Biomarker research: Submaximal exercise provokes increased activation of the anterior DMN during the resting state as a biomarker of PEM in ME/CFS

Posted on 01/19/2022 by wames

Submaximal exercise provokes increased activation of the anterior default mode network during the resting state as a biomarker of postexertional malaise in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome, by Rakib U Rayhan and  James N Baraniuk in Front. Neurosci., 15 Dec 2021 [doi.org/10.3389/fnins.2021.748426]

 

Research abstract:

Background: 

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by disabling fatigue and postexertional malaise. We developed a provocation paradigm with two submaximal bicycle exercise stress tests on consecutive days bracketed by magnetic resonance imaging, orthostatic intolerance, and symptom assessments before and after exercise in order to induce objective changes of exercise induced symptom exacerbation and cognitive dysfunction.

Method: 

Blood oxygenation level dependent (BOLD) scans were performed while at rest on the preexercise and postexercise days in 34 ME/CFS and 24 control subjects. Seed regions from the FSL data library with significant BOLD signals were nodes that clustered into networks using independent component analysis. Differences in signal amplitudes between groups on pre- and post-exercise days were determined by general linear model and ANOVA.

Results:

The most striking exercise-induced effect in ME/CFS was the increased spontaneous activity in the medial prefrontal cortex that is the anterior node of the Default Mode Network (DMN). In contrast, this region had decreased activation for controls. Overall, controls had higher BOLD signals suggesting reduced global cerebral blood flow in ME/CFS.

Conclusion: 

The dynamic increase in activation of the anterior DMN node after exercise may be a biomarker of postexertional malaise and symptom exacerbation in CFS. The specificity of this postexertional finding in ME/CFS can now be assessed by comparison to post-COVID fatigue, Gulf War Illness, fibromyalgia, chronic idiopathic fatigue, and fatigue in systemic medical and psychiatric diseases.

 

Health Rising: Exercise Challenge Reveals a “Remarkable Discordance” in the Brains of People with ME/CFS

  • Using a two-day exercise challenge, Georgetown researchers found a part of the brain that gets turned off in the post-exercise period actually gets turned on in people with ME/CFS.
  • The authors proposed that something called the default mode network which is associated with rumination and internal assessments had become activated in the post-exercise period in ME/CFS. (It was not activated in the pre-exercise period.
  • Because the DMN has to be turned off in order for action to take place, its activation in ME/CFS made tasks more difficult to complete. The authors called the process task-related deactivation.
  • As similar findings have shown up in Gulf War Illness, it’s possible that DMN activation post-exercise is a feature of all fatiguing and exertionally intolerant diseases.
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Research review: Brainstem abnormalities in ME/CFS… evaluation of MRI findings

Posted on 01/12/2022 by wames

Brainstem abnormalities in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A scoping review and evaluation of Magnetic Resonance Imaging findings, by Todd Nelson, Lan-Xin Zhang, Hui Guo, Luis Nacul, Xiaowei Son in Frontiers in Neurology Vol 12, p 769511, Dec 2021 [doi:10.3389/fneur.2021.769511]

 

Review abstract:

Background

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multisystem medical condition with heterogeneous symptom expression.

Currently, there is no effective cure or treatment for the standard care of patients. A variety of ME/CFS symptoms can be linked to the vital life functions of the brainstem, the lower extension of the brain best known as the hub relaying information back and forth between the cerebral cortex and various parts of the body.

Objective/Methods

Over the past decade, Magnetic Resonance Imaging (MRI) studies have emerged to understand ME/CFS with interesting findings, but there has lacked a synthesized evaluation of what has been found thus far regarding the involvement of the brainstem. We conducted this study to review and evaluate the recent MRI findings via a literature search of the MEDLINE database, from which 11 studies met the eligibility criteria.

Findings

Data showed that MRI studies frequently reported structural changes in the white and gray matter. Abnormalities of the functional connectivity within the brainstem and with other brain regions have also been found.

The studies have suggested possible mechanisms including astrocyte dysfunction, cerebral perfusion impairment, impaired nerve conduction, and neuroinflammation involving the brainstem, which may at least partially explain a substantial portion of the ME/CFS symptoms and their heterogeneous presentations in individual patients.

Conclusions

This review draws research attention to the role of the brainstem in ME/CFS, helping enlighten future work to uncover the pathologies and mechanisms of this complex medical condition, for improved management and patient care.

Excerpts from paper:

Taken together, the present review highlights the brainstem as a potential brain centre that may have a key role in the physiological defects in ME/CFS and recommends future MRI on ME/CFS studies to make the brainstem a specific target. Given the close association between the brainstem function impairments and the complex clinical expression of the disease, MRI, with its relatively high spatial and temporal resolutions for non-invasive in vivo applications, holds promise to uncover the mechanisms of the disease, and in turn enlightens effective strategies for improved patient care.

This review contributes to the research line by bringing the existing studies together and integrating them while highlighting the potential for more. As the big questions around ME/CFS remain unanswered (e.g., why does an initial viral event result in a debilitating ongoing life-long disease in some people, why does it not resolve like a typical infectious illness, and why are ME/CFS patients subject to frequent relapses), highlighting of the brainstem as a specific target is meaningful from both research and clinical practice perspectives.

…The paper draws increased attention to brainstem research in ME/CFS using multi-modality MRI, calling for improved experimental design, and increased sample size and follow-up duration. Targeting the brainstem abnormalities in relation to the heterogeneous symptoms has implications for uncovering ME/CFS mechanisms and thus improving management and patient care.

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Research: Experiences…on educational adaptations for students with CFS/ME (Norway)

Posted on 01/10/2022 by wames

Experiences among school personnel and school nurses on educational adaptations for students with CFS/ME: A qualitative interview study, by Wenche Ann Similä,  Torstein Baade Rø and  Torunn Hatlen Nøst in Front. Pediatr., 11 November 2021 [doi.org/10.3389/fped.2021.756963]

 

Research abstract:

Introduction:

Chronic fatigue syndrome (CFS/ME) is a disabling disease severely impacting school attendance, education, and social life in young students. Uncertainties surrounding CFS/ME etiology may impact the interpretation of CFS/ME in schools. Thus, school personnel need information from health care providers to make adequate adaptations to education and social life at school for these students.

Objectives:

To explore teachers, counselors, and school nurses’ experiences with adapting education for students with CFS/ME aged 13–19 in secondary and high schools.

Design:

A qualitative study with focus group interviews and individual interviews performed face-to-face or digitally between November 2020 and March 2021. Data were analyzed using Systematic text condensation.

Participants:

Six teachers, two counselors, and four school nurses in secondary and high school participated.

Results:

Adapting education for students with CFS/ME was challenging, especially before the students received a diagnosis. The challenges were related to identifying the students’ adaptational needs, maintaining a teacher-student relationship due to school absence, difficulties in maintaining continuity of education, and uncertainty regarding the diagnosis. Successful adaptations were related to quickly reacting to school absence, early referral to educational, psychological services, a close collaboration with the school management, and the development of digital teaching for students with CFS/ME. Interdisciplinary collaboration and a clear, constructive plan with adaptive measures, including maintained teacher-student communication and educational and social adaptations, may be useful in preventing the losses young people, with CFS/ME experience.

Conclusion:

Early interdisciplinary collaboration to adapt education and social life at school for students with CFS/ME, may support teachers, counselors, and school nurses in their efforts to adapt education and prevent losses related to academic and social development in students with CFS/ME.

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Research review: ME/CFS & POTS proposed as sub-types of long COVID

Posted on 01/06/2022 by wames

Proposed subtypes of post-COVID-19 syndrome (or long-COVID) and their respective potential therapies, by Shin Jie Yong, Shiliang Liu in Rev Med Virol. 2021 Dec 9; [doi: 10.1002/rmv.2315]

 

Review abstract:

The effects of coronavirus disease 2019 (COVID-19), a highly transmissible infectious respiratory disease that has initiated an ongoing pandemic since early 2020, do not always end in the acute phase. Depending on the study referred, about 10%-30% (or more) of COVID-19 survivors may develop long-COVID or post-COVID-19 syndrome (PCS), characterised by persistent symptoms (most commonly fatigue, dyspnoea, and cognitive impairments) lasting for 3 months or more after acute COVID-19.

While the pathophysiological mechanisms of PCS have been extensively described elsewhere, the subtypes of PCS have not. Owing to its highly multifaceted nature, this review proposes and characterises six subtypes of PCS based on the existing literature.

The subtypes are:

  1. non-severe COVID-19 multi-organ sequelae (NSC-MOS) [3.1]
  2. pulmonary fibrosis sequelae (PFS) [3.2]
  3. myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) [3.3]
  4. postural orthostatic tachycardia syndrome (POTS) [3.4]
  5. post-intensive care syndrome (PICS) [3.5]
  6. medical or clinical sequelae (MCS) [3.6]

Original studies supporting each of these subtypes are documented in this review, as well as their respective symptoms and potential interventions. Ultimately, the subtyping proposed herein aims to provide better clarity on the current understanding of PCS.

One of the phenotypes is ME/CFS, which was two-fold more likely to happen to COVID-19-positive than—negative patients, especially among women younger than 65 years, at 6- to 9-month post-infection. [from section 3.3]

Read full paper

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Research: Compression stockings improve cardiac output & cerebral blood flow during tilt testing in ME/CFS patients

Posted on 01/05/2022 by wames

Compression stockings improve cardiac output and cerebral blood flow during tilt testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients: a randomized crossover trial by  C. (Linda) M C van Campen, Peter C Rowe and Frans C Visser in Medicina 2022 58:1 [10.3390/medicina58010051] (This article belongs to the Special Issue Chronic Fatigue Syndrome: From Clinical Observations to Unifying Hypotheses of Disease Mechanisms)

 

Research 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). Limited data are available to guide the treatment of OI in ME/CFS patients. We and others have previously described patient-reported subjective improvement in symptoms using compression stockings. We hypothesized that these subjective reports would be accompanied by objective hemodynamic improvements.

Materials and Methods:

We performed a randomized crossover trial in 16 ME/CFS patients. Each underwent two 15-min head-up tilt table tests, one with and one without wearing knee-high compression stockings that provided 20–25 mm Hg compression. The order of the tests was randomized. We measured heart rate and blood pressure as well as cardiac output and cerebral blood flow (CBF) using extracranial Doppler of the internal carotid and vertebral arteries.

Results:

There were no differences in supine measurements between the 2 baseline measurements. There were no differences in heart rate and blood pressure at either end-tilt testing period. Compared to the test with the stockings off, the mean percentage reduction in cardiac output during the test with compression stockings on was lower, 15 (4)% versus 27 (6)% (p < 0.0001), as was the mean percentage CBF reduction, 14 (4)% versus 25 (5)% (p < 0.0001).

Conclusion:

In ME/CFS patients with orthostatic intolerance symptoms, cardiac output and CBF are significantly reduced during a tilt test. These abnormalities were present without demonstrable heart rate and blood pressure changes and were ameliorated by the use of compression stockings.

Comment from full paper:

…using a questionnaire in our previous study on compression stockings, the positive and negative responses of wearing compression stockings to a variety of physical activities was variable and dependent on the degree of physical activity in question. In contrast, in the present study we found a uniform hemodynamic improvement when patients wore the stockings. Future work will be able to address whether specific symptoms such as exercise intolerance, pain, cognitive symptoms, lightheadedness or co-morbid disease will be more likely to improve with compression stockings.

This new finding supports the use of the compression stockings in these patients. Compression stockings may also be beneficial in non-ME/CFS populations with orthostatic intolerance.

See also:

Compression Garment Reduces Orthostatic Tachycardia and Symptoms in Patients With Postural Orthostatic Tachycardia Syndrome by Kate Bourne et al

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Research: Cerebral blood flow in long-haul COVID-19 patients: similarities with ME/CFS

Posted on 01/03/2022 by wames

Orthostatic symptoms and cerebral blood flow in long-haul COVID-19 patients: similarities with Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome, by C (Linda) MC van Campen, Peter C Rowe and Frans C Visser in Medicina 2022, 58(1), 28, 24 Dec 2021 [doi.org/10.3390/medicina58010028] (This article belongs to the Special Issue Chronic Fatigue Syndrome: From Clinical Observations to Unifying Hypotheses of Disease Mechanisms)

 

Research abstract:

Background and Objectives:

Symptoms and hemodynamic findings during orthostatic stress have been reported in both long-haul COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), but little work has directly compared patients from these two groups.

To investigate the overlap in these clinical phenotypes, we compared orthostatic symptoms in daily life and during head-up tilt, heart rate and blood pressure responses to tilt, and reductions in cerebral blood flow in response to orthostatic stress in long-haul COVID-19 patients, ME/CFS controls, and healthy controls.

Materials and Methods:

We compared 10 consecutive long-haul COVID-19 cases with 20 age- and gender-matched ME/CFS controls with postural tachycardia syndrome (POTS) during head-up tilt, 20 age- and gender-matched ME/CFS controls with a normal heart rate and blood pressure response to head-up tilt, and 10 age- and gender-matched healthy controls. Identical symptom questionnaires and tilt test procedures were used for all groups, including measurement of cerebral blood flow and cardiac index during the orthostatic stress.

Results:

There were no significant differences in ME/CFS symptom prevalence between the long-haul COVID-19 patients and the ME/CFS patients. All long-haul COVID-19 patients developed POTS during tilt. Cerebral blood flow and cardiac index were more significantly reduced in the three patient groups compared with the healthy controls. Cardiac index reduction was not different between the three patient groups. The cerebral blood flow reduction was larger in the long-haul COVID-19 patients compared with the ME/CFS patients with a normal heart rate and blood pressure response.

Conclusions:

The symptoms of long-haul COVID-19 are similar to those of ME/CFS patients, as is the response to tilt testing. Cerebral blood flow and cardiac index reductions during tilt were more severely impaired than in many patients with ME/CFS. The finding of early-onset orthostatic intolerance symptoms, and the high pre-illness physical activity level of the long-haul COVID-19 patients, makes it unlikely that POTS in this group is due to deconditioning. These data suggest that similar to SARS-CoV-1, SARS-CoV-2 infection acts as a trigger for the development of ME/CFS

Comments:

Health rising: The Reduced Brain Blood Flow Diseases? Long COVID, ME/CFS and POTS

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Research: CFS & FM sometimes mistakenly attributed to Lyme Disease (US)

Posted on 12/22/2021 by wames

Mistaken identity: many diagnoses are frequently misattributed to Lyme Disease, by Takaaki Kobayashi, Yvonne Higgins, Michael T Melia, Paul G Auwaerter in The American Journal of Medicine Nov 2021 [doi.org/10.1016/j.amjmed.2021.10.040]

 

Highlights

  • The majority of patients with long-term symptoms referred for evaluation of Lyme disease had alternative diagnoses to explain their symptoms.
  • Among 1061 patients, the 139 diagnoses described suggest that Lyme disease may be a frequent inappropriate diagnosis in this population.
  • Both new and pre-existing conditions should be considered in the differential diagnosis.
  • Patients referred for Lyme disease, especially with chronic symptoms, deserve careful assessment for diagnoses other than Lyme disease.

Research abstract:

Background:

Prior studies have demonstrated that Lyme disease is frequently over-diagnosed. However, few studies describe which conditions are misdiagnosed as Lyme disease.

Methods: 

This retrospective observational cohort study evaluated patients referred for Lyme disease to a Mid-Atlantic academic center between 2000-2013 who lacked evidence for Borrelia burgdorferi infection. The primary outcome is clinically described diagnoses contributing to symptoms. Secondary outcomes included symptom duration and determination whether diagnoses were new or attributed to existing medical conditions.

Results: 

Of 1261 referred patients, 1061 (84%) had no findings of active Lyme disease, with 690 (65%) receiving other diagnoses resulting in 405 (59%) having newly diagnosed medical conditions, 134 (19%) attributed to pre-existing medical issues, and 151 (22%) had both new and pre-existing conditions. Among the 690 patients, the median symptom duration was 796 days, and a total of 139 discrete diagnoses were made. Infectious disease diagnoses comprised only 3.2%.

Leading diagnoses were anxiety/depression 222 (21%), fibromyalgia 120 (11%), chronic fatigue syndrome 77 (7%), migraine disorder 74 (7%), osteoarthritis 62 (6%) and sleep disorder/apnea 48 (5%). Examples of less frequent but non-syndromic diseases newly diagnosed included multiple sclerosis (11), malignancy (8), Parkinson’s disease (8), sarcoidosis (4) or amyotrophic lateral sclerosis (4).

Categories of diagnoses in patients without Lyme disease (% of n = 690*) *Individual patients can have more than one diagnosis.

Conclusions:

Most patients with long-term symptoms have either new or pre-existing disorders accounting for their symptoms other than Lyme disease, suggesting overdiagnosis in this population. Patients referred for consideration of Lyme disease for chronic symptoms deserve careful assessment for diagnoses other than Borrelia burgdorferi infection.

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Hypothesis: Lessons from heat stroke for understanding ME/CFS

Posted on 12/21/2021 by wames

Lessons from heat stroke for understanding Myalgic Encephalomyelitis / Chronic Fatigue Syndrome, by Dominic Stanculescu,  Nuno Sepúlveda,  Chin Leong Lim and  Jonas Bergquist in Frontiers in Neurology (2021). [doi: 10.3389/fneur.2021.789784]

 

Abstract:

We here provide an overview of the pathophysiological mechanisms during heat stroke and describe similar mechanisms found in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Both conditions are characterized by disturbed homeostasis in which inflammatory pathways play a central role. Splanchnic vasoconstriction, increased gut permeability, gut-related endotoxemia, systemic inflammatory response, central nervous system dysfunction, blood coagulation disorder, endothelial-cell injury, and mitochondrial dysfunction underlie heat stroke. These mechanisms have also been documented in ME/CFS.

Moreover, initial transcriptomic studies suggest that similar gene expressions are altered in both heat stroke and ME/CFS. Finally, some predisposing factors for heat stroke, such as pre-existing inflammation or infection, overlap with those for ME/CFS.

Notwithstanding important differences – and despite heat stroke being an acute condition – the overlaps between heat stroke and ME/CFS suggest common pathways in the physiological responses to very different forms of stressors, which are manifested in different clinical outcomes. The human studies and animal models of heat stroke provide an explanation for the self-perpetuation of homeostatic imbalance centered around intestinal wall injury, which could also inform the understanding of ME/CFS.

Moreover, the studies of novel therapeutics for heat stroke might provide new avenues for the treatment of ME/CFS. Future research should be conducted to investigate the similarities between heat stroke and ME/CFS to help identify the potential treatments for ME/CFS.

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Research review: COVID-19 & CFS: an endocrine perspective

Posted on 12/20/2021 by wames

COVID-19 and Chronic Fatigue Syndrome: An endocrine perspective, by Rashika Bansal, Sriram Gubbi, Christian A Koch in Journal of Clinical & Translational Endocrinology 3 Dec 2021 [doi.org/10.1016/j.jcte.2021.100284]

 

Research abstract:

Patients recovering from COVID-19 may have persistent debilitating symptoms requiring long term support through individually tailored cardiopulmonary and psychological rehabilitation programs. Clinicians need to be aware about the likely long-term complications and their diagnostic assessments to help identify any occult problems requiring additional help.

Endocrinological evaluations should be considered as part of the armamentarium in the management of such individuals with diligent cognizance about the involvement of the hypothalamo-pituitary-adrenal (HPA) axis, adrenals, and thyroid.

An uncanny resemblance has been observed between the long-COVID syndrome and clinical features of CFS, though this is not an unfamiliar concept.

The endocrine connection to Long-COVID syndrome:

ACE2 receptors, the route of entry of the SARS-CoV-2 virus into the human body, are expressed (https://www.proteinatlas.org/ENSG00000130234-ACE2/tissue) in the hypothalamus, pituitary, adrenal gland, thyroid, testes, and pancreatic islets leading to the involvement of the endocrine system during and after the recovery of the disease.

Longitudinal and postmortem studies conducted on SARS-CoV patients provide some guidance on the extent of endocrine gland involvement. On postmortem examination, SARS-CoV RNA was found in the pituitary gland, parathyroid, pancreas and adrenal gland (39).

In another study, both parafollicular and follicular cells were found to be apoptotic explaining the low serum triiodothyronine and thyroxine levels and the osteonecrosis of the femoral head associated with patients of SARS-CoV (40).

Evidence of hypocortisolism was found in 39% of sixty-one survivors of SARS prospectively recruited for hormonal derangements 3 months after recovery (41).

Nonetheless, information about the adverse effects on endocrine function by the SARS-CoV-2 virus remain limited [42], [43].

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Boosting health recovery by food supplements: the case of ME/CFS v Post-Covid-19 syndrome 

Posted on 12/16/2021 by wames

Boosting health recovery by food supplements: the case of ME/CFS versus Post-Covid-19 Syndrome, by Frank Comhaire and Jan Pen in J Clin Pharmacol Ther. 2021;2(3):JCPT-02-1022

 

Research abstract:  

Background and objectives:

Other than the direct impact of cardiopulmonary sequelae, COVID-19 disease may cause persistent signs and symptoms describes as post-COVID syndrome or long COVID. The clinical presentation and neuroimaging aspects of patients suffering from this condition are remarkably similar to those seen in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Inflammation, immune disorder and oxidative damage have been documented to cause metabolic deregulation with decreased glycolysis and impaired mitochondrial function.

Purpose of the study:

It is suggested that these alterations may be improved by the oral administration of a nutraceutical, Meldonium and sodium dichloroacetate (group designated as “oral treatment”; n=79) or intermittent intravenous infusions of magnesium sulphate together with multivitamins and essential amino acids (group designated as “infusion treatment”, n=18).

Materials and methods: 

97 patients suffering from ME/CFS (n=79) or post-COVID syndrome (n=9) were included in a pragmatic prospective open-label trial using either oral or infusion therapy for 1 month, and the effect of treatment was assessed by the Fatigue Severity Scale (FSS).

Results:

Upon interim analysis of 97 cases of ME/CFS and/or Post-COVID-19 syndrome therapeutic approach by either the oral or the infusion therapy was found to result in a reduction of the Fatigue Severity Scale (FSS) in two thirds of patients. The quotient of FSS after treatment divided by the FSS before treatment decreased by an average for all 97 cases by 14% within one month, with no difference between oral and infusion therapy (P=0.70), nor between the ME/CFS patient (mean quotient: 0.85, SD: 0.16) and the post-COVID cases (quotient: 0.87, SD: 0.16). Among the successful cases the FSS decreased by an average of 31%.

Conclusion: 

Preliminary results of the oral and the infusion therapy suggest a similar beneficial effect on fatigue in a substantial proportion of patients suffering from ME/CFS or Post-COVID syndrome. The result should be confirmed in a controlled trial, while the long-term efficacy is presently being investigated in a larger group of patients.

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