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).
RESEARCH INDEX
The ME Association maintains a comprehensive index of published research on ME/CFS and Long Covid that is free to use and updated weekly.
Audio Commentary by Dr Katrina Pears
ME/CFS Research Published 5 – 12 December 2022
It’s been a surprisingly busy week in the lead up to Christmas. There have been seven new ME/CFS studies and fourteen new Long Covid studies.
Included in the ME/CFS reference section this week is a PhD thesis looking at brain structure and function (Paper five (5)), a Master’s thesis looking into language as a predictor for depression and anxiety (Paper six (6)) as well as a study not directly on ME/CFS but hypothalamic disorder (HD), which found some women with this unexplained disorder also had ME/CFS (Paper seven (7)).
We have highlighted two of the ME/CFS studies:
Paper one (1) looks into sodium muscle content, as the underlying cause of muscle fatigue and pain is not yet fully understood. The authors also looked into the relationship between sodium content and handgrip strength. This study used MRI scanning to quantify sodium contents in the muscles.
The findings in this study are very clear, with significantly higher level of sodium in participants with ME/CFS before and after exercise than the controls. This finding was found in a range of different muscles, and the data/graphs displayed in this paper very clearly show the differences. There was also an association between reduced handgrip strength and increase in muscle sodium content. These findings are thought to be due to the function of the sodium-potassium pump (specifically its insufficient stimulation leading to overload), which also relies on energy (ATP) for its activity.
A few things to note from this study:
- Only 6 ME/CFS patients and 6 healthy controls were used. However, it is very likely that the significantly large increases would also be confirmed in a larger sample size.
- The study was restricted to females only due to the high prevalence in the female sex, (and also necessary due to the small sample size) but this is also a draw back as we don’t know if results would vary in males.
- People with ME/CFS are often advised to increase their sodium/salt intake to help with orthostatic intolerance, however, findings in this study would not be due to this as the differences are too large and excess sodium is excreted by the kidneys. Therefore, a lower dietary intake would not change the results.
- The findings in this study support a recent review article by Wirth and Scheibenbogen, 2021. However, it is a great shame that they did not investigate other cells which they hypothesise in this review to be affected by this overload, such as the mitochondria, cytoplasmatic metabolism and endothelium (membrane lining the blood vessels and heart).
- It is a great shame that other ions were not investigated for muscle content, such as magnesium, calcium and potassium which might help to further explain the dysfunction found, especially if this finding is due to the sodium-potassium pump.
- Finally, it is not known how the immobility of patients with ME/CFS would have affected these results, especially the variable levels of activity of those with ME/CFS. The study does not mention ME/CFS severity, so we don’t know how these results would vary in the more severely affected (assuming they were not included in this study) and therefore would be more inactive.
In conclusion, there are some very clear significant findings in this study on a very small sample size, however, more investigation is needed to explain these results, especially if potential treatments targeting the high sodium muscle content are to be considered.
Paper three (3) looks into the clinical effects of wasabi extract containing 6-MSITC on ME/CFS. Wasabi is a common spice used in Japan and the main root (rhizome) contains methylsulfinylhexyl isothiocyanate (6-MSITC) which has anti-inflammatory and antioxidant effects, as well as improving neuroinflammation and memory.
In this study 15 patients were orally administered wasabi extract daily (2 tablets 3 times a day) for 12 weeks. The study measured: performance status (PS) (which is a rating of 0-9 evaluating fatigue), self-rating questionnaires, pressure pain threshold (PPT) on the occiput, Trail Making test-A (TMT-A), and hemodynamic patterns determined by an active standing test.
This study showed a number of improvements from taking wasabi. To mention a few there was a significant increase in the performance status (PS) of participants following treatment, a range of symptoms were also seen to improve, including headache, myalgia, brain fog, difficulty finding words, pain sensitivity.There were no significant changes in the fatigue scores or hemodynamic/ orthostatic patterns.
A few things to note about this study:
- The study was small, only 15 participants, with an imbalance of male: female (3: 12 respectively).
- Patients in this study all met five different diagnosis criteria, meaning the inclusion criteria for ME/CFS was more rigorous than other studies. However, there is no mention of the different severities, which are likely to have varying effects from taking wasabi.
- Fatigue was primarily assessed using the chalder fatigue scale, which is criticised for its “ceiling effect” where most ME/CFS patients will record a maximum score, and cannot indicate further worsening of their fatigue.
- On reading more of the details in the paper the results do not look quite so promising, for example, performance status only improved in 6 patients and was unchanged in the other 9. The 6 patients who did improve reported large improvements, hence the significant result.
- It was an open-label trial which is also known as a “non-masked” or “unblinded” trial, where the researchers are fully aware of participants in each treatment group and what treatment they are receiving. Open-label trials often lead to an increase in the confidence about incidence rates, but the data is not so highly valued.
- Mostly importantly, there are no details of a healthy control group for comparison or a ME/CFS group receiving a placebo.
- It is extremely hard to rate the effectiveness of treatments without the measure of any biological specimens (such as in blood samples), which could give clearer indication of improvements. Obviously, this is extremely difficult in ME/CFS (due to the lack of biomarkers), but wasabi is said to have anti-inflammatory and antioxidant effects, therefore inflammation markers could have been used (e.g. C-reactive protein (CRP)).
In conclusion, an initial glance at this study offers some promising results, but on reading the details the findings are not so clear with a lack of positive effects seen on fatigue. Also, results are meaningless without comparisons to healthy controls or a placebo.
In the Long Covid reference section, you may also be interested in:
- Paper one (1) showing an increase in physical performance and symptoms following supplementation with arginine and vitamin C.
- Paper two (2) and three (3) show that Covid-19 vaccination helps to prevent Long Covid.
- Paper four (4) investigates the unique immune signature in Long Covid, showing key changes compared to healthy controls and those who have recovered from Covid-19.
ME/CFS Research References and Abstracts
1. Muscle sodium content in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Petter, E., Scheibenbogen, C., Linz, P. et al.
J Transl Med 20, 580 (2022).
Abstract
Background: Muscle fatigue and pain are key symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Although the pathophysiology is not yet fully understood, there is ample evidence for hypoperfusion which may result in electrolyte imbalance and sodium overload in muscles. Therefore, the aim of this study was to assess levels of sodium content in muscles of patients with ME/CFS and to compare these to healthy controls.
Methods: Six female patients with ME/CFS and six age, BMI and sex matched controls underwent 23Na-MRI of the left lower leg using a clinical 3T MR scanner before and after 3 min of plantar flexion exercise.
Sodium reference phantoms with solutions of 10, 20, 30 and 40 mmol/L NaCl were used for quantification. Muscle sodium content over 40 min was measured using a dedicated plugin in the open-source DICOM viewer Horos. Handgrip strength was measured and correlated with sodium content.
Results: Baseline tissue sodium content was higher in all 5 lower leg muscle compartments in ME/CFS compared to controls. Within the anterior extensor muscle compartment, the highest difference in baseline muscle sodium content between ME/CFS and controls was found (mean ± SD; 12.20 ± 1.66 mM in ME/CFS versus 9.38 ± 0.71 mM in controls, p = 0.0034). Directly after exercise, tissue sodium content increased in gastrocnemius and triceps surae muscles with + 30% in ME/CFS (p = 0.0005) and + 24% in controls (p = 0.0007) in the medial gastrocnemius muscle but not in the extensor muscles which were not exercised.
Compared to baseline, the increase of sodium content in medial gastrocnemius muscle was stronger in ME/CFS than in controls with + 30% versus + 17% to baseline at 12 min (p = 0.0326) and + 29% versus + 16% to baseline at 15 min (p = 0.0265). Patients had reduced average handgrip strength which was associated with increased average muscle tissue sodium content (p = 0.0319, R2 = 0.3832).
Conclusion: Muscle sodium content before and after exercise was higher in ME/CFS than in healthy controls. Furthermore, our findings indicate an inverse correlation between muscle sodium content and handgrip strength.
These findings provide evidence that sodium overload may play a role in the pathophysiology of ME/CFS and may allow for potential therapeutic targeting.
Bernhoff, G., Rasmussen-Barr, E. & Bunketorp Käll, L.
J Transl Med 20, 577 (2022).
Abstract
Background: In chronic fatigue syndrome/myalgic encephalomyelitis (ME/CFS), the capacity for activity and participation is strongly limited. The disease definition is very broad, and considering the lack of evidence for best treatment, it is important to understand what is ME/CFS-specific in the biopsychosocial perspective in comparison with similar syndromes.
The objective was to study the difference between those diagnosed with ME/CFS and those with similar symptoms but no ME/CFS diagnosis for self-perceived level of physical activity, work ability, anxiety/depression, and health-related quality of life.
Methods: This was a clinical cross-sectional study with data collected from mailed questionnaires. The following variables were compared between patients diagnosed with ME/CFS (n = 205) and those with similar symptoms but no diagnosis (n = 57); level of physical activity, Work ability index (WAI), Hospital anxiety and depression scale (HAD-A/HAD-D), and RAND-36 Physical functioning, Role limitations due to physical health problems, Role limitations due to personal or emotional problems, Social functioning, Energy/fatigue, Bodily pain, Emotional well-being, and General health perceptions.
The Chi-squared test (nominal data), the Mann-Whitney U test, the Student’s t test and regression analysis were used to analyze the data.
Results: The group diagnosed with ME/CFS had a more impaired physical and mental exertion ability as compared to the group that had similar symptoms but was not diagnosed with ME/CFS, shown by a RAND-36 lower index of physical role functioning, social functioning, energy, worse pain and poorer overall health (p ≤ 0.05).
In contrast, no significant group differences emerged for weekly level of physical activity, work ability, anxiety/depression, and RAND-36 Emotional role limitation and well-being.
Conclusion: Our results indicate that those with a diagnosis of ME/CFS are characterized by an impaired ability for physical or mental exertion, worse pain, and poorer overall health as compared to individuals with similar symptoms but for whom ME/CFS-diagnosis was not established.
The results may be cautiously interpreted as support when focusing on patients’ self-care in terms of management of energy levels. The results must however be verified in future studies.
Oka, T., Yamada, Y., Lkhagvasuren, B. et al.
BioPsychoSocial Med 16, 26 (2022).
Abstract
Background: Wasabi (Eutrema japonicum) is a common pungent spice used in Japan. 6-Methylsulfinylhexyl isothiocyanate (6-MSITC) found in the rhizome of wasabi has been shown to have anti-inflammatory and antioxidant effects, as well as improve neuroinflammation and memory. Therefore, we hypothesized that these effects would be beneficial for treating myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The present study was conducted to investigate the effectiveness of wasabi extract containing 6-MSITC on ME/CFS in an open-label trial.
Methods: Fifteen patients (3 males, 12 females, 20–58 years old) were orally administered wasabi extract (9.6 mg of 6-MSITC/day) for 12 weeks. The following parameters and test results were compared pre- and post-treatment: performance status (PS), self-rating questionnaires, pressure pain threshold (PPT) on the occiput, Trail Making test-A (TMT-A), and hemodynamic patterns determined by an active standing test.
Results: After treatment with 6-MSITC, PS improved significantly (p = 0.001). Although the scores on the 11-item Chalder Fatigue scale (CFS-11) and numerical rating scale (NRS) of fatigue did not show significant changes, subjective symptoms improved significantly, including headache frequency (4.1 to 3.0 times/week, p = 0.001) and myalgia (4.1 to 2.4 times/week, p = 0.019), NRS brain fog scores (5.7 to 4.5, p = 0.011), difficulty finding appropriate words (4.8 to 3.7, p = 0.015), photophobia (4.8 to 3.5, p = 0.008), and the Profile of Mood Status vigor score (46.9 to 50.0, p = 0.045).
The PPT of the right occiput (17.3 to 21.3 kPa, p = 0.01) and TMT-A scores (53.0 to 38.1 s, p = 0.007) also changed, suggesting reduced pain sensitivity, and improved cognitive function, respectively. Orthostatic patterns determined by a standing test did not show remarkable changes. There were no serious adverse reactions.
Conclusion: This study suggests that 6-MSITC improves PS as well as subjective symptoms such as pain and cognitive dysfunction, and psychological vitality of patients with ME/CFS. It also improved cognitive performance and increased pain thresholds in these patients. 6-MSITC may be a promising therapeutic option especially for improving cognitive dysfunction associated with ME/CFS.
4. What Causes ME/CFS: The Role of the Dysfunctional Immune System and Viral Infections
Amolak S Bansal, Aletta D Kraneveld, Elisa Oltra and Simon Carding
Journal of Immunology and Allergy 2022;3(2):1-15.
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remains an enigmatic highly disabling and complex long-term condition with a wide range of aetiologies and symptoms.
A viral onset is commonly mentioned by patients and several bodily systems are ultimately disturbed. The parallel with long-covid is clear.
However, immune dysregulation with impaired NK cell dysfunction and tendency to novel autoimmunity have been frequently reported. These may contribute to reactivation of previous acquired viruses/retroviruses accompanied by impaired endocrine regulation and mitochondrial energy generation.
The unpredictable nature of seemingly unconnected and diverse symptoms that are poorly responsive to several allopathic and alternative therapies then contributes to an escalation of the illness with secondary dysfunction of multiple other systems. Treatment of established ME/CFS is therefore difficult and requires multi-specialty input addressing each of the areas affected by the illness.
Almutairi, Basim S.
PhD thesis, University of Bristol
Abstract
Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is characterised by continuous fatigue and has many diagnostic criteria. Cognitive dysfunction affects 86-94% of adults with CFS/ME.
This thesis used MRI applications to investigate brain structure and function in CFS/ME. This thesis hypothesised to find brain volume differences, functional connectivity differences in brain networks, and functional differences measured by Blood Oxygenation Level Dependant (BOLD) signal activation during working memory task performance.
The working memory paradigm was designed to investigate working memory components, processing and storage separately and combined. The relationship between fatigue and performance was assessed. This thesis's original contribution provides evidence that the salience network might have altered resting-state functional connectivity in CFS/ME in the absence of morphological differences.
The salience network is involved in detecting and integrating salient sensory information; therefore, disruption in this network might disrupt incoming cognitive stimuli and influence other networks' connectivity, involved in fatigue and impaired memory.
In the more demanding task, participants with CFS/ME were slower and less accurate but used the same working memory network as healthy controls. No brain volume differences, nor atrophy were found. The differences between these findings compared to previous studies might be due to different study designs, analysis methods, sample sizes with different symptoms, including illness duration, physical inactivity and sleep disturbance.
The salience network alteration could potentially have a significant role in CFS/ME, as we cannot determine cause and effect with current experimental design the association with fatigue and other CFS/ME symptoms remains unclear. Using longitudinal studies that account for neurologically relevant confounders are needed in CFS/ME to further investigate the role of salience network.
Fennema, M.
Master’s thesis [Utrecht University]
Abstract
Nowadays, Artificial Intelligence (AI) models are being used in multiple areas of the healthcare sector. This thesis looks into the relationship between language use of teenaged patients with Chronic Fatigue Syndrome (CFS) and their anxiety, depression, self-efficacy, and CFS treatment outcome.
This research aims to make it easier for healthcare professionals to get an indication of the level of a patient’s anxiety or depression, the measure of their self-efficacy, and whether or not a specific type of treatment will work for a patient.
Using a short text written by the patient to get such an indication would facilitate an earlier start of effective treatment. This thesis uses data from 102 patients who received online email-based Cognitive Behavioural Therapy for its two main focus areas.
The first focus area looks at the correlation between a patient’s language use and their anxiety, depression, and self-efficacy. This is done by training n-gram-based language models and Naive Bayes on the text in the emails to predict the patients’ anxiety, depression, and self-efficacy scores. The language models’ results were compared to those of models trained on randomly generated scores, and it was shown that outputs of these models were statistically significant. The language model performed better than Naive Bayes, and it was concluded that there was a correlation between language use and anxiety, depression, and self-efficacy.
The second focus area looks at how well the language used by the patients in the emails sent to their therapists can be used with various AI models to predict the level of their anxiety and depression, the measure of their self-efficacy, and their CFS treatment outcome. This was done using the number of non-agentic language features per email, Bag of Words, and BERTje embeddings.
These features were used as input for both logistic regression models and neural networks. When using logistic regression, the models for predicting self-efficacy using BERTje embeddings performed best. The neural networks using BERTje embeddings outperformed the logistic regression models when predicting anxiety, depression, self-efficacy, and treatment outcome. Thus it was concluded that it is possible to predict anxiety, depression, self-efficacy, and patient recovery based on language use.
Hataya, Y., Okubo, M., Hakata, T. et al.
BMC Endocr Disord 22, 312 (2022).
Abstract
Background: The corticotropin-releasing hormone (CRH) challenge test can distinguish the disorders of the hypothalamus from those of the pituitary. However, the pathophysiology of hypothalamic disorder (HD) has not been fully understood. This study aimed to elucidate the clinical characteristics of patients with unexplainable HD, diagnosed by the CRH challenge test.
Methods: We retrospectively reviewed patients who underwent the CRH challenge test. Patients were categorized into four groups as follows: patients with peak serum cortisol ≥18 μg/dL were assigned to the normal response (NR) group (n = 18), among patients with peak serum cortisol < 18 μg/dL and peak adrenocorticotropic hormone (ACTH) increase ≥two-fold, patients without obvious background pathology were assigned to the unexplainable-HD group (n = 18), whereas patients with obvious background pathology were assigned to the explainable-HD group (n = 38), and patients with peak serum cortisol < 18 μg/dL and peak ACTH increase <two-fold were assigned to the pituitary disorder (PD) group (n = 15). Inter-group comparisons were performed based on clinical characteristics.
Results: In the CRH challenge test, the peak plasma ACTH levels were significantly lower in the unexplainable-HD group than in the NR group, despite more than two-fold increase compared to basal levels. The increase in serum cortisol was significantly higher in the unexplainable-HD group than in the explainable-HD and PD groups.
Although patients in the unexplainable-HD group showed a clear ACTH response in the insulin tolerance test, some patients had peak serum cortisol levels of < 18 μg/dL.
Furthermore, attenuated diurnal variations and low normal levels of urinary free cortisol were observed.
Most patients in the unexplainable-HD group were young women with chronic fatigue. However, supplementation with oral hydrocortisone at physiological doses reduced fatigue only in some patients.
Conclusions: Patients with unexplainable HD diagnosed by the CRH challenge test had hypothalamic–pituitary–adrenal (HPA) axis dysfunction and some patients had mild central adrenal insufficiency.
Hydrocortisone supplementation reduced fatigue only in some patients, suggesting that HPA axis dysfunction may be a physiological adaptation. Further investigation of these patients may help elucidate the pathophysiology of myalgic encephalitis/chronic fatigue syndrome.
Long-COVID Research References
- Post-Viral Fatigue Following SARS-CoV-2 Infection during Pregnancy: A Longitudinal Comparative Study
Dr Katrina Pears,
Research Correspondent.
The ME Association.
