Research Roundup: ME/CFS Research Published 11-17 January 2022

January 21, 2022


The weekly research round-up includes recent publications about ME/CFS and Long Covid. We highlight the studies that have particularly caught our interest and follow these with the full list of publications together with their abstracts (summaries).

All research relating to ME/CFS can be located in the ME Association: Index of ME/CFS Published Research. It is a FREE resource, available to anyone, and updated at the beginning of each month.

The Index provides an A-Z of published research studies, selected key documents and articles, listed by subject matter, on myalgic encephalomyelitis, myalgic encephalopathy, and/or chronic fatigue syndrome (ME/CFS).

You can use it to easily locate and read any research that you might be interested in regard to, e.g., epidemiology, infection, neurology, post-exertional malaise etc.

You can also find the Research Index in the Research section of the website together with a list of Research Summaries that provide more detailed lay explanations of the more interesting work that has been published to date.

Audio comment on this week's research

ME/CFS Research Published 11 – 17 January 2022 

There have been a range of new studies on ME/CFS research this week, with five new research studies as well as nine studies on Long Covid.  

We have highlighted two of the studies below:  

Paper one (1) is from the well-known research group which we have seen a number of studies from of late, van Campen et al. This research group focuses on orthostatic intolerance and cerebral blood flow. This study differs as the researchers investigated whether patients with frequent syncope spells (fainting) previously diagnosed with conversion or psychogenic pseudosyncope (PPS) might have another explanation of their fainting spells than behavioral psychiatric disorders.  

The results from the study show that reduced blood flow may offer an explanation for the fainting spells in those patients previously diagnosed with psychiatric disorders, which questions previous diagnosis. 

It is refreshing to see a study of this nature, further showing that ME/CFS is a physical illness and is not in the mind. This study not only measures heart rate, blood pressure during a tilt table test but blood flow to the brain, allowing other explanations for fainting spells. The small scale of this study is a shame,  30 patients in each group, however, I would think it is rather unlikely that a larger sample size would produce a different result. 

I asked the authors of the paper for a comment on their study and the reasoning behind their study. They said: 

The reason to study patients with the diagnosis of psychogenic pseudo syncope is that we met a few patients with ME/CFS who also had a diagnosis of psychogenic pseudo syncope in the past. That diagnosis was made by a neurologist. To accurately diagnose this psychogenic pseudo syncope other causes, that could explain the syncope, should be excluded. For example, low blood glucose levels, epilepsy, a stroke, and a very low or high heart rate etc. should be ruled out. 

Thus, the take-home message is that if you have a diagnosis of ME/CFS and a diagnosis of psychogenic pseudo syncope the chances are very high that psychogenic pseudo syncope is a wrong diagnosis and you should ask for an additional testing while standing like the method we use or ask for a transcranial Doppler, or ask for a specialist who is experienced in diagnosing orthostatic intolerance based on your complaints. In this way you may receive proper treatment for the orthostatic intolerance instead of counseling.” (NB this is a shortened version of the comment provided by the authors, the unabbreviated version can be found under the abstract for Paper one (1)). 

Paper three (3) compares ME/CFS and cancer-related fatigue (CRF) finding common elements in these two conditions and suggesting that stress is involved in the pathology of disease. 

This study is a review article, focusing mostly on CRF and trying to draw comparisons. There are a number of reasons why I am not convinced by the strength of this study: 

  • The researchers leading this study’s expertise lies in the area of radiation, which for one makes me question their knowledge of ME/CFS.  
  • This article was published in a Special issue of Molecular Research in Radiobiology which is not where we commonly see ME/CFS. 
  • A whole section of the article relates to ionising radiation and its role in ME/CFS, and this theme runs throughout the research paper. However, this is not mentioned in the title, only briefly in the abstract, but is an important part of the conclusion. 
  • The authors claim that “fatigue as a common symptom may indicate this connection” between ME/CFS and CRF. However, fatigue is a symptom in a number of conditions, e.g. MS, fibromyalgia, depression 
  • There are a number of differences in the fatigue experienced by these two groups, e.g. post-exertional malaise (PEM) which is experienced by ME/CFS patients and not typically seen in CRF patients. 
  • The authors themselves say currently the most evidence for the cause of ME/CFS is due to neurological dysfunction, where for cancer it is due to endocrine and immune dysfunction. Therefore, I am not sure why they are trying to draw links between the two conditions when the likely process and cause differs. 

In conclusion, I do not feel this study adds to our understanding of ME/CFS and the reasoning within the research seems very confused. I do not feel this warrants further investigation into radiation being the cause of fatigue onset. 

ME/CFS Research References and Abstracts  

1. Psychogenic Pseudosyncope: Real or Imaginary? Results from a Case-Control Study in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Patients 

van Campen, C.M.C.; Visser, F.C 

Medicina2022, 58, 98. 

Abstract 

Background and objectives: Orthostatic intolerance (OI) is a clinical condition in which symptoms worsen upon assuming and maintaining upright posture and are ameliorated by recumbency.  

OI has a high prevalence in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Exact numbers on syncopal spells especially if they are on a weekly or even daily basis are not described. Although not a frequent phenomenon, this symptomatology is of very high burden to the patient if present.  

To explore whether patients with very frequent (pre)syncope spells diagnosed elsewhere with conversion or psychogenic pseudosyncope (PPS) might have another explanation of their fainting spells than behavioral psychiatric disorders, we performed a case–control study comparing ME/CFS patients with and without PPS spells.  

Methods and results: We performed a case–control study in 30 ME/CFS patients diagnosed elsewhere with PPS and compared them with 30 control ME/CFS patients without syncopal spells.  

Cases were gender, age and ME/CFS disease duration matched. Each underwent a tilt test with extracranial Doppler measurements for cerebral blood flow (CBF).  

ME/CFS cases with PPS had a significant larger CBF reduction at end tilt than controls: 39 (6)% vs. 25 (4)%; (p < 0.0001).  

Cases had more severe disease compared with controls (chi-square p < 0.01 and had a p = 0.01) for more postural orthostatic tachycardia syndrome in cases compared with controls.  

PETCO2 end-tilt differed also, but the magnitude of difference was smaller than compared with the CBF reduction: there were no differences in heart rate and blood pressure at either end-tilt testing period. Compared with the test with the stockings off, the mean percentage reduction in cardiac output during the test with compression stockings on was lower, 25 (5) mmHg versus 29 (4) mmHg (p < 0.005).  

Conclusions: This study demonstrates that in ME/CFS patients suspected of having PPS, or conversion, CBF measurements end-tilt show a large decline compared with a control group of ME/CFS patients. Therefore, hypoperfusion offers an explanation of the orthostatic intolerance and syncopal spells in these patients, where it is clear that origin might not be behavioral or psychogenic, but have a clear somatic pathophysiologic background. 

Full comment from van Campen, Rowe and Visser: 

“The reason to study patients with the diagnosis of psychogenic pseudo syncope is that we met a few patients with ME/CFS who also had a diagnosis of psychogenic pseudo syncope in the past. That diagnosis was made by a neurologist. To accurately diagnose this psychogenic pseudo syncope other causes, that could explain the syncope, should be excluded. For example, low blood glucose levels, epilepsy, a stroke, and a very low or high heart rate etc. should be ruled out. 

The majority of ME/CFS patients have orthostatic intolerance complaints, having complaints in the upright position like while standing, walking and sitting, which disappear after lying down. The diagnosis of orthostatic intolerance can be made using a tilt table test or a standing test. The conventional approach is to monitor heart rate and blood pressures during such a test. When the heart rate goes up to high (called postural orthostatic tachycardia syndrome) or when the blood pressure drops too much (called orthostatic hypotension) the diagnosis of orthostatic intolerance is made. 

The point is that these tests are also used to diagnose psychogenic pseudo syncope. In the absence of POTS or orthostatic hypotension, the diagnosis of psychogenic pseudo syncope can be made (taking the exclusion criteria into account).  

However, we go further than alone measuring heart rate and blood pressure: we also measure the blood flow to the brain by measuring the blood flow of the vessels that go to the brain.  

The blood flow to the brain in ME/CFS patients is, however, also abnormal in ME/CFS patients who have a normal heart rate and a normal blood pressure during a tilt test. By not measuring the blood flow to the brain, one may miss the diagnosis of orthostatic intolerance and therefore, an erroneous diagnosis of psychogenic pseudo syncope can be made. Indeed the patients with psychogenic pseudo syncope had a far more profound reduction in blood flow of the brain than ME/CFS patients without this erroneous diagnosis. This reduction of flow to the brain while standing is very near the reduction of blood flow to the brain in patients who have syncope. 

Thus, the take-home message is that if you have a diagnosis of ME/CFS and a diagnosis of psychogenic pseudo syncope the chances are very high that psychogenic pseudo syncope is a wrong diagnosis and you should ask for an additional testing while standing like the method we use or ask for a transcranial Doppler, or ask for a specialist who is experienced in diagnosing orthostatic intolerance based on your complaints. In this way you may receive proper treatment for the orthostatic intolerance instead of counseling.” 

2. Circadian rhythm disruption in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Implications for the post-acute sequelae of COVID-19 

Michael J. McCarthy 

Brain, Behavior, & Immunity – Health, Volume 20, 2022 

Highlights 

  • Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is characterized by ​disrupted ​sleep ​and activity ​implicating ​circadian clocks. 
  • The incidence of ME/CFS is expected to increase as a result of the post-acute sequelae of COVID-19. 
  • Biomarker studies in ME/CFS patients implicate Transforming Growth Factor B (TGFB). 
  • TGFB has roles in synchronizing circadian rhythms in peripheral cells. 
  • Identification of biomarkers and new methodologies may facilitate progress in the chronobiological basis of ME/CFS. 

Abstract 

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a common and disabling disorder primarily characterized by persistent fatigue and exercise intolerance, with associated sleep disturbances, autonomic dysfunction, and cognitive problems.  

The causes of ME/CFS are not well understood but may coincide with immune and inflammatory responses following viral infections. During the current SARS-CoV2 coronavirus pandemic, ME/CFS has been increasingly reported to overlap with persistent “long COVID” symptoms, also called the post-acute sequelae of COVID-19 (PASC).  

Given the prominence of activity and sleep problems in ME/CFS, circadian rhythm disruption has been examined as a contributing factor in ME/CFS. While these studies of circadian rhythms have been pursued for decades, evidence linking circadian rhythms to ME/CFS remains inconclusive.  

A major limitation of older chronobiology studies of ME/CFS was the unavailability of modern molecular methods to study circadian rhythms and incomplete understanding of circadian rhythms outside the brain in peripheral organ systems. Major methodological and conceptual advancements in chronobiology have since been made. Over the same time, biomarker research in ME/CFS has progressed. Together, these new developments may justify renewed interest in circadian rhythm research in ME/CFS.  

Presently, we review ME/CFS from the perspective of circadian rhythms, covering both older and newer studies that make use of modern molecular methods.  

We focus on transforming growth factor beta (TGFB), a cytokine that has been previously associated with ME/CFS and has an important role in circadian rhythms, especially in peripheral cells.  

We propose that disrupted TGFB signaling in ME/CFS may play a role in disrupting physiological rhythms in sleep, activity, and cognition, leading to the insomnia, energy disturbances, cognition problems, depression, and autonomic dysfunction associated with ME/CFS.  

Since SARS-like coronavirus infections cause persistent changes in TGFB and previous coronavirus outbreaks have caused ME/CFS-like syndromes, chronobiological considerations may have immediate implications for understanding ME/CFS in the context of the COVID-19 pandemic and possibly suggest new avenues for therapeutic interventions. 

3. Commonalities in the Features of Cancer and Chronic Fatigue Syndrome (CFS): Evidence for Stress-Induced Phenotype Instability? 

Rusin, A.; Seymour, C.; Cocchetto, A.; Mothersill, C.  

Int. J. Mol. Sci.2022, 23, 691. 

Abstract 

Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) and Cancer-Related Fatigue (CRF) are syndromes with considerable overlap with respect to symptoms.  

There have been many studies that have compared the two conditions, and some of this research suggests that the etiologies of the conditions are linked in some cases.  

In this narrative review, CFS/ME and cancer are introduced, along with their known and putative mechanistic connections to multiple stressors including ionizing radiation.  

Next, we summarize findings from the literature that suggest the involvement of HPA-axis dysfunction, the serotonergic system, cytokines and inflammation, metabolic insufficiency and mitochondrial dysfunction, and genetic changes in CRF and CFS/ME.  

We further suspect that the manifestation of fatigue in both diseases and its causes could indicate that CRF and CFS/ME lie on a continuum of potential biological effects which occur in response to stress. The response to this stress likely varies depending on predisposing factors such as genetic background.  

Finally, future research ideas are suggested with a focus on determining if common biomarkers exist in CFS/ME patients and those afflicted with CRF. Both CFS/ME and CRF are relatively heterogenous syndromes, however, it is our hope that this review assists in future research attempting to elucidate the commonalities between CRF and CFS/ME. 

4. Chronic Fatigue After Thyroidectomy: A Patient-Centered Survey 

Lumpkin ST, Button J, Stratton L, Strassle PD, Kim LT.  

Am Surg. 2022 Feb;88(2):260-266. 

Abstract 

Background: Fatigue after thyroidectomy is common, but there is a paucity of data regarding its prevalence and duration. We hypothesized that total thyroidectomy (TT) patients would have more long-term fatigue than thyroid lobectomy (TL) patients. 

Methods: Statewide survey of thyroidectomy patients (2004-2017) was carried out. 

Results: 281 patients completed the survey. 216 respondents (77%) had TT and 65 (23%) had TL. Within one year of surgery, 172 (61%) respondents recalled being troubled by new fatigue all, most, or some of the time. Total thyroidectomy patients were more likely to report new fatigue (69% vs. 44%, aOR 2.72, 95% CI 1.44 to 5.18). Of patients (n = 172) reporting new fatigue, 67 (39%) reported at least moderate improvement. Nineteen (28%) saw improvement within 1 year, 35 (52%) saw improvement in 1-2 years, and 11 (16%) saw improvement after 2 years. 

Conclusion: Long-term fatigue after TT can be debilitating, long-lasting, and less prevalent after TL. 

5. Efficacy and safety of Ma's Bamboo-based medicinal moxibustion therapy for chronic fatigue syndrome- An exploratory study protocol for randomized controlled trial 

Xue Kaiyang, Wang Xianzhu, Quan,Fei, Tang Jiaxuan, Wang Xin, Lan Lan, Fu Jing, Cui Jin  

Medicine Case Reports and Study Protocols: January 2022 – Volume 3 – Issue 1 – p e0193 

Abstract 

Background: Chronic fatigue syndrome (CFS) is a recurrent functional disease with an unknown pathogenesis. Modern treatment mainly focuses on symptomatic and supportive care, but no specific treatment has emerged. Ma's Bamboo-based Medicinal Moxibustion therapy is a folk traditional Chinese medicine developed in Jinsha County, Guizhou Province. Over a long period of practice in the primary health care setting, it has been confirmed in folk medicine that the therapy can significantly improve the symptoms of patients with CFS, but there is no sufficient and scientific clinical evidence. Therefore, this randomised controlled pilot study was designed to preliminarily evaluate the efficacy and safety of Ma's Bamboo-based Medicinal Moxibustion therapy. 

Methods/design: This is a parallel, randomized, controlled, and exploratory study. Sixty patients with CFS admitted to the First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine will be randomly assigned to the experimental or control group.  

The experimental group will receive Ma's Bamboo-based Medicinal Moxibustion therapy, whereas the control group will undergo conventional acupuncture. Both groups will be treated once daily for 6 consecutive days as a course of treatment, and two courses separated by 1 day will be completed (12 total treatments). All patients will undergo follow-up after the end of treatment. The baseline period is 2 days.  

The Fatigue Assessment Instrument score as the primary efficacy measure and secondary efficacy measures, including the Clinical Symptom Score and Fatigue Scale-14, will be evaluated at baseline, after one and two courses of treatment, and during follow-up. Serum T lymphocyte subset counts (CD3+, CD4+, CD8+, CD4+/CD8+) and safety measures ((blood routine test, liver and kidney function and electrocardiogram) will be evaluated at baseline and after two courses of treatment.  

All adverse events occurring between baseline and the end of follow-up will be summarised at the end of the follow-up. 

Discussion: The results of this trial will clarify whether Ma's Bamboo-based Medicinal Moxibustion therapy can improve the symptoms of patients with CFS and provide preliminary evidence for the effectiveness and safety of Ma's Bamboo-based Medicinal Moxibustion therapy for this indication. 

Long-COVID Research References   

  1. “LONG COVID”-A hypothesis for understanding the biological basis and pharmacological treatment strategy 
  1. Could SARS-CoV-2 Spike Protein Be Responsible for Long-COVID Syndrome? 
  1. Exercise as a Moderator of Persistent Neuroendocrine Symptoms of Covid 19 
  1. Associations of Post-Acute COVID syndrome with physiological and clinical measures 10 months after hospitalization in patients of the first wave 
  1. Vaccination Hesitancy and Postacute Sequelae of SARS-CoV-2: Is It Time to Reconsider? 
  1. Acute and chronic neurological disorders in COVID-19: potential mechanisms of disease 
  1. Chronic Post-Covid-19 Syndrome – a Variety of the Chronic Fatigue Disease? 
  1. Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection 
  1. Functional status, mood state, and physical activity among women with post-acute COVID-19 syndrome 

Dr Katrina Pears
MEA Research Correspondent

  

  

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