Stress-inducible WASF3 regulates brain metabolism and cognitive function

Abstract:

Wiskott-Aldrich syndrome protein family member 3 (WASF3) disrupts mitochondrial respiration and is induced in association with endoplasmic reticulum stress in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Because cognitive impairment is a hallmark of ME/CFS, we investigated the role of WASF3 in brain metabolism and function using WASF3 transgenic and knockout mouse models.

WASF3 disrupted respiratory complex IV and localized to mitochondria-associated membranes, known to modulate cellular processes important for neuronal activity. Overexpression of WASF3 in the hippocampus, a critical region for memory formation, induced a metabolic shift toward glycolysis and promoted a “hypometabolic” state. Increased WASF3 also caused a reduction in ATPIF1, previously shown to facilitate cognitive function, and impaired learning. Conversely, WASF3 deficiency increased ATPIF1 level, enhanced oxidative metabolism, and preserved cognitive function under stress.

Together, these findings demonstrate that WASF3 suppresses oxidative metabolism in the brain and contributes to cognitive dysfunction, providing mechanistic insights into the “brain fog” reported in ME/CFS.

Source: Syed AM, Ma J, Wang PY, Son Y, Penjweini R, Mattu N, Knutson JR, Nakamori-Yamashita S, Springer DA, Ganguly A, Liu C, Hwang PM. Stress-inducible WASF3 regulates brain metabolism and cognitive function. Proc Natl Acad Sci U S A. 2026 Nov 3;123(44):e2617198123. doi: 10.1073/pnas.2617198123. Epub 2026 Oct 27. PMID: 42945241. https://www.pnas.org/doi/10.1073/pnas.2617198123 (Full text)

CATCH-EVseq, an Ultra-Sensitive Capture Assay to Monitor Human Enterovirus RNA

Abstract:

The detection of low-abundance viral RNA in chronic or persistent infections remains a major challenge in virology, constrained by the sensitivity and specificity of traditional methods. One such infection, chronic enterovirus (EV) infection, has been proposed as a potential underlying factor in Myalgic Encephalomyelitis (ME), although this hypothesis remains debated. Supporting evidence for EVs as a viral trigger includes historical spatiotemporal overlaps between ME outbreaks and poliomyelitis epidemics, frequent reports of “flu-like” illness at disease onset, seasonal outbreaks patterns, and serological findings. To address the problem of EV detection, we developed CATCH-EVseq, an ultra-sensitive platform built on the CATCH framework.

By integrating high-throughput sequencing with cDNA capture using 49,847 probes targeting 3410 EV genomes, CATCH-EVseq achieved a detection limit in artificially created samples as low as one copy in a microgram of RNA for two out of three biological replicates. Additionally, spike-in controls allow for rigorous validation of the capture and sequencing throughout the CATCH-EVseq procedure. When applied to a small number of blood samples from both ME patients and healthy controls, CATCH-EVseq detected no EV RNA, either in direct assays or after in vitro viral amplification.

While these results do not support the presence of circulating EV RNA in the blood of individuals with ME, they do not rule out persistent infection in other tissues or organs. Critically, CATCH-EVseq establishes a robust, ultra-sensitive framework for future investigations of low-level EV persistence in biopsies, post-mortem tissues, or other clinical contexts where chronic enterovirus infection is suspected.

Source: Germain A, Hanson MR. CATCH-EVseq, an Ultra-Sensitive Capture Assay to Monitor Human Enterovirus RNA. Int J Mol Sci. 2026 Oct 13;27(20):9065. doi: 10.3390/ijms27209065. PMID: 42941838; PMCID: PMC13705469. https://www.mdpi.com/1422-0067/27/20/9065 (Full text)

ME/CFS and the thalamus as a precision gate: what reversible thalamocortical connectivity reveals about central gain in post-infectious fatigue

Abstract:

Kim and colleagues report a finding that is easy to understate: thalamic hyperconnectivity with sensorimotor and visuo-occipital cortices, present in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) at baseline, shifts back toward the pattern seen in healthy controls after hyperbaric oxygen therapy and does so most in the patients who improve clinically. To my knowledge, this is the first treatment-coupled, apparently reversible thalamocortical signature in ME/CFS.

Viewed through predictive processing (the framework in which the brain continually predicts its own sensory and bodily inputs), the thalamus is theorised to be a gain-control gate that helps set the precision or weight assigned to ascending bodily signals. I argue that the baseline hyperconnectivity reflects deficient filtering of expected input, and that its post-treatment reduction may index restored filtering. The same failure of attenuation offers a parsimonious account of several symptoms that often co-occur in patients, including sensory hypersensitivity, pain, orthostatic intolerance, and cognitive “brain fog”, as one mechanism expressed across exteroceptive, nociceptive, autonomic, and cognitive domains.

Because hyperbaric oxygen therapy is a vascular intervention and resting-state connectivity is an indirect measure this gain interpretation remains a hypothesis and I outline how it can be tested across exertion and post-exertional malaise rather than at baseline alone.

Source: Strube A. ME/CFS and the thalamus as a precision gate: what reversible thalamocortical connectivity reveals about central gain in post-infectious fatigue. J Transl Med. 2026 Jul 29;24(1):1345. doi: 10.1186/s12967-026-08718-6. PMID: 42934697. https://link.springer.com/article/10.1186/s12967-026-08718-6 (Full text)

Overlapping Post-COVID Conditions: A Case of Myalgic Encephalomyelitis and Postural Orthostatic Tachycardia Syndrome Triggered by Sequential Epstein-Barr Virus (EBV) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infections

Abstract:

The rise in post-infectious syndromes following COVID-19, such as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Postural Orthostatic Tachycardia Syndrome (POTS), has become increasingly common in clinical practice, representing an emerging clinical challenge. This case highlights a possible clinical scenario involving the interaction between sequential viral infections – such as the Epstein-Barr virus (EBV) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) – in triggering overlapping chronic conditions. This report presents the case of a patient who developed ME/CFS and POTS following SARS-CoV-2 infection, with a prior history of EBV mononucleosis, and discusses the diagnostic, therapeutic, and pathophysiological implications.

A 48-year-old woman with a history of mononucleosis in childhood developed persistent and disabling symptoms after COVID-19 in January 2022. She presented with extreme fatigue, orthostatic intolerance, paresthesia, cognitive dysfunction, and multisystem symptoms. After extensive investigation, she was diagnosed with ME/CFS (early 2023) and POTS (later that year). Mast Cell Activation Syndrome (MCAS) was considered as a hypothesis during follow-up, but objective testing was not confirmatory. Management included pharmacological therapy (including low-dose naltrexone, duloxetine, and palmitoylethanolamide (PEA)), activity adjustments (pacing), and a multidisciplinary approach, with partial and fluctuating responses.

This case illustrates how viral infections such as EBV and SARS-CoV-2 may act as sequential triggers in an individual clinical trajectory compatible with the development of ME/CFS and POTS. The symptomatic overlap, the lack of readily available objective biomarkers in this patient, and the need for a predominantly clinical and functional diagnostic approach in her evaluation highlight the complexity of these conditions. This experience also underscores the importance of continued efforts in research, clinical training, and integrated care models to improve the management of patients presenting with post-COVID conditions (PCC).

Source: Mayrink Magalhães VR, Ribeiro Oliveira LA, Lourenço AJ, Ribeiro Camargos I, Da Silva LG, Filgueiras PS, De Souza Lima AE, Marques Contin SV, Costa M, Istilli P, Ferreira da Costa Gomes M, Pedretti CB, Correa PRL, Grenfell RF. Overlapping Post-COVID Conditions: A Case of Myalgic Encephalomyelitis and Postural Orthostatic Tachycardia Syndrome Triggered by Sequential Epstein-Barr Virus (EBV) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infections. Cureus. 2026 Sep 24;18(9):e116844. doi: 10.7759/cureus.116844. PMID: 42927133; PMCID: PMC13695498. https://pmc.ncbi.nlm.nih.gov/articles/PMC13695498/ (Full text)

Transient clinical improvement and immune modulation following recombinant Zoster vaccination in a patient with ME/CFS

Abstract:

Introduction: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem disorder associated with immune dysregulation yet lacks definitive biomarkers or effective therapies. Acute immune perturbations may transiently modulate disease manifestations.

Methods: We report the case of a female patient in her 60s with severe, long-standing ME/CFS who experienced changes in symptom following administration of recombinant zoster vaccine (RZV; Shingrix). Peripheral blood mononuclear cells were analyzed pre- and post-vaccination using flow cytometry, with comparison to a female healthy control. Plasma galectin-9 (Gal-9) levels were quantified by ELISA.

Results: Both RZV doses were associated with rapid, transient remission of symptoms, including improved sleep, cognition, pain, mobility, and respiratory function, followed by relapse. Immunologically, pre-vaccination profiling revealed elevated monocytes, increased CD71+ erythroid cells, and features of T cell exhaustion marked by Gal-9/PD-1 co-expression and impaired cytokine responses. Post-vaccination, monocyte frequency decreased, Gal-9+/PD-1+ T cells were reduced, and NK cell degranulation improved, indicating partial restoration of immune function.

Conclusion: This case demonstrates that immune stimulation via RZV may transiently reverse immune dysfunction and improve clinical symptoms in ME/CFS. These findings support a role for reversible immune exhaustion in disease pathogenesis and highlight potential avenues for biomarker development and therapeutic intervention.

Source: Bigleri A, Alimo ET, Abouda A, Osman M, Cohen Tervaert JW, Elahi S. Transient clinical improvement and immune modulation following recombinant Zoster vaccination in a patient with ME/CFS. Brain Behav Immun Health. 2026 Oct 13;58:101388. doi: 10.1016/j.bbih.2026.101388. PMID: 42927120; PMCID: PMC13694728. https://pmc.ncbi.nlm.nih.gov/articles/PMC13694728/ (Full text)

Recognizing and managing post-exertional malaise in primary care

Abstract:

Post-exertional malaise (PEM) is a syndrome characterized by a worsening of symptoms after physical, cognitive, or emotional exertion. It presents as increased fatigue, usually accompanied by other clinical symptoms, such as muscle pain or cognitive impairment. First described in patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), PEM is now recognized as a hallmark of post-infectious syndromes that have received increasing attention through the emergence of long COVID. PEM is a distinguishing symptom of these conditions, and its early detection and appropriate management are essential to prevent long-term functional decline of affected patients. This review describes the definition and clinical impact of PEM and summarizes current recommendations for its management.

Source: Garcia S, Tzartzas K, von Plessen C, Favrat B, Kokkinakis I. Reconnaître et gérer le malaise post-effort en médecine de premier recours [Recognizing and managing post-exertional malaise in primary care]. Rev Med Suisse. 2026 Oct;22(1):17-21. French. doi: 10.53738/REVMED.2026.22.1.e48753. PMID: 42899626. https://pubmed.ncbi.nlm.nih.gov/42899626/

Explaining Fatigue and Post-Exertional Malaise in Long COVID and ME/CFS: From Skeletal Muscle To Exercise Immunology

Abstract:

The SARS-CoV-2 viral outbreak in 2020 resulted in a record number of global hospitalizations and deaths. Although most people recover from an initial COVID infection within 3 months, around 10% of people have symptoms that do not improve after 3 months, which is called long COVID. Other viruses and bacterial infections can also result in long-term symptoms, which is known as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

One of the most common symptoms of long COVID or ME/CFS is post-exertional malaise, which is the worsening of symptoms or development of new symptoms after physical, mental or emotional stress. This can lead to patients leading less physically active lifestyles. Physical activity is known to be beneficial for overall health and wellbeing, mostly by increasing exercise capacity, which is a significant predictor in long-term health. Physical inactivity.

It is thought that many symptoms of long COVID and ME/CFS can be explained by lower physical activity of patients. However, people who are less physically active don’t experience post-exertional malaise, implying there are disease-specific changes. Many of the benefits that come from exercise come from a persons ability to adapt to an exercise session. Usually, exercise will create a short energy deficit, which then may result in small amounts of muscle damage. This then triggers a short-lived immune response, led first by neutrophils and macrophages, which result in activation of fibroadipogenic progenitor cells (FAP cells) and satellite cells (muscle stem cells). FAP cells and satellite cells communicate to repair damage to the muscle itself, while immune cells clear debris surrounding the muscle. In healthy situations, this creates a stronger, more resilient muscle. It is unknown whether these responses are still seen in long COVID or ME/CFS. The goal of this thesis then to 1) understand muscle changes in patients with long COVID and ME/CFS, 2) to better understand how these changes may relate to PEM, 3) to understand whether the muscle changes in patients are a result of physical inactivity.

Within the thesis, I find that patients with long COVID and ME/CFS have specific patterns of skeletal muscle that separate them from healthy individuals. This is highlighted by more fast-twitch fibre types, slow-twitch muscle atrophy, lower mitochondrial respiration that is separate from just mitochondrial loss, less metabolites related to oxidative capacity and antioxidation, less lipids that are required for cell membrane maintenance, and lower amounts of satellite cells and FAP cells.

Beyond this, I find that ME/CFS can be distinguished from long COVID by less capillaries, less slow-twitch fibres, less local immune cells, and lower amounts of several essential amino acids. As well, I find evidence that physical inactivity alone cannot explain long COVID and ME/CFS symptoms. Where all of long COVID, ME/CFS, and physical inactivity have lower whole-body aerobic capacity, physical inactivity causes a decrease in muscle fibre size, loss of mitochondria, increases in muscle lipotoxic lipids, and decreases in metabolites related to carnitine metabolism. These changes are not seen in either long COVID nor ME/CFS, and support the idea that long COVID and ME/CFS have disease specific muscle changes.

Overall, I find that the reduced whole-body capacity of long COVID and ME/CFS patients is not cause by physical inactivity, and is defined by reduced muscle oxidative ability. The lower amounts of local cells that would normally support exercise and damage responses are lower in both long COVID and ME/CFS, which partially explains the occurrence of PEM. This also suggests that patients experiencing PEM should not undertake normal rehabilitation, however it might be that more individually tailored, and severely monitored approaches may still be beneficial.
Source: Charlton, B. T. (2026). Explaining Fatigue and Post-Exertional Malaise in Long COVID and ME/CFS: From Skeletal Muscle To Exercise Immunology. [PhD-Thesis – Research and graduation internal, Vrije Universiteit Amsterdam]. https://doi.org/10.5463/thesis.1979 https://research.vu.nl/en/publications/explaining-fatigue-and-post-exertional-malaise-in-long-covid-and-/ https://research.vu.nl/ws/portalfiles/portal/517511531/aio01877%20braeden%20charltonfinal%20-%206acf4153820e1.pdf (Full text)

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)

“Mary Ann’s Transfusion”

by Dr. David Bell

This is the case history of a nurse who improved dramatically after a blood transfusion. It is excerpted from Dr. Bell’s book, Faces of CFS – Case Histories of Chronic Fatigue Syndrome, published in August, 2000. “Mary Ann’s Transfusion” illustrates one aspect of cases he has followed since the mid-1980’s. 

Reprinted with the kind permission of Prohealth.

***

Mary Ann was a bold and highly competent nurse in the intensive care unit of our local hospital, and I depended on her. Given that my specialty is pediatric medicine, I was always a little nervous treating adult patients who were in the midst of medical crises. I quickly learned I could count on the vivacious Mary Ann, who was then in her thirties, for the most up-to-date and reliable information about my patient’s status. Often, she suggested successful solutions to problems for which I had never been trained in medical school, like constipation. There should be a course on constipation in octogenarians who have suffered heart  attacks, but there isn’t.

In 1985, when the epidemic of CFS in Lyndonville began, eventually affecting more than two-hundred people in a town of 1,500 (or whatever), Mary Ann got sick, too, although some years passed before her diagnosis was readily apparent. The one constant, however, which began in 1985, was exhaustion. Mary Ann was weighted down with a panoply of other problems, as well: arthritis-like pains in her joints, sinus infections, allergies, migraine headaches, chest pain, shortness of breath. As the years wore on, these symptoms and many more resulted in her slide from being perhaps the finest ICU nurse I have ever known to little more than – in the eyes of the medical specialists she consulted – a hypochondriac. As a result, she was inhabiting a remorselessly bleak netherworld.

I tried to help Mary Ann, too, over the years. It was rapidly apparent to me, and eventually to her, that she had same disease from which so many of the patients she had met in the hospital in 1985 had suffered. I tried everything I could think of by way of drugs and other therapies to help her, but none of them worked to any appreciable degree. There was an aspect of her case that I found very interesting, perhaps because it seemed to me to be one of those elusive clues that might lead me to a more comprehensive understanding of the mechanism of the disease.

Mary Ann had a remarkable requirement for water. She rarely came into my clinic without a large container of ice water, from which she sipped continuously. I was pretty sure it was water, anyway; if it was vodka, I knew we were in for some big problems. It turned out not to be vodka, of course. Once, I asked Mary Ann to keep track of the amount of water she drank in one twenty-four hour period. Her consumption turned out to be four gallons a day. Persistent thirst is a sign of diabetes, and Mary Ann did indeed have diabetes, in addition to all her other problems. She had a rare kind, however, one called “diabetes insipidus,” which is not the “sugar diabetes” with which most people are familiar. In the primitive days of medicine, doctors would actually differentiate between the two forms of diabetes by tasting their patients’ urine. If the urine had a sweet taste, their diagnosis was sugar diabetes, known today more formally as “diabetes mellitus.” In the case of diabetes insipidus, the urine was tasteless, or “insipid.” Recalling this piece of medical history makes me wonder if I really want to return to the good old days of clinical medicine.

What struck me as most interesting about Mary Ann’s diabetes is the fact that it is caused by a deficiency of the brain hormone,  vasopressin, which, as I have noted, is a common finding in CFS sufferers. Among its many functions, vasopressin helps the kidneys absorb water and maintain the body’s fluid balance. When vasopressin is low, or missing entirely, water runs through the body without being absorbed, like a bucket with a hole in the bottom. Usually, diabetes insipidus signals damage to the pituitary gland in the brain, which manufactures vasopressin. Paradoxically, in spite of her gargantuan intake of water, lab tests suggested that Mary Ann was living in a state of perpetual dehydration.

I decided to measure the volume of blood circulating in Mary Ann’s body. In case anyone was wondering, it is not a good idea to measure someone’s circulating blood by taking it all out at once. Instead, a high-tech system deployed in a hospital radiology department requires only two small blood samples to determine the body’s entire circulating blood supply. A normal person has about five quarts of blood in their system. It turned out that Mary Anne had only 51 percent of the amount of circulating blood that would have been considered normal for a woman of her age and size.

This was a startling finding. If a person loses as much as 40 percent of their blood volume suddenly, they will usually die from shock. In science and in medicine, when one is trying to calculate what is “normal,” and what is “abnormal,” one will always encounter pitfalls. Mary Ann’s radically reduced blood volume caused me to think about what constitutes a true “normal” value for blood volume. Mary had gained weight in the course of her struggle with CFS, for instance, and I wondered if blood volume can be reduced in people who are overweight. I tried to come up with all sorts of explanations for Mary Ann’s radically low blood volume. In the end, I could draw only one conclusion: no matter what the mitigating circumstances of her case, Mary Ann’s blood volume was below normal.

The blood volume assay has been used for almost thirty years, and is considered to be highly reliable. The fact that Mary Ann – no matter how hard she tried – could not possibly fake the results of this particular test, seems especially significant to me given the vast array of medical experts who continue to insist that CFS is a psychosomatic condition. I will give my little finger to anyone who can successfully argue that this finding was psychosomatic.

I must confess that I am not the first doctor to discover that CFS patients have dramatically lowered blood volumes. Dr. David Streeten had been measuring the low blood volumes in CFS patients for some by the time I tested Mary Ann for the condition. Mary Ann just happened to be my first patient in whom I personally observed the phenomenon.

Dr. Streeten and I, being doctors, were excited by these findings and were enjoying our collaboration. Mary Ann, the patient, was enjoying very little about her life. In fact, she told me she was eager to experiment with therapies. I felt that her informed  consent was reliable, in part because of her nursing experience, which had left her well-versed in medical matters, and because she was, in my opinion, entirely rational. Thus, in December of 1997, I decided to attempt to raise Mary Ann’s blood volume level by giving her injections of vasopressin. I reasoned that, if she improved, I could reasonably suspect that low blood volume was at the root of  her symptoms and might also play an important role in CFS.

Unfortunately, complications with this therapy set in almost immediately. Mary Ann began suffering from “water intoxication,” the main risk of this treatment, since vasopressin causes the body to retain water. The newly expanded blood volume causes a dilution of the salt in the blood and Mary Ann’s blood sodium levels dropped markedly. Upon measuring her blood sodium, I halted the drug therapy immediately.

I was relieved when I determined that Mary Ann had suffered no physical difficulties because of the sharp drop in her blood sodium. In fact, curiously, two days after the therapy was stopped, she began feeling better than she had felt in years. However, the risks that accumulate with water “intoxication” and low blood sodium levels, in my mind, failed to justify the treatment, and we abandoned that particular effort.

I found myself unable to sleep at night thinking about why Mary Ann had felt so much better after her vasopressin infusion, even when it had caused complications. I was, and remain, perplexed by this seeming contradiction. Clearly, low blood volume levels are important and meaningful in some way to our understanding of the mechanisms of CFS, but, I am sorry to report, the puzzle remains unsolved at this date. And, soon enough, Mary Ann was just as ill as she had been prior to the vasopressin treatment.

Then, a wonderful thing happened: she developed a bleeding ulcer. I suspected the problem could be blamed on the large doses of ibuprofen Mary Ann routinely swallowed to control her muscle and joint pain. At any rate, the hemorrhage inside her abdomen caused her so much pain that Mary Ann rapidly found her way to the emergency room of our local hospital. The staff there determined that she was bleeding internally, and they followed standard protocol for such a condition: they gave her a blood transfusion. In fact, they gave her several pints until her stomach quit bleeding, at which point they sent her home. She began keeping a journal the day she came home and called it, “Diary of Lab Rat # 1.”

I always ask my CFS patients to fill out a questionnaire before each visit. I sometimes suspect that they believe these questionnaires, which force them to respond to a great many detailed inquiries about their symptoms and their level of activity, are a kind of punishment. Inevitably, these forms remind them of just how thoroughly rotten they feel. Nevertheless, I have found these questionnaires to be extremely helpful in monitoring their illness. It turns out, in case anyone was wondering, that the secret to interpreting fluctuating energy levels in CFS is in the fine details.

Mary Ann filled out one of these questionnaires the day after her transfusion and wrote that she was “whoogy and very tired.” I have never demanded of Mary Ann that she define “whoogy” for me, mostly because I can pretty well guess by the sound of it. The following day, however, Mary Ann was able to walk through the rooms of her house and even venture outside to her garden. She also discovered that, for the first time in her recent memory, she was not thirsty.

Before her blood transfusion, Mary Ann typically experienced about an hour a day during which she could be upright. A week after the transfusion, however, Mary Ann’s life began to change radically. One morning, she wrote in her lab rat diary, “Did I get healthy blood–or what???” It seemed to her that virtually every symptom of illness had been muted – dramatically. One of the most exciting new developments was her newfound sense of mental clarity, something that CFS sufferers inevitably lose when they become sick. Before falling ill with CFS, Mary Ann had been a crossword puzzle whiz; now she began to work the crosswords again. She felt as if she was opening up all the dusty, long-shuttered cabinets in her memory, and was discovering that although they had been closed for a long time, the contents had remained in tact. She found she could keep her focus on the written page, too. She took up reading after a long hiatus. One evening, she set the newspaper down and realized with wonderment that, for the first time in years, she had read the journal from front to back.

She noted in her diary that she had pulled her grandchildren, all of them squeezed together in a red wagon, down the sidewalk. On the eleventh day after the transfusion, she wrote that she had played baseball with her older grandchildren for the first time. Soon afterward, she and her husband drove 200 miles looking for the perfect pair of bicycles – Mary Ann was anticipating long rides along the country roads. After all, she felt perfectly well. Mary Ann was even ready to do a TV commercial about her hair. One of the oddest symptoms of CFS is the complaint by many patients that they are losing their hair. Women in the most severe episodes of the disease often report they find clumps of hair in their brushes. My patients, women particularly, get annoyed with me over this particular issue, and not only because it’s hard for me to objectively assess this complaint. I rarely consider hair loss to be a pressing concern when there are so many more serious medical matters to face. I suggested to Mary Ann that blood transfusions were not currently the modality of choice to correct thinning hair.

Diary of Lab Rat # 1: “No nightmares like I used to have. I don’t feel ‘sick’ all the time. I’m praying that it will last, but if it doesn’t, I pray that I won’t get depressed. I know that God could heal me in a minute if He wanted, but He’s given me this illness, and now, feeling better, for a purpose. So I guess my job is to do His will and whatever He has in His plan.”

Whenever Mary Ann came to my clinic during her incredible respite from suffering, I was always reminded of the old Mary Ann who had worked in the ICU at the hospital. She was perky; she looked great. For the first time in years I was able to enjoy that wonderful, relaxed sense of comic timing that was her hallmark. It is incredible what CFS can do to a person.

The scientist in me was at war with the clinician in me over Mary Ann’s case. The scientist was insisting that Mary Ann’s metamorphosis could easily be ascribed to the placebo effect. Finally, I had to tell the scientist to stuff a sock in it. Mary Ann’s come-back-kid status had been precipitated by an event – a transfusion for an abdominal hemorrhage – that was virtually an accident. Still, I asked myself again and again: what was the secret of the blood transfusion? What was it telling me about CFS?

I began thinking about other blood-related clues I had observed over the years. People with CFS typically report they feel much worse after lab technicians draw multiple vials of blood from them for diagnostic tests. In addition, I had observed that by administering IV fluids to people with CFS, I could often generate a temporary improvement in their symptoms. Most significantly, I realized, the constellation of symptoms that make up the entity we know as CFS, particularly weakness, dizziness, and difficulty concentrating resemble the symptoms of shock due to blood loss.

Nevertheless, from my experience with Mary Ann, I had learned that simply expanding a patient’s blood volume wasn’t the answer. I have since speculated – but it is only speculation – that the answer might lie in the red blood cells themselves or the blood vessels carrying them. Scientists in Australia and England have suggested that red blood cells of CFS patients are misshapen, and appear to be damaged. They have advanced the hypothesis that the capability of red blood cells to carry oxygen around the body is impaired in CFS sufferers. Maybe the infusion of new red blood cells into Mary Ann’s body was what made the difference. Maybe this really was, as my patient had called it, “healthy blood.” In other words, normal, undamaged red blood cells, coupled with an increase in general blood volume, might explain Mary Ann’s rebound. Mary Ann’s deterioration began six weeks later.

“Day 46,” she wrote in her diary. “Starting to spiral down.” She had to put her crossword puzzles away; her mind was growing foggy and confused. “Fingers keep latching up and dropping and breaking stuff,” she wrote a few days later. On another day, she wrote, “Dizzy if I stand up and I have to hold on to something.” The following day: “It’s been worth it…but if it’s over I have to keep from falling apart.” And finally, “Quietly starting to panic.” She was unable to pull her grandchildren in their wagon.

Months passed. My heart broke whenever Mary Ann came to the office. Searching for a therapy that might help, or at least do no harm, I decided to give her weekly intravenous infusions of a liter, or about a quart, of saline water, the salty, purified water that is titrated to mimic the salt content of our bodies. I offered the therapy to her on the grounds that we might be able to raise her blood volume simply by administering extra fluid to her blood stream. Mary Ann felt a bit better after this treatment, though its good effects lasted just two days. I continue to provide Mary Ann with this treatment on a weekly basis, because it offers her some relief, which happens to be more than any other therapy can offer.

One might ask: why not give Mary Ann with another blood transfusion? The question goes to the heart of clinical medicine. As doctors, we must err on the side of caution. In fact, my profession and the federal government each has a responsibility to protect us all from medical charlatans. Before the government can approve a new treatment for a disease, for instance, scientists must apply for grant money, submit protocols for their experimental therapy to review boards, and those protocols must be approved by these boards. After all this, the therapy must be thoroughly tested on significant numbers of patients, and the results submitted to the government for further review. It’s a good system, and without it, great harm might be done.

Doctors who work each day in the trenches of clinical medicine cannot undertake this kind of research. We would require sizable grants from the government to begin the work, an enormous amount of free time, and a veritable hoard of interns and residents to carry out the study using real patients. Clearly, a small town doc like me, living near the end of the world, cannot test in an appropriately scientific fashion the effect of blood transfusions in CFS. And it’s hard to imagine any medical journal would publish Mary Ann’s case history, because it is merely speculative, even if highly provocative. Sometimes, I feel the only solution for me is to develop multiple personalities or else go mad.

When I am wearing my “scientist” hat, I remain skeptical. When I am in my office, talking to Mary Ann, I sometimes think I’m going to go ballistic over the scientific establishment’s onerous demands for expensive, lengthy, double blind studies. Yet, giving Mary Ann another transfusion cannot be done now, as there is no established protocol for
this treatment in CFS. I’m not just worried about going to jail. It is possible that another transfusion might cause Mary Ann harm. I just don’t know.

In the old days, patients rarely learned very much about whatever disease had laid them low. There were no support groups, no newsletters, no conferences, and no unscientific books like this one. As a result, patients were rarely frustrated about scientific progress in their particular disease. For the most part, they remained blissfully ignorant about new ideas and new developments that could directly impact their destinies. Most especially, patients did not read about crackpot ideas like blood transfusions as a treatment for CFS.

I remain convinced that CFS is a treatable disease. Perhaps it will be impossible to fully reverse CFS once it has a foothold in a patient, but I believe many of the symptoms will be alleviated, once we learn how. It saddens me profoundly to see Mary Ann as she is today. Only our shared faith that CFS may someday be amenable to treatment allows me to shield her from that sadness.

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.

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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.