Tag: hypothesis

Letter: Could endothelial dysfunction and vascular damage contribute to pain, inflammation and post-exertional malaise in individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)?

To the Editor,

In their hypothesis paper, Wirth, Scheibenbogen, and Paul describe how endothelial dysfunction could produce a wide range of neurological symptoms in people with ME/CFS [1]. As they and others work to refine their understanding of ME/CFS and the related Long COVID syndrome, I would encourage consideration of the possibility that endothelial dysfunction and vascular damage could also explain other symptoms, including widespread pain and inflammation and post-exertional malaise.

For the past four years, my wife and I have been caregivers for our teenage daughter, who has ME/CFS, hypermobile Ehlers-Danlos syndrome, craniocervical instability, Chiari malformation and several other comorbid conditions. Through observation and trial and error, I have developed a number of hypotheses on these matters that I offer here in the hope they might prompt formal research into how to effectively treat these conditions [2].

Widespread pain and inflammation

Discussion of endothelial dysfunction and vascular damage in ME/CFS and Long COVID generally focuses on how leakages from dysfunctional blood vessels lead to reduced blood flow, which has many consequences, including reduced oxygenation of muscles and reduced cerebral brain flow. As researchers study this phenomenon, I would encourage consideration of the additional possibility that the leaking fluid causes independent damage. Lipedema researchers have found that leakages from microangiopathic blood vessels cause an excess of interstitial fluid that stimulates the formation of subcutaneous adipose tissue [3], which generates hypoxic conditions and becomes fibrotic, contributing to pain and inflammation [4].

I hypothesize that a similar process happens when fluid leaks from faulty blood vessels in ME/CFS, possibly exacerbated by endothelial dysfunction in lymphatic vessels that inhibit the fluid’s removal, causing widespread pain and inflammation. This mechanism appears most pronounced among people with hypermobility or other connective tissue disorders, a common trait among people with both ME/CFS and lipedema.

My daughter experiences pain from fibrotic adipose tissue as well as what appears to be nerve compression from accumulated interstitial / lymphatic fluid. Manual lymphatic drainage, the squeezing of affected tissue, and the manual break-up of fibrotic adipose tissue have helped to ameliorate these symptoms.

In my daughter, I have also observed impaired drainage of fluid from the glymphatic system, both at the cribriform plate and down her spine. Could this be related to damaged lymphatic vessels or blockages from fibrotic adipose tissue?

Post-exertional malaise

Like many people with moderate or severe ME/CFS, my daughter struggles to recover from even small amounts of physical exertion. In addition to mitigating her pain, manual lymphatic drainage and the squeezing of affected tissue greatly accelerates this recovery process. We have observed a direct dose–response relationship: the more exercise, the more fluid is present in her tissues, and the more manual draining / squeezing is necessary for her to recover.

Based on this experience, I hypothesize that excess interstitial fluid resulting from dysfunctional blood and lymphatic vessels contributes to the experience of post-exertional malaise, with fluid literally drowning affected tissue, leading to hypoxic conditions and inflammation. Possible explanations for the increased interstitial fluid are increases in blood pressure during physical exertion, hypermobile joints going out of place, prompting localized increases in interstitial fluid, and increases in cortisol that generate an increase in fluid and blood volume. Increases in fluid leakage due to elevated cortisol levels may also explain why some people with ME/CFS feel worse when stressed or anxious. The role of cortisol (or another mediator with fluid retaining properties) may explain why cognitive exertion can also generate post-exertional malaise. When present, elevated estrogen levels may exacerbate leakage by increasing fluid volume.

I am not sure why there is typically a delay between physical exertion and the experience of the most acute symptoms of post-exertional malaise. One possibility is that it takes time for the tissue inundated with fluid to feel the full effects of the hypoxic conditions. Another possibility is that a biphasic reaction triggered during physical exertion leads to the release of a mediator that causes heightened endothelial dysfunction and fluid release.

Further research is needed into the causes of endothelial dysfunction and damage (in addition to initial infection and inflammatory overreaction, consider major “crashes,” mast cell activations, surgeries and microclots as additional contributors) and appropriate treatment.

References

1. Wirth KJ, Scheibenbogen C, Paul F. An attempt to explain the neurological symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. J Transl Med. 2021;19:471. https://doi.org/10.1186/s12967-021-03143-3.

Article PubMed PubMed Central Google Scholar

2. For background, see Lubell, J. To speed progress in treating chronic conditions, engage patients and caregivers as research partners. 2021 Sept.20 In: BMJ Opinion. https://blogs.bmj.com/bmj/2021/09/20/to-speed-progress-in-treating-chronic-conditions-engage-patients-and-caregivers-as-research-partners/

3. Allen M, Schwartz M, Herbst KL. Interstitial Fluid in Lipedema and Control Skin. Womens Health Rep (New Rochelle). 2020;1(1):480–7. https://doi.org/10.1089/whr.2020.0086.PMID:33786515;PMCID:PMC7784769.

Article Google Scholar

4. Herbst KL. Subcutaneous Adipose Tissue Diseases: Dercum Disease, Lipedema, Familial Multiple Lipomatosis, and Madelung Disease. [Updated 2019 Dec 14]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. South Dartmouth (MA).

Source: Lubell J. Letter: Could endothelial dysfunction and vascular damage contribute to pain, inflammation and post-exertional malaise in individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)? J Transl Med. 2022 Jan 24;20(1):40. doi: 10.1186/s12967-022-03244-7. PMID: 35073915. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03244-7

Endothelial Senescence and Chronic Fatigue Syndrome, a COVID-19 Based Hypothesis

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome is a serious illness of unknown etiology, characterized by debilitating exhaustion, memory impairment, pain and sleep abnormalities. Viral infections are believed to initiate the pathogenesis of this syndrome although the definite proof remains elusive. With the unfolding of COVID-19 pandemic, the interest in this condition has resurfaced as excessive tiredness, a major complaint of patients infected with the SARS-CoV-2 virus, often lingers for a long time, resulting in disability, and poor life quality.

In a previous article, we hypothesized that COVID-19-upregulated angiotensin II triggered premature endothelial cell senescence, disrupting the intestinal and blood brain barriers. Here, we hypothesize further that post-viral sequelae, including myalgic encephalomyelitis/chronic fatigue syndrome, are promoted by the gut microbes or toxin translocation from the gastrointestinal tract into other tissues, including the brain. This model is supported by the SARS-CoV-2 interaction with host proteins and bacterial lipopolysaccharide. Conversely, targeting microbial translocation and cellular senescence may ameliorate the symptoms of this disabling illness.

Source: Sfera A, Osorio C, Zapata Martín Del Campo CM, Pereida S, Maurer S, Maldonado JC, Kozlakidis Z. Endothelial Senescence and Chronic Fatigue Syndrome, a COVID-19 Based Hypothesis. Front Cell Neurosci. 2021 Jun 25;15:673217. doi: 10.3389/fncel.2021.673217. PMID: 34248502; PMCID: PMC8267916. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267916/ (Full study)

Persistent Brainstem Dysfunction in Long-COVID: A Hypothesis

Abstract:

Long-COVID is a postviral illness that can affect survivors of COVID-19, regardless of initial disease severity or age. Symptoms of long-COVID include fatigue, dyspnea, gastrointestinal and cardiac problems, cognitive impairments, myalgia, and others. While the possible causes of long-COVID include long-term tissue damage, viral persistence, and chronic inflammation, the review proposes, perhaps for the first time, that persistent brainstem dysfunction may also be involved.

This hypothesis can be split into two parts. The first is the brainstem tropism and damage in COVID-19. As the brainstem has a relatively high expression of ACE2 receptor compared with other brain regions, SARS-CoV-2 may exhibit tropism therein. Evidence also exists that neuropilin-1, a co-receptor of SARS-CoV-2, may be expressed in the brainstem. Indeed, autopsy studies have found SARS-CoV-2 RNA and proteins in the brainstem. The brainstem is also highly prone to damage from pathological immune or vascular activation, which has also been observed in autopsy of COVID-19 cases.

The second part concerns functions of the brainstem that overlap with symptoms of long-COVID. The brainstem contains numerous distinct nuclei and subparts that regulate the respiratory, cardiovascular, gastrointestinal, and neurological processes, which can be linked to long-COVID. As neurons do not readily regenerate, brainstem dysfunction may be long-lasting and, thus, is long-COVID. Indeed, brainstem dysfunction has been implicated in other similar disorders, such as chronic pain and migraine and myalgic encephalomyelitis or chronic fatigue syndrome.

Source: Yong SJ. Persistent Brainstem Dysfunction in Long-COVID: A Hypothesis. ACS Chem Neurosci. 2021 Feb 4;12(4):573–80. doi: 10.1021/acschemneuro.0c00793. Epub ahead of print. PMID: 33538586; PMCID: PMC7874499. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874499/ (Full text)

Hypothesis: Mechanisms That Prevent Recovery in Prolonged ICU Patients Also Underlie Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Here the hypothesis is advanced that maladaptive mechanisms that prevent recovery in some intensive care unit (ICU) patients may also underlie Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Specifically, these mechanisms are: (a) suppression of the pituitary gland’s pulsatile secretion of tropic hormones, and (b) a “vicious circle” between inflammation, oxidative and nitrosative stress (O&NS), and low thyroid hormone function. This hypothesis should be investigated through collaborative research projects.

Introduction:

Critical illness refers to the physiological response to virtually any severe injury or infection, such as sepsis, liver disease, HIV infection, head injury, pancreatitis, burns, cardiac surgery, etc. (1). Researchers make a distinction between the acute phase of critical illness—in the first hours or days following severe trauma or infection; and the chronic or prolonged phase—in the case of patients that survive the acute phase but for unknown reasons do not start recovering and continue to require intensive care (i.e., “chronic ICU patients”). Independent of the nature of the critical illness, the acute phase is associated with an excessive response of pro-inflammatory cytokines (2) and is characterized by a uniform dysregulation of the endocrine axes (3). In prolonged critical illness, this dysregulation is maintained even once the initial inflammatory surge has settled (4). Regardless of the initial injury or infection, patients that suffer from prolonged critical illness experience profound muscular weakness, cognitive impairment, loss of lean body mass, pain, increased vulnerability to infection, skin breakdown, etc. (1, 5, 6). Whereas, the acute phase is considered to be an adaptive response to the severe stress of injury or infection (shifting energy and resources to essential organs and repair), the physiological mechanisms in the prolonged phase are now increasingly considered to be maladaptive responses to the stress of severe injury or infection, hindering recovery (7–10). Some have also suggested that the non-recovery from endocrine disturbances could explain the development of “post-intensive care syndrome” (PICS) (11); i.e., “the cognitive, psychiatric and/or physical disability after treatment in ICUs” (12, 13).

Source: Dominic Stanculescu, Lars Larsson and Jonas Bergquist. Hypothesis: Mechanisms That Prevent Recovery in Prolonged ICU Patients Also Underlie Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Front. Med., 28 January 2021 | https://doi.org/10.3389/fmed.2021.628029 https://www.frontiersin.org/articles/10.3389/fmed.2021.628029/full (Full text)

The putative glymphatic signature of chronic fatigue syndrome: A new view on the disease pathogenesis and therapy

Abstract:

The underlying pathophysiology of chronic fatigue syndrome remains incompletely understood and there are no curative treatments for this disorder at present. However, increasing neuroimaging evidence indicates that functional and structural abnormalities exist in the brains of chronic fatigue syndrome patients, suggesting that the central nervous system is involved in this disorder and that at least some chronic fatigue syndrome patients may have an underlying neurological basis for their illness.

In the present paper, we speculate that glymphatic dysfunction, causing toxic build up within the central nervous system, may be responsible for at least some cases of chronic fatigue syndrome. We further postulate that cerebrospinal fluid diversion such as lumboperitoneal shunting may be beneficial to this subgroup of patients by restoring glymphatic transport and waste removal from the brain.

Although recent evidence indicates that at least some chronic fatigue syndrome patients may benefit from cerebrospinal fluid drainage, further studies are needed to confirm this finding and to determine whether this can be attributed to enhancement of glymphatic fluid flow and interstitial fluid clearance. If confirmed, this could offer promising avenues for the future treatment of chronic fatigue syndrome. Clearly, given the relative invasive nature of cerebrospinal fluid diversion, such procedures should be reserved for chronic fatigue syndrome patients who are severely debilitated, or for those with severe headaches. Anyhow, it seems worthwhile to make every effort to identify new therapies for patients who suffer from this devastating disease, especially given that there are currently no effective treatments for this condition.

Source: Wostyn P, De Deyn PP. The putative glymphatic signature of chronic fatigue syndrome: A new view on the disease pathogenesis and therapy. Med Hypotheses. 2018 Sep;118:142-145. doi: 10.1016/j.mehy.2018.07.007. Epub 2018 Jul 6. https://www.ncbi.nlm.nih.gov/pubmed/30037603

Infection Elicited Autoimmunity and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Explanatory Model

Abstract:

Myalgic encephalomyelitis (ME) often also called chronic fatigue syndrome (ME/CFS) is a common, debilitating, disease of unknown origin. Although a subject of controversy and a considerable scientific literature, we think that a solid understanding of ME/CFS pathogenesis is emerging. In this study, we compiled recent findings and placed them in the context of the clinical picture and natural history of the disease.

A pattern emerged, giving rise to an explanatory model. ME/CFS often starts after or during an infection. A logical explanation is that the infection initiates an autoreactive process, which affects several functions, including brain and energy metabolism. According to our model for ME/CFS pathogenesis, patients with a genetic predisposition and dysbiosis experience a gradual development of B cell clones prone to autoreactivity. Under normal circumstances these B cell offsprings would have led to tolerance. Subsequent exogenous microbial exposition (triggering) can lead to comorbidities such as fibromyalgia, thyroid disorder, and orthostatic hypotension.

A decisive infectious trigger may then lead to immunization against autoantigens involved in aerobic energy production and/or hormone receptors and ion channel proteins, producing postexertional malaise and ME/CFS, affecting both muscle and brain. In principle, cloning and sequencing of immunoglobulin variable domains could reveal the evolution of pathogenic clones. Although evidence consistent with the model accumulated in recent years, there are several missing links in it. Hopefully, the hypothesis generates testable propositions that can augment the understanding of the pathogenesis of ME/CFS.

Source: Jonas Blomberg, Gerhard Gottfries, Amal Elfaitouri, Muhammad Rizwan and Anders Rosén. Infection Elicited Autoimmunity and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Explanatory Model. Hypothesis and Theory Article, Front. Immunol., 15 February 2018 | https://doi.org/10.3389/fimmu.2018.00229 (Full article)

New Hypothesis Proposed For Cause Of Chronic Fatigue Syndrome

Press Release: COLUMBUS, Ohio — Researchers here have proposed a new theory for the cause of chronic fatigue syndrome (CFS) — one that blames the illness both on a low-level viral infection and on the body’s own immune response to that virus.

If true, it would offer an explanation for why virologists so far haven’t found evidence of a common virus when looking at a population of CFS patients. The hypothesis was included in a paper published in the current issue of the American Journal of Medicine.

The new theory, proposed by Ronald Glaser, professor of medical microbiology and immunology, and Janice Kiecolt-Glaser, professor of psychology and psychiatry at Ohio State University, is the latest work in more than two decades of their research on the effects of stress on the human immune system.

“Our data suggests that stress may be causing the expression of certain viral proteins and that these proteins may be modulating the body’s immune response, turning it on or off,”Glaser said.

CFS was first characterized by researchers in the mid-1980s who described it as a combination of symptoms including low-grade fevers, body aches, malaise, and depression among other signs. The condition seems more prevalent among young adult women. Those diagnosed with CFS often experience stress and depression.

Symptoms routinely linger for six months or more and may continue for years. The federal Centers for Disease Control and Prevention estimate that CFS may affect anywhere from four to 10 of every 100,000 people in the United States.

Other researchers have reported higher-than-normal titers of antibodies to various latent viruses — Epstein-Barr virus, cytomegalovirus, human herpes virus 6, for example — in the blood of patients diagnosed as having CFS. But no one viral infection was present in all patients — evidence that would be needed to prove a viral cause of the illness.

The Ohio State researchers’ new theory poses several mechanisms that might be linked to CFS.

Once a person is infected, these viruses can remain latent in the body for long periods of time. Glaser proposes that the viruses could be partially reactivated, that is, viral proteins could be produced at levels high enough to cause a low-grade infection but too low to be seen using current laboratory assays.

Glaser and Kiecolt-Glaser suggest that CFS patients may experience an ongoing, low-grade viral infection — more like a smoldering fire rather than a three-alarm blaze — which could stimulate parts of the immune response without raising antibody titers to typically high levels.

That low-grade infection would be enough to increase production of various cytokines — chemical mediators for the immune system — and begin the immune response.

“A lot of the symptoms that you find in chronic fatigue syndrome are the same ones induced by cytokines during our normal immune response,” Glaser said.

He admits that studies of patients have yet to show a pattern of abnormal cytokine behavior that would substantiate their theory but he has an explanation for that.

“We haven’t discovered all the cytokines involved in immunity. We may not have found the right one, yet,” he said, adding that new cytokines are steadily being identified.

Stress and depression may be playing a related role as well, Kiecolt-Glaser said. Earlier research has repeatedly shown that increased stress and depression can reactivate latent viruses, decrease the body’s immune response, and stimulate the production of certain cytokines linked to some CFS-like symptoms.

“Part of this is a chicken-and-egg problem,” Kiecolt-Glaser said. “People diagnosed with CFS often are depressed since they’re unable to carry out normal, daily activities. What we don’t know is whether the depression followed the diagnosis of CFS or if CFS contributed to it.

“We do know, however, that this kind of depression can weaken our immune response.”

Glaser said researchers need to reconsider past work on CFS.

“We need to look for immune system changes that are much more subtle and specific than those we’ve been using as benchmarks,” he said.

 

Source: Ohio State University. “New Hypothesis Proposed For Cause Of Chronic Fatigue Syndrome.” ScienceDaily. ScienceDaily, 3 November 1998. https://www.sciencedaily.com/releases/1998/10/981031180910.htm

The role of the hippocampus in the pathogenesis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a severe acquired illness characterized by a profound sensation of fatigue, not ameliorated by rest and resulting in a substantial decrease in the amount and quality of occupational, social and recreational activities.

Despite intense research, the aetiology and pathogenesis of ME/CFS is still unknown and no conclusive biological markers have been found. As a consequence, an accepted curative treatment is still lacking and rehabilitation programmes are not very effective, as few patients recover. Increased knowledge of the mechanisms leading to the emergence and maintenance of the illness is called for.

In this study, I will put forth an alternative hypothesis to explain some of the pathologies associated with ME/CFS, by concentrating on one of the major strategic organs of the brain, the hippocampus. I will show that the ME/CFS triggering factors also impact the hippocampus, leading to neurocognitive deficits and disturbances in the regulation of the stress system and pain perception. These deficits lead to a substantial decrease in activity and to sleep disorders, which, in turn, impact the hippocampus and initiate a vicious circle of increased disability.

Copyright © 2015 Elsevier Ltd. All rights reserved.

 

Source: Saury JM. The role of the hippocampus in the pathogenesis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Med Hypotheses. 2016 Jan;86:30-8. doi: 10.1016/j.mehy.2015.11.024. Epub 2015 Nov 27. https://www.ncbi.nlm.nih.gov/pubmed/26804593

 

Myalgic encephalomyelitis, chronic fatigue syndrome: An infectious disease

Abstract:

The etiology of myalgic encephalomyelitis also known as chronic fatigue syndrome or ME/CFS has not been established. Controversies exist over whether it is an organic disease or a psychological disorder and even the existence of ME/CFS as a disease entity is sometimes denied. Suggested causal hypotheses have included psychosomatic disorders, infectious agents, immune dysfunctions, autoimmunity, metabolic disturbances, toxins and inherited genetic factors.

Clinical, immunological and epidemiological evidence supports the hypothesis that: ME/CFS is an infectious disease; the causal pathogen persists in patients; the pathogen can be transmitted by casual contact; host factors determine susceptibility to the illness; and there is a population of healthy carriers, who may be able to shed the pathogen.

ME/CFS is endemic globally as sporadic cases and occasional cluster outbreaks (epidemics). Cluster outbreaks imply an infectious agent. An abrupt flu-like onset resembling an infectious illness occurs in outbreak patients and many sporadic patients. Immune responses in sporadic patients resemble immune responses in other infectious diseases.

Contagion is shown by finding secondary cases in outbreaks, and suggested by a higher prevalence of ME/CFS in sporadic patients’ genetically unrelated close contacts (spouses/partners) than the community. Abortive cases, sub-clinical cases, and carrier state individuals were found in outbreaks.

The chronic phase of ME/CFS does not appear to be particularly infective. Some healthy patient-contacts show immune responses similar to patients’ immune responses, suggesting exposure to the same antigen (a pathogen). The chronicity of symptoms and of immune system changes and the occurrence of secondary cases suggest persistence of a causal pathogen.

Risk factors which predispose to developing ME/CFS are: a close family member with ME/CFS; inherited genetic factors; female gender; age; rest/activity; previous exposure to stress or toxins; various infectious diseases preceding the onset of ME/CFS; and occupational exposure of health care professionals. The hypothesis implies that ME/CFS patients should not donate blood or tissue and usual precautions should be taken when handling patients’ blood and tissue. No known pathogen has been shown to cause ME/CFS.

Confirmation of the hypothesis requires identification of a causal pathogen. Research should focus on a search for unknown and known pathogens. Finding a causal pathogen could assist with diagnosis; help find a biomarker; enable the development of anti-microbial treatments; suggest preventive measures; explain pathophysiological findings; and reassure patients about the validity of their symptoms.

 

Source: Underhill RA. Myalgic encephalomyelitis, chronic fatigue syndrome: An infectious disease. Med Hypotheses. 2015 Dec;85(6):765-73. Epub 2016 Oct 19. https://www.ncbi.nlm.nih.gov/pubmed/26604026

 

Mitoprotective dietary approaches for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Caloric restriction, fasting, and ketogenic diets

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome is an idiopathic illness characterized by debilitating fatigue and neuro-immune abnormalities. A growing body of evidence proposes mitochondrial dysfunction as a central perpetrator of the illness due to activation of immune-inflammatory pathways that burden the mitochondria.

Under a model of mitochondrial dysfunction, this paper explores dietary strategies that are mitoprotective. Studied for decades, the cellular mechanisms of ketogenic diets, fasting, and caloric restriction now reveal mitochondria-specific mechanisms which could play a role in symptom reduction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Future research should examine the physiological effects of these dietary strategies in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Copyright © 2015 Elsevier Ltd. All rights reserved.

 

Source: Craig C. Mitoprotective dietary approaches for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Caloric restriction, fasting, and ketogenic diets. Med Hypotheses. 2015 Nov;85(5):690-3. doi: 10.1016/j.mehy.2015.08.013. Epub 2015 Aug 21. https://www.ncbi.nlm.nih.gov/pubmed/26315446