The challenges of chronic pain & fatigue [for clinicians]

Posted on 02/14/2021 by wames

The challenges of chronic pain and fatigue, by Jessica A Eccles and Kevin A Davies in Clin Med January 2021 [doi.org/10.7861/clinmed.2020-1009]

 

Review abstract:

In this review, we explore the challenges of chronic pain and fatigue in clinical practice. Both pain and fatigue are common, troubling and frequently overlapping symptoms, and we describe both the clinical burden and the ‘clinical problem’. We explore commonly associated symptoms and possible pathological associations, including variant connective tissue (joint hypermobility), small fibre neuropathy, mast cell activation, dysregulated inflammatory and interoceptive processes, which may inform treatment targets. We suggest a multidisciplinary management approach.

[The paper explores ME/CFS, Fibromyalgia, POTs, Long COVID, Mast Cell Activation, Small fibre neuropathy, Joint hypermobility, IBS]

Excerpt:

Outpatient assessment of a patient with fatigue and chronic pain can be challenging. This is particularly the case when the patient is polysymptomatic and they have had many interactions with healthcare professionals before. It is all too easy to ‘admit defeat’ as in Dr A’s case, or initiate a test or another referral in ‘response’ to every symptom described by the patient during the course of their illness (Dr B). How can this be avoided?

One approach is to adopt the ‘snapshot’ approach and ask the patient to identify a maximum of three ‘live’ clinical problems (eg in the previous 2 weeks), highlighting which is the most significant one. If the primary problem is fatigue or pain (as in our exemplar Patient A), it can be highly informative to identify the single most important additional symptom: the ‘plus one’ approach. This should raise a specific subset of diagnostic possibilities, often limited in number, which will prompt further, more focused ‘direct’ questioning, and may inform an initial investigation strategy, if considered appropriate.

All physicians are trained to identify ‘red flag’ symptoms, such as unexplained weight loss, which, in older patients particularly, may point to a diagnosis of malignancy, malabsorption, endocrine disease or depression. However, there is a number of conditions that are frequently missed, and easily identified. Some of these are summarised in Table 1. We focus on the ‘plus one’. The average time it takes to diagnose Behçet’s, for example, may be up to 7 years and there is frequently a delay in the diagnosis of Sjogren’s syndrome; few doctors ask about sicca.64 Inflammatory bowel disease or endometriosis can also easily be missed, as can HIV, especially in older patients.65,66.

What is rarely helpful or informative in a busy clinic setting is to rehearse in detail with a patient the detailed chronology of what may be several years of ill-health. This can all too often result in a ‘memory test’ for the patient, with the physician seeking to corroborate dates and details in the notes or electronic patient record. This wastes time, and can be frustrating for all concerned. However, it may be useful before, or more often after, the consultation to look back at previous letters, imaging or pathology results to help substantiate or refute a presumptive diagnosis.

In patients with a ‘long history’ and multiple medical interactions, it is, however, important to avoid ‘medical transference’ and give undue credence to diagnoses made by other doctors, often years before. Firstly, the patient’s recollection of the outcome of a previous consultation may be far from accurate, and secondly, the professor may well have been wrong. It does happen.

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Experiences of living with severe CFS/ME

Posted on 02/12/2021 by wames

Experiences of living with severe Chronic Fatigue Syndrome/Myalgic Encephalomyelitis, by  Victoria Strassheim, Julia L Newton and Tracy Collins in Healthcare 2021, 9(2), 168 [doi.org/10.3390/healthcare9020168] (This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)

 

Research abstract:

Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is a rare disease with no known etiology. It affects 0.4% of the population, 25% of which experience the severe and very severe categories; these are defined as being wheelchair-, house-, and bed-bound. Currently, the absence of biomarkers necessitates a diagnosis by exclusion, which can create stigma around the illness.

Very little research has been conducted with the partly defined severe and very severe categories of CFS/ME. This is in part because the significant health burdens experienced by these people create difficulties engaging in research and healthcare provision as it is currently delivered.

This qualitative study explores the experiences of five individuals living with CFS/ME in its most severe form through semi-structured interviews. A six-phase themed analysis was performed using interview transcripts, which included identifying, analysing, and reporting patterns amongst the interviews. Inductive analysis was performed, coding the data without trying to fit it into a pre-existing framework or pre-conception, allowing the personal experiences of the five individuals to be expressed freely.

Overarching themes of ‘Lived Experience’, ‘Challenges to daily life’, and ‘Management of the condition’ were identified. These themes highlight factors that place people at greater risk of experiencing the more severe presentation of CFS/ME. It is hoped that these insights will allow research and clinical communities to engage more effectively with the severely affected CFS/ME population.

 

Conclusions

This study is novel, as it has accessed this hard to reach population group and recorded their experience. Most of the participants had received some form of specialist CFS/ME support or had access to the healthcare services. However, their experiences ranged from accepting the limitations of the service to having a very negative view.

CFS/ME is a medically unexplained illness lying at the boundaries of understanding within the legacy biomedical model. An illness where there is no single, simple cause or theoretical model, no clear mind/body division, and no definitive classification [1] does not sit easily in the current healthcare system. The CFS/ME presentation conflicts with the current health and social care model [1,2]. The severe CFS/ME presentation sits outside the model and therefore is not acknowledged.

This illness ranks low within primary care, as it is not life threatening [23]. However, it is potentially life shortening [14]. There are certainly physical and mental health symptoms that are often disregarded or missed within the complex presentation [14], and reports suggest that 88 suicides have been partly attributed to CFS/ME between 2001 and 2016. However, it has been noted that it is not necessarily intrinsic factors that lead to suicide, but a combination of extrinsic factors, which include a lack of medical care and social support, failure to control key symptoms, and inadequate financial help. Depression is not always a feature in CFS/ME-related suicide [49].

…Currently, the healthcare system and research community are failing to provide resources and opportunities for this group to engage, and so enable the positive outcome of increased independence. Longer periods of intervention, home visits and telephone consultations and in extreme cases inpatient rehabilitation in specialist services are effective evidenced interventions in the research literature [10,16,44,53]. Such services would meet the needs of CFS/ME individuals much better than the status quo which often forces patients to meet the needs of the system in order to secure the care that they need.

A re-evaluation of the approach taken to CFS/ME and other unexplained illness is ever more urgent given the upcoming surge in numbers of long-haul COVID-19 individuals. A major symptom of such long-haul COVID-19 is fatigue [54,55]. Research and healthcare communities have much experience to share and further research to perform, particularly in the area of health, social care, and societal attitudes allowing vulnerable ill people to remain valued members of society.

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All in your head? Brain research in ME/CFS

Posted on 02/11/2021 by wames

ME Research UK blog post: All in your head? Brain research in ME/CFS,  8 February 2021

 

Following last week’s introduction to the brain, here is an overview of some of the brain research conducted in ME/CFS in recent years, and how it has helped us understand more about the illness.

The World Health Organisation has classified ME/CFS as a neurological disease, and brain inflammation has long been hypothesised as a potential cause of the condition. What’s more, findings from the field of neurological research have started to show just how significant the brain is in ME/CFS, with evidence of neuroinflammation and changes in brain activity during post-exertional malaise.

As the brain is responsible for regulating and controlling all of the functions of the body – from physical movement to unconscious regulation of the heart and temperature – dysfunction in this organ could easily explain why ME/CFS has the wide range of symptoms illustrated below. [see image on MERUK site]

An excellent review summarising studies looking for neurological issues in ME/CFS was published in 2020 by Maksoud and colleagues in the journal PLOS ONE.  The paper presented findings, consistencies and discrepancies in fifty-five studies on brain research in ME/CFS.

The authors noted that the vast majority of studies used the less stringent Fukuda diagnostic criteria for patient selection, which may have contributed to inconsistencies between the studies. This meant identification of a single consistent neurological impairment was difficult.

Nevertheless, some consistencies were still found and demonstrated the importance of the brain in this disease. The key findings of the review included:

  • Consistent abnormalities in the brain structure of ME/CFS patients, with a decrease in the white matter of the brain, which is responsible for transferring information through nerve connections via the spinal cord.
  • Disruption of the autonomic nervous system network, which is responsible for regulating unconscious bodily processes such as heart rate, digestion and pupil dilation.
  • Impaired cognitive processing, including problems with functional connectivity (synchronisation of different regions of the brain) and disruptions to working memory.

Another interesting paper published in 2020 was by Washington and colleagues in the journal Brain Communications. This study examined the effect of exercise on brain activity in ME/CFS patients and in people with Gulf War illness (which is also associated with post-exertional malaise).

Using functional MRI to measure brain activity while participants carried out a working-memory task, the authors found notable differences in several areas of the brain.

People with ME/CFS had an increase in activity in the midbrain, right middle insula and left rolandic operculum after exercise, while people with Gulf War illness had a decrease in activity in the cerebellum and right angular gyrus.

According to the investigators, the regions affected are involved in pain, threat assessment, interoception (the sense of feeling what is wrong with your body), negative emotion and vigilant attention (ability to focus). They even suggest that further investigation may eventually lead to treatment by deep-brain stimulation of specific regions.

Evidence of neuroinflammation in ME/CFS was demonstrated by Nakatomi and colleagues in 2014 in a paper published in the Journal of Nuclear Medicine. In this small study, they authors detected expression of a specific protein linked to activation of microglia or astrocytes (which are types of cell found in the brain with a wide range of regulatory functions).

Activated microglia/astrocytes provides evidence of neuroinflammation in ME/CFS, and the authors were also able to correlate activation in specific areas of the brain to symptom severity. For example, activation in the amygdala, thalamus and midbrain correlated with cognitive impairment symptom severity and activation, while activation in the cingulate cortex and the thalamus correlated with pain.

Finally, a series of papers published by a team in Australia over the past decade has shown repeated anomalies in the brain, which were also linked to symptom severity. In particular, Barnden and colleagues showed impairments in nerve signalling in the brainstem in people with ME/CFS, which the authors claim may explain some of autonomic symptoms seen in the disease.

Next week, we will summarise some of the research on the brain and nervous system that ME Research UK has funded over the last few years, showing what advances in the field have been made possible by your donations.

 

The principal aim of ME Research UK is to commission and fund high-quality scientific (biomedical) investigation into the causes, consequences and treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (also known as ME/CFS).

Make a donation

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In memoriam: Derryan Paul 2021

Posted on 02/10/2021 by wames

Dr Elizabeth Derryan Paul d. 2021

 

Past members of the Mid & West Wales ME Group (MWWMEG) will be sorry to hear about the death of Derryan Paul on Monday 8th February 2021.

Derryan had ME for many years and was a very efficient secretary of MWWMEG until its closure in 2013. She had also been a lecturer at the College of Librarianship Wales in Aberystwyth, and an author of bibliographies and books and articles about the local history of both Cardiganshire and Herefordshire.

Derryan will be remembered for her quiet concern for people and her willingness to help. She was born in England, but learned Welsh and for some time was the ME group’s only Welsh speaker who was able and willing to be interviewed by the media, sometimes ‘live on air’. She earned many people’s admiration for that!

After retiring Derryan found her health had deteriorated further and eventually she moved to a care home in Meirionnydd where she had been living happily.  Recently she became weaker and died peacefully. Many of us will continue to be grateful for her help and support over many years.

Poem by Derryan Paul: Words escape

Tribute from Mair Jones:

About Derryan, my memories of our committee meetings, at Frongog, are of her detailed work as secretary taking minutes and then writing them up regularly over many years, and I think we met at least three times a year, but there would be extra meetings sometimes, so possibly four or five times a year. Then there would be the Annual Report, and many letters to organisations to protest and raise the profile of ME as well as to MPs and MAs (Assembly then, Senedd now). During which she completed her PhD!

My more recent fond memory is of the way Derryan opened her home in Penrhyncoch for a group of us to be able to meet for therapeutic, restorative yoga classes run by experienced teacher Cathy Crick.  We met there weekly on Thursday afternoons for almost 2 years from  April 2012 to March 2014, before moving to a larger venue at Aberystwyth. Preparing her living room in advance meant moving furniture around and she would do this in advance a little at a time over the days before. Her unfailing welcome and hospitality was an added feature to the restorative quality of the afternoons.

Personally, I will always appreciate Derryan’s deep commitment to friendship through letter writing. As we were both French students, her grasp of the language at a much more advanced stage to mine, she would write to me in French, send me an occasional card, always stunningly beautiful cards, in solidarity, as we both battled the long fight against ME. Sometimes the language changed and she would practice her Welsh reaching to my heart in my mother tongue.

Her selfless service to others, despite her physical limitations due to ME, was an inspiration to all.

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Off label use of Aripiprazole shows promise as a treatment for ME/CFS

Posted on 02/09/2021 by wames

Off label use of Aripiprazole shows promise as a treatment for Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS): a retrospective study of 101 patients treated with a low dose of Aripiprazole, by LD Crosby, S Kalanidhi, A Bonilla, A Subramanian, JS Ballon & H Bonilla in Journal of Translational Medicine vol 19, Article number: 50 (2021)

 

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic, debilitating illness of unknown etiology. An ME/CFS diagnosis is based solely on symptoms with case definitions made by expert consensus, including the Fukuda (1994), Canadian Consensus Criteria (CCC, 2003), International Consensus Criteria (ICC, 2011), and the Institute of Medicine (IOM, 2015) case criteria. According to the most recent IOM case definition, the core symptoms of ME/CFS include debilitating fatigue, unrefreshing sleep, post-exertional malaise, and either cognitive dysfunction or orthostatic intolerance [1].

Although the cause of the illness is unknown, a growing body of evidence suggests that ME/CFS involves inflammation of the brain. Up to 85% of patients with ME/CFS report symptoms of cognitive impairment also referred to as “brain fog,” which includes difficulty with memory, attention, and information processing. Additional evidence includes changes in inflammatory cytokines in both plasma and cerebrospinal fluid correlated with the severity of symptoms [2]. Other studies using positron emission tomography (PET) show evidence of activated microglia or astrocytes in various regions of the brain in patients with ME/CFS [3].

Dopamine D2 receptor agonists have been shown to mediate neuroinflammation, microglial activation, and cell death in animal models and humans [4,5,6]. This suggests that dopamine-modulating drugs like aripiprazole may lead to clinical improvement in fatigue and cognitive symptoms in ME/CFS. Given the lack of approved drugs for treating this condition, we were interested in exploring the potential benefit of low doses of aripiprazole in our Stanford University ME/CFS clinical practice.

…In summary, the number of positive responders in a group of 101 patients taking aripiprazole was significantly greater than the number of patients who did not respond or had negative experiences. Also, the magnitude of perceived improvement was significant. Some patients failed to observe any benefit, and a small subset of patients experienced side effects that required the medication to be discontinued. Overall, these results suggest that aripiprazole may effectively reduce symptoms of ME/CFS and warrants further investigation in a randomized clinical trial. Exploring the mechanism of action for aripiprazole in neuroinflammatory conditions may also provide new insight into the pathogenesis of ME/CFS.

 

Health rising blog: Abilify shows promise in retrospective Chronic Fatigue Syndrome (ME/CFS) study, by Cort Johnson

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Lived experiences in daily life with ME (Denmark)

Posted on 02/09/2021 by wames

Lived experiences in daily life with myalgic encephalomyelitis, by Reeti KK Sandhu, Maj Sundby, Sidsel Ørneborg, Svetlana Solgaard Nielsen, Jeanette Reffstrup Christensen, Anette Enemark Larsen in British Journal of Occupational Therapy, November 2020 [doi.org/10.1177/0308022620966254]

 

Research abstract:

Introduction
Myalgic encephalomyelitis is a complex systemic condition, causing severe symptoms that limit the quality of life of the people living with it. This study examined changes in life, coping strategies, and the ability to obtain a successful occupational adaptation in people with myalgic encephalomyelitis in Denmark, viewed from the perspective of the model of human occupation.

Method
In-depth qualitative interviews with seven persons with myalgic encephalomyelitis aged 31–61 years were analysed with qualitative content analysis.

Results
The participants experienced severe changes in their lives leading to impaired occupational competences which affected their occupational identity and made them lonely. Pacing and environmental changes were the preferred coping strategies in their attempt to adapt to the new circumstances.

Conclusion
The participants experienced major changes in everyday life with the onset of myalgic encephalomyelitis. Pacing and environmental changes were not sufficient strategies to secure a successful occupational adaptation. Thus, people living with myalgic encephalomyelitis need assistance to enable a successful occupational adaptation and preserve hope. Access to occupational therapy within the Danish programme for people living with myalgic encephalomyelitis may support more effective occupational adaptation in the population.

Read full paper

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ME/CFS: Where will the drugs come from?

Posted on 02/08/2021 by wames

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Where will the drugs come from?, by Peter L Toogood, Daniel J Clau, Sameer Phadke, DavidHoffman in Pharmacological Research [doi.org/10.1016/j.phrs.2021.105465] 30 January 2021

 

Review abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic debilitating disease characterized by severe and disabling fatigue that fails to improve with rest; it is commonly accompanied by multifocal pain, as well as sleep disruption, and cognitive dysfunction. Even mild exertion can exacerbate symptoms.

The prevalence of ME/CFS in the U.S. is estimated to be 0.5-1.5% and is higher among females. Viral infection is an established trigger for the onset of ME/CFS symptoms, raising the possibility of an increase in ME/CFS prevalence resulting from the ongoing COVID-19 pandemic.

Current treatments are largely palliative and limited to alleviating symptoms and addressing the psychological sequelae associated with long-term disability. While ME/CFS is characterized by broad heterogeneity, common features include immune dysregulation and mitochondrial dysfunction. However, the underlying mechanistic basis of the disease remains poorly understood.

Herein, we review the current understanding, diagnosis and treatment of ME/CFS and summarize past clinical studies aimed at identifying effective therapies. We describe the current status of mechanistic studies, including the identification of multiple targets for potential pharmacological intervention, and ongoing efforts towards the discovery of new medicines for ME/CFS treatment.

6. Conclusion

While ME/CFS remains a poorly understood disease, there is a growing understanding of its mechanistic roots. New research directions are emerging with the potential to generate better diagnostic tools, biomarkers and pharmacological treatments. Approaches to therapy under investigation are directed at specific molecular or cellular irregularities associated with ME/CFS such as autoantibodies, immune dysregulation (e.g. NK cell function) or mitochondrial dysfunction. Recent discoveries suggest the possibility of target-based drug discovery programs directed against specific proteins implicated in either the initiation or propagation of ME/CFS symptoms (e.g. PDHK).

These developments are occurring at the same time as advances in the diagnosis and detection of ME/CFS. Investments in patient profiling and tool generation are starting to yield fruit, and we anticipate the availability of reliable clinical diagnostic tools in the near future.

Despite its significant human cost and economic impact, ME/CFS research has yet to attract major financial support.

Recognizing this deficiency, the U.S. National Institutes of Health (NIH) have established a Trans-NIH ME/CFS working group to coordinate a multi-institute effort to learn about and treat this disease. Nonetheless with an overall budget of ∼$42Bn, NIH’s spend on ME/CFS research in 2019 amounted to only ∼$15 M compared to $111 M on multiple sclerosis and $94 M on rheumatoid arthritis, both conditions for which there are multiple drugs already on the market.

Various private foundations and patient groups have been established to help support research and to advocate for increased government support, and these continue to play an essential role in increasing awareness and funding for the ME/CFS field (see for example Solve M.E. and ME Action).

However, at the current time, interest among pharmaceutical companies and biotech/venture investors appears to be almost non-existent. It is to be hoped that increased awareness of the basis and impact of ME/CFS will stimulate the investment in research that will be necessary for development of effective new therapies.

ME Association: What drugs are being developed for the treatment of ME/CFS?, by Dr Charles Shepherd, 2 Feb 2021

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Modulatory effects of cognitive exertion on regional functional connectivity of the salience network in women with ME/CFS

Posted on 02/05/2021 by wames

Modulatory effects of cognitive exertion on regional functional connectivity of the salience network in women with ME/CFS: A pilot study, by Riccardo Manca, Katija Khan, Micaela Mitolo, Matteo De Marco, Lynsey Grieveson, Rosemary Varley, Iain D Wilkinson, Annalena Venneri in Journal of the Neurological Sciences, January 2021 [doi.org/10.1016/j.jns.2021.117326]

 

Highlights

  • Cognitive effort can induce PEM and worsening of ME/CFS symptoms.
  • PEM is associated with changes in functional connectivity of the salience network.
  • Increased right insular FC with frontal areas is associated with symptom worsening.

Research abstract:

Background

A common symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is post-exertional malaise (PEM). Various brain abnormalities have been observed in patients with ME/CFS, especially in insular and limbic system, but their link with ME/CFS symptoms is still unclear. This pilot study aimed at investigating the association between PEM in ME/CFS and changes in functional connectivity (FC) of two main networks: the salience network (SN) and the default-mode network (DMN).

Methods

A total of 16 women, 6 with and 10 without ME/CFS, underwent clinical and MRI assessment before and after cognitive exertion. Resting-state FC maps of 7 seeds (3 for the SN and 4 for the DMN) and clinical measures of fatigue, pain and cognition were analysed with repeated-measure models. FC-symptom change associations were also investigated

Results

Exertion induced increases in fatigue and pain in patients with ME/CFS, compared to the control group, while no changes were found in cognitive performance. At baseline, patients showed altered FC between some DMN seeds and frontal areas and stronger FC between all SN seeds and left temporal areas and the medulla. Significantly higher FC increases in patients than in controls were found only between the right insular seed and frontal and subcortical areas; these increases correlated with worsening of symptoms.

Conclusions

Cognitive exertion can induce worsening of ME/CFS-related symptoms.

These changes were here associated with strengthening of FC of the right insula with areas involved in reward processing and cognitive control.

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Numeric rating scales show prolonged post-exertional symptoms after orthostatic testing of adults with ME/CFS

Posted on 02/03/2021 by wames

Numeric rating scales show prolonged post-exertional symptoms after orthostatic testing of adults with Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome, by C (Linda) M C van Campen, Peter C Rowe, Freek WA Verheugt, Frans C Visser in Frontiers in Medicine Vol 7, p 602894, January 27 2021 [doi.org/10.3389/fmed.2020.602894]

 

Research abstract:

Introduction:

Muscle pain, fatigue, and concentration problems are common among individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). These symptoms are commonly increased as part of the phenomenon of postexertional malaise (PEM). An increase in the severity of these symptoms is described following physical or mental exercise in ME/CFS patients.

Another important symptom of ME/CFS is orthostatic intolerance, which can be detected by head-up tilt testing (HUT). The effect of HUT on PEM has not been studied extensively. For this purpose, we assessed numeric rating scales (NRS) for pain, fatigue, and concentration pre- and post-HUT. As pain is a core symptom in fibromyalgia (FM), we subgrouped ME/CFS patients by the presence or absence of FM.

Methods and Results

In eligible ME/CFS patients who underwent HUT, NRS of pain, fatigue, and concentration were obtained pre-HUT, immediately after HUT, at 24 and 48 h, and at 7 days post test. We studied 174 ME/CFS patients with FM, 104 without FM, and 30 healthy controls (HC). Values for all symptoms were unchanged for HC pre- and post-HUT. Compared with pre-HUT, the three NRS post-HUT were significantly elevated in both ME/CFS patient groups even after 7 days. NRS pain was significantly higher at all time points measured in the ME/CFS patients with FM compared with those without FM.

In ME/CFS patients, the maximum fatigue and concentration scores occurred directly post-HUT, whereas pain perception reached the maximum 24 h post-HUT.

Conclusion

NRS scores of pain, fatigue, and concentration were significantly increased even at 7 days post-HUT compared with pre-HUT in ME/CFS patients with and without FM, suggesting that orthostatic stress is an important determinant of PEM.

 

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ME/CFS: the human herpesviruses are back!

Posted on 02/03/2021 by wames

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: the human herpesviruses are back! by  Maria Eugenia Ariza in Biomolecules 2021, 11(2), 185; 29 January 2021 [doi.org/10.3390/biom11020185]  (This article belongs to the Special Issue Epstein-Barr Virus Disease Mechanisms and Stress Responses)

 

Review abstract:

Figure 1. Model depicting how the combined effect of environmental insults, and stress in genetically susceptible individuals can trigger neurological, immune and metabolic dysfunction, which together could contribute to the symptomology observed in ME/CFS

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) or Systemic Exertion Intolerance Disease (SEID) is a chronic multisystem illness of unconfirmed etiology. There are currently no biomarkers and/or signatures available to assist in the diagnosis of the syndrome and while numerous mechanisms have been hypothesized to explain the pathology of ME/CFS, the triggers and/or drivers remain unknown.

Initial studies suggested a potential role of the human herpesviruses especially Epstein-Barr virus (EBV) in the disease process but inconsistent and conflicting data led to the erroneous suggestion that these viruses had no role in the syndrome.

New studies using more advanced approaches have now demonstrated that specific proteins encoded by EBV could contribute to the immune and neurological abnormalities exhibited by a subgroup of patients with ME/CFS. Elucidating the role of these herpesvirus proteins in ME/CFS may lead to the identification of specific biomarkers and the development of novel therapeutics.

5. Conclusions and Future Directions

It is clear that the lack of a universally accepted clinical criteria has led to multiple discrepancies, problems and confusion as to how to accurately diagnose and stratify patients with ME/CFS. This has severely hampered the pursue of studies to clearly define the environmental and genetic factors that act as triggers or the downstream mechanisms responsible for the development/progression of ME/CFS. Furthermore, numerous studies using small size patient cohorts, which lack the statistical power to achieve reproducible and rigorous results, have further complicated the task of identifying biomarkers/signatures that would be useful for diagnosing patients.

The role of some herpesviruses in the development and evolution of ME/CFS in a subset of patients has also been hampered because of the use of classical serological approaches focused primarily on viral proteins expressed during latency or late in the replicative cycle of these viruses or viral load as indicators for the involvement of herpesviruses in the pathobiology of ME/CFS. Recent studies using more advanced serological approaches as well as mechanistic studies have demonstrated the possible role of the EBV BRRF1 and BLLF3 gene products in ME/CFS pathophysiology.

Future directions should focus on exploring the use of these gene products for the development of novel therapeutics and/or as biomarkers with diagnostic application or disease progression. Additionally, additional studies need to be performed in light of the new evidence showing high level of abortive lytic replication of these viruses to determine whether other early herpesvirus proteins could contribute to the disease process.

Finally, since there is evidence suggesting simultaneous reactivation of multiple herpesviruses in a large percentage of ME/CFS patients, studies should examine whether or not there is cooperative effects between these viruses as well as other viruses within the virome that could contribute to human disease.

 

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