnected physiological systems operating over distinct post-exertional timescales. Such disruption may result in altered post-exertional physiological trajectories that contribute to multisystem manifestations and potential cardiometabolic consequences.

This perspective outlines a conceptual approach for investigating PEM through longitudinal assessment of post-exertional physiological trajectories while considering disease severity and underlying cardiometabolic health, including obesity and type 2 diabetes. Integrating these dimensions may help contextualize post-exertional responses, inform future longitudinal cardiometabolic profiling, facilitate patient stratification, and provide a framework for future mechanistic and interventional studies in ME/CFS and Long COVID.

Source: Westermeier F, Pretorius E, Untersmayr E, Bertinat R, Sepúlveda N, Fisman E. A cardiometabolic perspective on post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID. Cardiovasc Diabetol. 2026 Aug 20;25(1):250. doi: 10.1186/s12933-026-03316-8. PMID: 42625219. https://link.springer.com/article/10.1186/s12933-026-03316-8 (Full text)

Experimental hypoxia to probe neuro-metabolic and vascular dysregulation in ME/CFS: a multimodal proof-of-concept MRI study

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a poorly understood, debilitating multisystem condition. Converging evidence implicates impaired cellular bioenergetics, neuroinflammation and defective neurovascular coupling that may manifest as “virtual hypoxia” only under physiological stress.

Methods: We performed a single-session multimodal 3T MRI study combining brain volumetry, arterial spin labelling (ASL) and multivoxel proton magnetic resonance spectroscopy under normoxia and two controlled hypoxic challenges (oxygen saturation 87 ± 3%) in 26 ME/CFS patients and 27 age- and sex-matched healthy controls.

Results: After intracranial-volume normalization, patients showed a reduced brainstem volume (1.46 ± 0.14 vs. 1.55 ± 0.18 % of eTIV; p = 0.013, FDR-p = 0.039), whereas deep grey matter and whole-brain parenchymal fraction did not differ between groups. Whole-brain cerebral blood flow (CBF) rose under hypoxia in both groups (controls +4.8 ± 13.0%, patients +3.7 ± 11.7%), with greater initial inter-individual variability in patients (patient-to-control variance ratio up to 6.94; FDR-p = 0.001). Thalamic lactate-to-creatine (Lac/tCr) ratios increased with hypoxia in controls (FDR-p = 0.028) but were already elevated at normoxia in patients (0.171 vs. 0.135; FDR-p = 0.021) and did not rise further (FDR-p = 0.38). In exploratory analyses, patients showed exaggerated inverse coupling between thalamic total N-acetylaspartate (tNAA/tCr) and white-matter CBF.

Conclusions: These findings provide in vivo evidence of impaired neuro-metabolic and vascular adaptive capacity in ME/CFS, supporting the virtual hypoxia hypothesis and highlighting candidate imaging markers for stratification that warrant validation.

Source:  Viola Bader, Katharina Estermann, Eva Niess, Tobias Zrzavy, Florian Fischmeister, Teresa Haider, Birgit Ludwig, Frederik Barkof, Henk JMM Mutsaerts, Gregor Kasprian, Fabian Niess, Wolfgang Bogner, Kathrin Kollndorfer, Lukas Haider. Experimental hypoxia to probe neuro-metabolic and vascular dysregulation in ME/CFS: a multimodal proof-of-concept MRI study. medRxiv 2026.08.10.26359935; doi: https://doi.org/10.64898/2026.08.10.26359935 https://www.medrxiv.org/content/10.64898/2026.08.10.26359935v1.full-text (Full text)

Cerebrospinal fluid opening pressure in relation to symptomatology and craniocervical anatomy in patients with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease that affects millions worldwide. Its cause remains unknown, although many physiological mechanisms are impaired. Structural abnormalities in the craniocervical region seem to be more prevalent in patients with ME/CFS, with a possible impact on intracranial pressure (ICP) and lumbar puncture (LP) measurements. This study aimed to quantify the occurrence of elevated cerebrospinal fluid (CSF) opening pressure and a possible association with clinical symptoms and radiological variables in craniocervical segments in a cohort of patients with ME/CFS.

Methods: This study included 34 patients previously diagnosed with ME/CFS as part of a larger case-control study, for whom LP was performed only in the case group. Key measurements included age, sex, opening pressure from LP, symptomatic relief post-LP, and radiological variables with potential influence on CSF dynamics. Individuals were stratified into two groups according to opening pressure (OP) measurements using 20 cmH2O as the cutoff value, with subsequent statistical comparisons.

Results: Overall, the majority of participants reported moderate disease severity (65%) and concomitant self-reported low quality of life. The median CSF opening pressure was 18 (IQR 8) cmH2O, ranging from 11 to 29.5. Opening pressure stratification showed that 21 of the 34 cases (62%) had an OP measurement of <20 cmH2O (low-OP group) and 13 cases (38%) had an OP measurement of ≥20 cmH2O (high-OP group). The two OP groups did not differ significantly in baseline characteristics, including disease severity and quality of life. However, for certain radiological measurements, the high-OP group presented with measures reflecting a wider spinal canal, including a significantly larger foramen magnum diameter (33.9 mm), which was higher than the measures in the low-OP group (31.7 mm). Estimates of symptom relief 1-4 days post-LP were significantly higher among patients in the high-OP group (80%) than among those in the low-OP group (19%).

Conclusion: This study suggests that a proportion of patients with ME/CFS have elevated CSF opening pressures and may experience symptom relief following CSF subtraction. Our data indicate that some anatomical structures in the craniocervical area may be related to CSF pressure, although interpretation is challenging and merits further investigation.

Source: Jolley C, Bragée B, Soinne L, Huhmar H, Billing H, Bertilson B, Sjogren P. Cerebrospinal fluid opening pressure in relation to symptomatology and craniocervical anatomy in patients with myalgic encephalomyelitis/chronic fatigue syndrome. Front Med (Lausanne). 2026 Aug 4;13:1869714. doi: 10.3389/fmed.2026.1869714. PMID: 42614190; PMCID: PMC13481257. https://pmc.ncbi.nlm.nih.gov/articles/PMC13481257/ (Full text)