Hypothesis: Lessons from heat stroke for understanding ME/CFS

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

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 

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 nutraceuticalMeldonium 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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Biomarker research: The maintained attention assessment in patients affected by ME/CFS

The maintained attention assessment in patients affected by Myalgic encephalomyelitis/ chronic fatigue syndrome: A reliable biomarker?, by Inigo Murga, Larraitz Aranburu, Pascual A Gargiulo, Juan-Carlos Gomez-Esteban, Jose-Vicente Lafuente in Journal of Translational Medicine Vol 19, #1, p 494, December 4, 2021

 

Research abstract

The maintained attention is the cause of great functional limitations in CFS/ME, a disease that mainly affects women in the central period of life. Cognitive function is explored using the Montreal Cognitive Assessment, the maintained attention using the Toulouse-Pieron test with which the Global Index of Attention and Perception (GIAP) is obtained, the fatigue using the visual analog scale and the perception of effort using the modified Borg scale.

The final sample were 84 patients (66 women/18 men) who met diagnostic criteria (Fukuda-1994, Carruthers-2011) and 22 healthy controls (14 women/8 men). Most of patients maintain normal cognitive function, showing low or very low attention score in the 70% of patients with a marked cognitive fatigue compared to the control group (p<0.05).

There were no significant differences between genders in GIAP or fatigue for CFS/ME; however, sick women perceive cognitive effort higher than men. Deficits in sustained attention and the perception of fatigue, so effort after performing the proposed test are a sensitive and reliable indicator that allows us to substantiate a clinical suspicion and refer patients for further studies in order to confirm or rule out CFS/ME.

Conclusion

General cognition remains preserved in most patients, only a small group of them shows a significant mild cognitive impairment. Maintained attention is clearly deficient, showing a marked fatigability after the Toulouse-Piéron test. The effort was perceived as very hard by both gender, but higher by women.

This study proposes a simple clinical way to assess maintained attention. Present results support the reliability of maintained attention as biomarker of CFS/ME. Attention deficit is a significant disability in patients affected of central fatigue.

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Hidden from sight: why the complexity of ME/CFS needs to be recognised by policy makers

Hidden from Sight: Why the complexity of ME/CFS needs to be recognised by policy makers, by Tomruk Ustunkaya and Richard Machin, by People, Place and Policy Vol 15, #2, pp. 91-99, November 2021

 

Background:

An estimated 260,000 people in the UK are living with Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS); this neurological condition has been described as

‘a serious, chronic, complex, and multisystem disease that frequently and dramatically limits the activities of affected patients’ (Institute of Medicine, 2015).

Despite this, there remains a lack of clarity about the diagnosis and treatment of ME/CFS. The authors of this paper refer to ME/CFS but recognise that other terms (for example systemic exertion intolerance disease, chronic fatigue immunity deficiency syndrome, and post-viral fatigue syndrome) are used to describe this neurological condition, and for some people these are preferred names. This paper adopts the definition of ME/CFS as a neurological condition of unknown origin as defined by the World Health Organisation and accepted by the UK Department of Health (WHO, n.d.).

The House of Commons debate which took place on 21 June 2018 will be taken as a significant starting point for the discussion on ME treatment and research; this is regarded as a key moment in the public debate and recognition of the condition stating that ME is ‘a hidden illness’ (Hansard HC Deb., 21 June 2018d).

Historically, there has been an emphasis on ME/CFS as being psychological in nature and this continues to exert a damaging influence on key areas of public policy. This paper considers the hidden nature of ME/CFS in relation to two particular issues: funding for research and social security policy.

  1. It is argued that medical research into the condition is impeded by a lack of adequate government funding. This is identified as critical in achieving a comprehensive health regime for sufferers.
  2. Social security is an important area of concern for ME/CFS suffers and a key policy area; correct entitlement to social security benefits is crucial for people with disabilities but appropriate access to welfare benefits is often obstructed by misunderstanding of the condition.

It is argued that in both of these areas, a greater understanding of the impact of ME/CFS is required to allow policy makers and practitioners to more appropriately meet the needs of people living with the condition.

Conclusion

Clarity is paramount to bring ME/CFS out from the ‘invisible’ sphere in terms of both the treatment and definitions of the illness, and the ways in which the condition is
understood by government departments, institutions, and society. This clarity will be
difficult to attain without adequate funding for research into the illness and may explain the ongoing preference for psychological treatments.

The emergence of post-COVID syndrome (long-COVID) has emphasised how important it is to appropriately fund research into long-term and debilitating conditions. Interestingly, the Department for Work and Pensions have issued new guidance stating that children suffering with post-COVID syndrome can be awarded disability benefit for a period of 12 months (DWP, 2021); this has provided the type of clarity that is lacking for ME/CFS patients. The authors of this paper recognise the challenges that a lack of funding presents for the treatment of the condition and are supportive of the medical profession and the on-going medical support provided to ME/CFS patients.

For those members of society with greatly reduced quality of lives due to the
challenges presented by ME/CFS, it is clear that public policy and bureaucratic decision-making processes must respond more appropriately to their needs. Positive government intervention is necessary to end the uncertainty for ME/CFS patients. The human cost of policy failure for people with ME/CFS is paramount; however, the financial costs are also significant. A study estimated that the total cost of ME/CFS to the UK economy is £3.3 billion per year, or only £16,966 per person living with the condition (Hunter et al., 2017).

These figures underscore the importance of providing adequate funding for treatment
and a functioning social security safety net. Until the WHO classification of ME/CFS as a neurological condition is fully recognised by policy makers, we will continue to see challenges for patients, not only in terms of funding for treatment and social security which have been examined in this paper, but across the full spectrum of public policy. ME/CFS patients experience ‘multiple pathophysiological changes that affect multiple systems’ (Centers for Disease Control, 2018). Policy makers must recognise the severity of the condition to make appropriate responses to it.

The hidden nature of this condition can be linked to an absence of a biomarker and
because uncertainty surrounds it medically and in society. However, this should not
mean that the needs of ME/CFS patients are overlooked or marginalised; the challenges presented by the condition are a reality for patients and their families. Patients are entitled to expect appropriate support from the Department of Health, Department for Work and Pensions, employers, and educational establishments.

The words of Alex Chalk, MP, (Hansard HC Deb., 21 June 2018c) offer hope for a future characterised by a determined, active effort to help

“I conclude by paying tribute to the silent sufferers of this cruel disease in our country. Let the word go out from the House of Commons: they shall be silent no longer”.

Read the full paper

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Subgroup research: Tryptophan metabolites, cytokines & FAPB-2 in ME/CFS

Tryptophan metabolites, cytokines, and fatty acid binding protein 2 in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, by Manuela Simonato, Stefano Dall’Acqua, Caterina Zilli, Stefania Sut, Romano Tenconi, Nicoletta Gallo, Paolo Sfriso, Leonardo Sartori, Francesco Cavallin, Ugo Fiocco, Paola Cogo, Paolo Agostinis, Anna Aldovini, Daniela Bruttomesso, Renzo Marcolongo, Stefano Comai and Aldo Baritussio in Biomedicines 2021, 9(11), 1724 [doi.org/10.3390/biomedicines9111724]

 

Research abstract:

Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) differ for triggers, mode of start, associated symptoms, evolution, and biochemical traits. Therefore, serious attempts are underway to partition them into subgroups useful for a personalized medicine approach to the disease.

Here, we investigated clinical and biochemical traits in 40 ME/CFS patients and 40 sex- and age-matched healthy controls. Particularly, we analyzed serum levels of some cytokines, Fatty Acid Binding Protein 2 (FAPB-2), tryptophan, and some of its metabolites via serotonin and kynurenine.

ME/CFS patients were heterogeneous for genetic background, trigger, start mode, symptoms, and evolution. ME/CFS patients had higher levels of IL-17A (p = 0.018), FABP-2 (p = 0.002), and 3-hydroxykynurenine (p = 0.037) and lower levels of kynurenine (p = 0.012) and serotonin (p = 0.045) than controls. Changes in kynurenine and 3-hydroxykynurenine were associated with increased kynurenic acid/kynurenine and 3-hydroxykynurenine/kynurenine ratios, indirect measures of kynurenine aminotransferases and kynurenine 3-monooxygenase enzymatic activities, respectively.

No correlation was found among cytokines, FABP-2, and tryptophan metabolites, suggesting that inflammation, anomalies of the intestinal barrier, and changes of tryptophan metabolism may be independently associated with the pathogenesis of the disease.

Interestingly, patients with the start of the disease after infection showed lower levels of kynurenine (p = 0.034) than those not starting after an infection. Changes in tryptophan metabolites and increased IL-17A levels in ME/CFS could both be compatible with anomalies in the sphere of energy metabolism.

Overall, clinical traits together with serum biomarkers related to inflammation, intestine function, and tryptophan metabolism deserve to be further considered for the development of personalized medicine strategies for ME/CFS.

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Research: Limbic perfusion is reduced in patients with ME/CFS

Limbic perfusion is reduced in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), by Xia Li, Per Julin and Tie-Qiang Li in Tomography 2021, 7(4), 675-687; [doi.org/10.3390/tomography7040056] 1 Nov 2021

 

Research abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an illness characterized by a diverse range of debilitating symptoms including autonomic, immunologic, and cognitive dysfunction. Although neurological and cognitive aberrations have been consistently reported, relatively little is known regarding the regional cerebral blood flow (rCBF) in ME/CFS.

In this study, we studied a cohort of 31 ME/CSF patients (average age: 42.8 ± 13.5 years) and 48 healthy controls (average age: 42.9 ± 12.0 years) using the pseudo-continuous arterial spin labeling (PCASL) technique on a whole-body clinical 3T MRI scanner.

Besides routine clinical MRI, the protocol included a session of over 8 min-long rCBF measurement. The differences in the rCBF between the ME/CSF patients and healthy controls were statistically assessed with voxel-wise and AAL ROI-based two-sample t-tests. Linear regression analysis was also performed on the rCBF data by using the symptom severity score as the main regressor.

Hypoperfusion is a term that describes “a reduced amount of blood flow”

In comparison with the healthy controls, the patient group showed significant hypoperfusion (uncorrected voxel wise p ≤ 0.001, FWE p ≤ 0.01) in several brain regions of the limbic system, including the anterior cingulate cortex, putamen, pallidum, and anterior ventral insular area. For the ME/CFS patients, the overall symptom severity score at rest was significantly associated with a reduced rCBF in the anterior cingulate cortex.

In the human brain, the anterior cingulate cortex (ACC) is involved in certain higher-level functions, such as attention allocation, reward anticipation, decision-making, ethics and morality, impulse control (e.g. performance monitoring and error detection), and emotion. [Wikipedia]

The results of this study show that brain blood flow abnormalities in the limbic system may contribute to ME/CFS pathogenesis.

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Research: Analysis of post COVID-19 & its overlap with ME/CFS

Long COVID overlap with ME/CFS

 

A group of researchers from around the world have joined together to analyse long COVID’s symptom overlap with ME/CFS.

Highlights

  • Serious side effects and post-infection sequelae have been reported in SARS-CoV-2-infected patients after acute disease phase.
  • Long-COVID patient characteristics and symptoms were compared to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
  • The onset, progression, and symptom profile of long-COVID patients have considerable overlap with ME/CFS.
  • Longitudinal monitoring of COVID-19 patients is warranted to understand the virus long-term effects.

 

 

 

 

 

 

 

Analysis of post COVID-19 condition and its overlap with myalgic encephalomyelitis/

chronic fatigue syndrome, by Olga A Sukocheva, Rebekah Maksoud, Narasimha M Beeraka, SabbaRao V Madhunapantula, Mikhail Sinelnikov, Vladimir N Nikolenko, Margarita E Neganova, Sergey G Klochkov, Mohammad Amjad Kamali, Donald R Staines, Sonya Marshall-Gradisnik in  Journal of Advanced Research, Volume 40, September 2022, Pages 179-196 [doi.org/10.1016/j.jare.2021.11.013] Preprint Nov 2021

Research abstract

Background

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) disease (COVID-19) triggers the development of numerous pathologies and infection-linked complications and exacerbates existing pathologies in nearly all body systems. Aside from the primarily targeted respiratory organs, adverse SARS-CoV-2 effects were observed in nervous, cardiovascular, gastrointestinal/metabolic, immune, and other systems in COVID-19 survivors. Long-term effects of this viral infection have been recently observed and represent distressing sequelae recognised by the World Health Organisation (WHO) as a distinct clinical entity defined as post-COVID-19 condition. Considering the pandemic is still ongoing, more time is required to confirm post COVID-19 condition diagnosis in the COVID-19 infected cohorts, although many reported post COVID-19 symptoms overlap with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Aims of Review

In this study, COVID-19 clinical presentation and associated post-infection sequelae (post-COVID-19 condition) were reviewed and compared with ME/CFS symptomatology.

Key Scientific Concepts of Review

The onset, progression, and symptom profile of post COVID-19 condition patients have considerable overlap with ME/CFS. Considering the large scope and range of pro-inflammatory effects of this virus, it is reasonable to expect development of post COVID-19 clinical complications in a proportion of the affected population. There are reports of a later debilitating syndrome onset three months post COVID-19 infection (often described as long-COVID-19), marked by the presence of fatigue, headache, cognitive dysfunction, post-exertional malaise, orthostatic intolerance, and dyspnoea. Acute inflammation, oxidative stress, and increased levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFalpha), have been reported in SARS-CoV-2 infected patients.

Longitudinal monitoring of post COVID-19 patients is warranted to understand the long-term effects of SARS-CoV-2 infection and the pathomechanism of post COVID-19 condition.

 

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Hypothesis: An attempt to explain the neurological symptoms of ME/CFS

An attempt to explain the neurological symptoms of Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome, by Klaus J Wirth, Carmen Scheibenbogen & Friedemann Paul in Journal of Translational Medicine volume 19, no: 471 (2021)

 

Review abstract

There is accumulating evidence of endothelial dysfunction, muscle and cerebral hypoperfusion in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS).

In this paper we deduce the pathomechanisms resulting in central nervous pathology and the myriad of neurocognitive symptoms. We outline tentative mechanisms of impaired cerebral blood flow, increase in intracranial pressure and central adrenergic hyperactivity and how they can well explain the key symptoms of cognitive impairment, brain fog, headache, hypersensitivity, sleep disturbances and dysautonomia.

Excerpt from Introduction

Key neurological pathomechanisms in ME/CFS

ME/CFS is classified as a neurological disease. This is based on neurological symptoms including mental fatigue, impaired cognition, psychomotor slowing, disturbed sleep, hypersensitivities to noise, light and smells, headache, pain and paresthesias and severe dysautonomia.

Many symptoms are, however, not obviously explained by neurological pathology including the cardiovascular situation with orthostatic intolerance, hypovolemia and a low activity of the renin–angiotensin–aldosterone system (RAAS), or the impaired muscle function (reduced handgrip strength and fatigability) and energetic disturbance. This co-occurrence of seemingly unrelated symptoms and findings prompts to look for a unifying explanation (the most parsimonious explanation).

 The authors discuss:

  • Decreased cerebral blood flow (CBF)
  • Disturbed local blood flow regulation and neurovascular coupling
  • Increase in intracranial pressure
  • Disturbances of reflexes and autonomic function, hypervigilance and hypersensitivity to sensory stimuli such as light, noises and smells and brain fog
  • Hypocapnia, hyperventilation, respiratory alkalosis and possible consequences for skeletal muscle metabolism
  • Sleep disturbances and non-restorative sleep

Conclusion

Neurological symptoms in ME/CFS can be severe and debilitiating, but no clear specific brain pathology or lesions have been detected so far. Whether neuroinflammation or a brain stem pathology exists—where dysautonomia may have its origin as the primary disturbance eliciting ME/CFS—remains to be shown.

Decreased CBF, disturbed local blood flow regulation and neurovascular coupling, central adrenergic hyperactivity, hypocapnia and increase in intracranial presssure seem to play a strong role in the pathophysiology of the neurological symptoms in ME/CFS (Fig. 1). They can well explain cognitive impairment, brain fog, headache, psychomotor slowing, ataxia and loss of coordination of movements, hypersensitivity, sleep disturbances and dysautonomia.

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