Mental health screening in adolescents with CFS/ME

Mental health screening in adolescents with CFS/ME, by Maria E Loades, Paul Stallard, David Kessler & Esther Crawley in European Child & Adolescent Psychiatry (2021) [doi.org/10.1007/s00787-021-01734-5]

 

Excerpts from Letter to the editor:

Psychiatric co-morbidity in adolescents is common, with the majority of those who have depression also having at least one anxiety disorder, and many meeting the diagnostic criteria for more than one anxiety disorder. In our recent paper published in this journal, we reported that approximately one in three adolescents with Chronic Fatigue Syndrome (CFS/ME) has either an anxiety disorder, or major depressive disorder, or both.

In clinical practice, screening questionnaires which ask about depression and anxiety symptoms, such as the Revised Children’s Anxiety and Depression Scale, RCADS, and the Hospital Anxiety and Depression Scale, HADS, are often used as part of the assessment process. However, in our paper, we reported our findings of variable discriminative validity of these questionnaires for detecting anxiety and depression separately. Whilst we found sufficiently accurate threshold scores for classifying those with anxiety disorders on both the 47-item and 25-item parent and child versions of the RCADS, we could not identify a sufficiently accurate threshold score for classifying those with depression. We also could not identify sufficiently accurate threshold scores on the HADS for either anxiety or depression.

Clinicians treating children with health disorders need a simple screening mechanism to identify those with co-morbid mental health problems that will require further assessment. Using one threshold score is therefore arguably more useful than calculating two separate scores (for depression and anxiety). Given the high co-morbidity between depression and anxiety in this population, we sought to identify the threshold score for mental health problems on two commonly used screening questionnaires, the RCADS-total and the HADS-total…

A total of 164 participants, mean age 15, mostly female (70%) completed the HADS and a subsample of 89 (54%) completed the RCADS. The subsample did not differ significantly on fatigue, physical functioning, HADS total, or age (data not shown)…

For identifying co-morbid mental health problems (anxiety and/or depression), we found that both the full 47-item version and the brief 25-item version of the RCADS were sufficiently accurate and could identify threshold scores deemed to be suitably sensitive and specific to be useful for screening in a clinical setting…

Participants were recruited from specialist services, so findings may not generalise to other settings, nor to those who were too severely affected to participate. The diagnostic interview was also assumed to be completely accurate, and whilst we made every attempt to ensure that it was robustly conducted, diagnostic judgements may mean that errors were made. Nonetheless, our findings suggest that a total cut-off score of ≥ 27 on the 25-item RCADS offers a simple way of identifying children with CFS/ME with co-morbid anxiety and depression.

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Dysregulated provision of oxidisable substrates to the mitochondria in ME/CFS lymphoblasts

Dysregulated provision of oxidisable substrates to the mitochondria in ME/CFS lymphoblasts, by Daniel Missailidis, Oana Sanislav, Claire Y Allan, Paige K. Smith, Sarah J Annesley, and Paul R Fisher in Int. J. Mol. Sci. 2021, 22(4), 2046; 19 February 2021 [doi.org/10.3390/ijms22042046]  (This article belongs to the Special Issue Environmental Sensitivity Illnesses: Mechanisms and Molecular Signatures 2.0)

 

Research abstract:

Although understanding of the biomedical basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is growing, the underlying pathological mechanisms remain uncertain.

We recently reported a reduction in the proportion of basal oxygen consumption due to ATP synthesis by Complex V in ME/CFS patient-derived lymphoblast cell lines, suggesting mitochondrial respiratory inefficiency. This was accompanied by elevated respiratory capacity, elevated mammalian target of rapamycin complex 1 (mTORC1) signaling activity and elevated expression of enzymes involved in the TCA cycle, fatty acid β-oxidation and mitochondrial transport.  These and other observations led us to hypothesise the dysregulation of pathways providing the mitochondria with oxidisable substrates.

In our current study, we aimed to revisit this hypothesis by applying a combination of whole-cell transcriptomics, proteomics and energy stress signaling activity measures using subsets of up to 34 ME/CFS and 31 healthy control lymphoblast cell lines from our growing library.

While levels of glycolytic enzymes were unchanged in accordance with our previous observations of unaltered glycolytic rates, the whole-cell proteomes of ME/CFS lymphoblasts contained elevated levels of enzymes involved in the TCA cycle (p = 1.03 × 10−4), the pentose phosphate pathway (p = 0.034, G6PD p = 5.5 × 10−4), mitochondrial fatty acid β-oxidation (p = 9.2 × 10−3), and degradation of amino acids including glutamine/glutamate (GLS p = 0.034, GLUD1 p = 0.048, GOT2 p = 0.026), branched-chain amino acids (BCKDHA p = 0.028, BCKDHB p = 0.031) and essential amino acids (FAH p = 0.036, GCDH p = 0.006). The activity of the major cellular energy stress sensor, AMPK, was elevated but the increase did not reach statistical significance.

The results suggest that ME/CFS metabolism is dysregulated such that alternatives to glycolysis are more heavily utilised than in controls to provide the mitochondria with oxidisable substrates.

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Sex-based differences in plasma autoantibodies to CNS proteins in Gulf War veterans versus healthy & symptomatic controls

Sex-based differences in plasma autoantibodies to Central Nervous System proteins in Gulf War veterans versus healthy and symptomatic controls, by Mohamed B Abou-Donia, Maxine H Krengel, Elizabeth S Lapadula, Clara G Zundel, Jessica LeClair, Joseph Massaro, Emily Quinn, Lisa A Conboy, Efi Kokkotou, Daniel D Nguyen, Maria Abreu, Nancy G Klimas, Kimberly Sullivan in Brain Sci. 2021 Jan 23;11(2):148 [doi: 10.3390/brainsci11020148] (This article belongs to the Special Issue Advancing the Role of Neuroimmunity and Genetic Susceptibility in Gulf War Illness)

 

Research abstract

Veterans from the 1991 Gulf War (GW) have suffered from Gulf War illness (GWI) for nearly 30 years. This illness encompasses multiple body systems, including the central nervous system (CNS). Diagnosis and treatment of GWI is difficult because there has not been an objective diagnostic biomarker. Recently, we reported on a newly developed blood biomarker that discriminates GWI from GW healthy controls, and symptomatic controls with irritable bowel syndrome (IBS) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

The present study was designed to compare levels of these biomarkers between men and women with GWI, as well as sex-specific effects in comparison to healthy GW veterans and symptomatic controls (IBS, ME/CFS). The results showed that men and women with GWI differ in 2 of 10 plasma autoantibodies, with men showing significantly elevated levels. Men and women with GWI showed significantly different levels of autoantibodies in 8 of 10 biomarkers to neuronal and glial proteins in plasma relative to controls.

In summary, the present study addressed the utility of the use of plasma autoantibodies for CNS proteins to distinguish among both men and women veterans with GWI and other healthy and symptomatic control groups.

Excerpt

Our next analyses compared male veterans with GWI to all male controls from our prior study (healthy GW veterans, non-veterans with IBS or ME/CFS) [19]. We then performed the same analyses comparing women veterans with GWI to the combined all women control group (non-veterans with IBS and ME/CFS). The results showed that men with GWI had significantly higher levels of autoantibodies for 9 out of the 10 autoantibodies when compared with male healthy GW veterans or with the combined male control group. Women with GWI showed significantly higher values for 2 out of the 10 autoantibodies when compared with women healthy GW veterans and with 8 out of 10 autoantibodies when compared with their respective combined women control group (nonveterans with IBS and ME/CFS).

These results suggest that women with GWI appear to be showing more neuronal cytoskeletal and neuroinflammatory changes when compared to healthy GW controls or women with IBS or ME/CFS

This suggests that male GWI veterans may be showing more chronic glial activation, neuronal damage, and neuroinflammation than their male control healthy and symptomatic counterparts with IBS and ME/CFS because S100B is a marker of current BBB disruption and GFAP is a marker of current neuroinflammation [39,40]. This is because GFAP is secreted by activated astrocytes, which leads to neuroinflammation [41,42,43].

A major strength of our study is that it represents both healthy and symptomatic GW veteran groups as well as symptomatic non-veteran controls with ME/CFS or IBS. This suggests that both men and women veterans with GWI differ not only from their healthy GW veteran controls but also have more CNS differences than other groups of men and women with chronic multi-symptom illnesses. In addition, the CNS autoantibody analyses were performed with the laboratory staff blinded to the case status of all participants.

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Sick of the sick role: narratives of what ‘recovery’ means to people with CFS/ME

Sick of the sick role: narratives of what “Recovery” means to people with CFS/ME, by Anna Cheshire, Damien Ridge, Lucy V Clark, Peter D White in Qualitative Health Research Vol 31, Issue 2, 2021 [doi.org/10.1177/1049732320969395]

 

Research abstract:

Little is known about what recovery means to those with chronic fatigue syndrome/ myalgic encephalomyelitis, a poorly understood, disabling chronic health condition.

To explore this issue, semi-structured interviews were conducted with patients reporting improvement (n = 9) and deterioration (n = 10) after a guided self-help intervention, and analyzed via “constant comparison.”

The meaning of recovery differed between participants—expectations for improvement and deployment of the sick role (and associated stigma) were key influences. While some saw recovery as complete freedom from symptoms, many defined it as freedom from the “sick role,” with functionality prioritized. Others redefined recovery, reluctant to return to the lifestyle that may have contributed to their illness, or rejected the concept as unhelpful.

Recovery is not always about eliminating all symptoms. Rather, it is a nexus between the reality of limited opportunities for full recovery, yet a strong desire to leave the illness behind and regain a sense of “normality.”

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Plasma proteomics publication shows disrupted cell-to-cell signaling in ME/CFS

Cornell University news post from the Center for Enervating NeuroImmune Disease: Plasma proteomics publication shows disrupted cell-to-cell signaling

 

We are proud to announce our latest plasma proteomics publication is available as open access in Proteomes.

In-depth analysis of the plasma proteome in ME/CFS exposes disrupted Ephrin-Eph and immune system signaling by Arnaud Germain, Susan M Levine and Maureen R Hanson in Proteomes 2021, 9(1), 6; [doi.org/10.3390/proteomes9010006]

This manuscript takes a look at 4,790 circulating plasma proteins from 20 ME/CFS women compared to 20 healthy women, over an unprecedented range, for ME/CFS, of 9 orders of magnitude.

Pathway analysis uncovered disrupted cell-to-cell communication, specifically in the ephrin-Eph signaling pathway. This pathway is crucial for many aspects of our body’s homeostasis, including development, physiology, and disease regulation.

Additionally, the paper outlines promising results for the development of a diagnostic test using protein ratios.

First author, Arnaud Germain, PhD, outlines these findings in a video abstract below (4 mins).

A transcript for the video: English        German

 

 

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Open‐label study with the monoamine stabilizer (‐)‐OSU6162 [drug] in ME/CFS

Open‐label study with the monoamine stabilizer (‐)‐OSU6162 in myalgic encephalomyelitis/ chronic fatigue syndrome, by Sara Haghighi, Sara Forsmark, Olof Zachrisson, Arvid Carlsson, Marie K L Nilsson, Maria L Carlsson, Robert C Schuit, Carl‐Gerhard Gottfries in Brain and Behavior, 02 February 2021 [doi.org/10.1002/brb3.2040]

 

Research abstract:

Objectives

The purpose of the present study was to investigate the safety and tolerability of the monoaminergic stabilizer (‐)‐OSU6162 in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In addition, a potential therapeutic effect of (‐)‐OSU6162 in ME/CFS was evaluated by means of observer‐rated scales and self‐assessment rating scales.

Materials and Methods

In the current study using an open‐label single‐arm design ME/CFS patient received treatment with (‐)‐OSU6162 during 12 weeks. The patients received the following doses of (‐)‐OSU6162: 15 mg b.i.d. during the first 4‐week period, up to 30 mg b.i.d. during the second 4‐week period and up to 45 mg b.i.d. during the third 4‐week period, with follow‐up visits after 16 and 20 weeks.

Results

Out of 33 included patients, 28 completed the 12 weeks treatment period. (‐)‐OSU6162 was well tolerated; only one patient discontinued due to an adverse event. Vital signs and physical examinations showed no abnormal changes. Blood analyses showed an increase in serum prolactin. Therapeutically, improvements were seen on the Clinical Global Impression of Change scale, the FibroFatigue scale, the Mental Fatigue Scale, the Fatigue Severity Scale, Beck Depression Inventory, and the Short Form 36 Health Survey Questionnaire.

Conclusions

(‐)‐OSU6162 is well tolerated in ME/CFS patients and shows promise as a novel treatment to mitigate fatigue and improve mood and health‐related quality of life in ME/CFS. Obviously, the present results need to be confirmed in future placebo‐controlled double‐blind trials.

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Diagnostic & pharmacological potency of Creatine in Post-Viral Fatigue Syndrome

Diagnostic and pharmacological potency of creatine in Post-Viral Fatigue Syndrome
by  Sergej M. Ostojic in Nutrients 2021, 13(2), 503; [doi.org/10.3390/nu13020503] (This article belongs to the Special Issue Creatine Supplementation for Health and Clinical Diseases)

 

Review abstract

Post-viral fatigue syndrome (PVFS) is a widespread chronic neurological disease with no definite etiological factor(s), no actual diagnostic test, and no approved pharmacological treatment, therapy, or cure.

Among other features, PVFS could be accompanied by various irregularities in creatine metabolism, perturbing either tissue levels of creatine in the brain, the rates of phosphocreatine resynthesis in the skeletal muscle, or the concentrations of the enzyme creatine kinase in the blood. Furthermore, supplemental creatine and related guanidino compounds appear to impact both patient- and clinician-reported outcomes in syndromes and maladies with chronic fatigue.

This paper critically overviews the most common disturbances in creatine metabolism in various PVFS populations, summarizes human trials on dietary creatine and creatine analogs in the syndrome, and discusses new frontiers and open questions for using creatine in a post-COVID-19 world.

Conclusions

Currently, there is not enough evidence to unequivocally endorse supplemental creatine for PVFS. However, the findings from initial trials on the metabolic substrate of PVFS, along with promising results from interventional studies, emphasize the need to explore creatine and similar compounds in this ever-prevalent yet baffling disorder.

The need for an effective, low-risk, and affordable dietary intervention to tackle post-COVID-19 fatigue, which is going to remain an issue for years to come, perhaps provides a unique research opportunity to explore creatine in PVFS using expedited yet diligent approaches.

 

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Chronic COVID-19 Syndrome & ME/CFS following the first pandemic wave in Germany

Chronic COVID-19 Syndrome and Chronic Fatigue Syndrome (ME/CFS) following the first pandemic wave in Germany – a first analysis of a prospective observational study, n medRxiv 2021.02.06.21249256 [doi.org/10.1101/2021.02.06.21249256]  This article is a preprint and has not been peer-reviewed

 

Research abstract:

Objective:

Characterization of the clinical features of patients with persistent symptoms after mild to moderate COVID-19 infection and exploration of factors associated with the development of Chronic COVID-19 Syndrome (CCS).

Methods Setting:

Charité Fatigue Center with clinical immunologists and rheumatologist, neurologists and cardiologists at Charité University hospital.

Participants:

42 patients who presented with persistent moderate to severe fatigue six months following a mostly mild SARS-CoV-2 infection at the Charité Fatigue Center from July to November 2020.

Main outcome measures:

The primary outcomes were clinical and paraclinical data and meeting diagnostic criteria for Chronic Fatigue Syndrome (ME/CFS). Relevant neurological and cardiopulmonary morbidity was excluded.

Results: 

The median age was 36.5, range 22–62, 29 patients were female and 13 male. At six months post acute COVID-19 all patients had fatigue (Chalder Fatigue Score median 25 of 33, range 14–32), the most frequent other symptoms were post exertional malaise (n=41), cognitive symptoms (n=40), headache (n=38), and muscle pain (n=35). Most patients were moderately to severely impaired in daily life with a median Bell disability score of 50 (range 15–90) of 100 (healthy) and Short Form 36 (SF-36) physical function score of 63 (range 15-80) of 100. 19 of 42 patients fulfilled the 2003 Canadian Consensus Criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

These patients reported more fatigue in the Chalder Fatigue Score (p=0.006), more stress intolerance (p=0.042) and more frequent and longer post exertional malaise (PEM) (p=0.003), and hypersensitivity to noise (p=0.029), light (p=0.0143) and temperature (p=0.024) compared to patients not meeting ME/CFS criteria. Handgrip force was diminished in most patients compared to healthy control values, and lower in CCS/CFS compared to non-CFS CCS (Fmax1 p=0.085, Fmax2, p=0.050, Fmean1 p=0.043, Fmean2 p=0.034, mean of 10 repeat handgrips, 29 female patients). Mannose-binding lectin (MBL) deficiency was observed frequently (22% of all patients) and elevated IL-8 levels were found in 43% of patients.

Conclusions:

Chronic COVID-19 Syndrome at months 6 is a multisymptomatic frequently debilitating disease fulfilling diagnostic criteria of ME/CFS in about half of the patients in our study. Research in mechanisms and clinical trials are urgently needed.

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Long COVID – we’ve been here before

British Medical Association newsLong COVID – we’ve been here before
by Jennifer Trueland, 12 February 2021

 

Long COVID is a new condition, but those who have endured years of ME/CFS can share their common experience – and a long history of being misunderstood

When it was becoming clear that COVID-19 was a serious issue early last year, Nina Muirhead (pictured) had a strong suspicion about what would happen next.

As a doctor who had developed ME/CFS following an attack of glandular fever four years ago, and in common with others in the scientific and ME patient community, she predicted that there would be a sub-set of people who, like her, would still be suffering months or even years after contracting the virus.

‘I wrote to Professor Whitty [England’s chief medical officer] and Sir Patrick Vallance [chief scientific officer] back in March saying there’s going to be a long COVID, and maybe there should be a health warning put out about this – maybe people should be advised of the long-term consequences, maybe we could do a study.

‘But they were so overwhelmed with fighting the big fire [acute COVID], and because ME is so misunderstood by the medical profession, they didn’t have the same end of the binoculars as I do. They didn’t see it coming in the same way.’

Nearly a year on, it’s becoming accepted that long COVID is a serious problem. The Office for National Statistics said in December that an estimated one in five people testing positive for COVID-19 exhibit symptoms for five weeks or longer, with one in 10 exhibiting symptoms for 12 weeks or longer…

Amy Small, a GP in Lothian who has campaigned on long COVID after becoming ill herself, acknowledges that she has learned a lot about management of the condition from the experience of people with ME/CFS.

‘One of the first things I did when I realised that I wasn’t getting better was that I phoned a friend who has had severe ME for several years.

‘I asked her what would you want to know if you were me now, and you could see this coming – what would you do? She suggested pacing first and foremost – learn to pace properly. I had never really understood what pacing was – I thought it was to do what you’re doing, but do it more slowly.

‘But someone on Twitter recommended a book to me called Classic Pacing for a Better Life with ME and that was a real turning point for me.’

h long COVID had found giving up sugar very helpful, and she’s got me on a load of supplements. I said to my husband years ago that if he ever caught me taking turmeric for medicinal purposes, then shoot me,’ she laughs. ‘Boy did I live to regret that. I think my attitude has changed.’

Keeping a symptom diary and consulting a nutritionist have also been helpful – although Dr Small admits that some of the advice would previously have been anathema to her as an evidence-focused medic.

Read more from Dr Nina Muirhead, Dr Charles Shepherd and Dr David Strain, an ME/CFS researcher, now leading the BMA’s COVID response.

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Young and exhausted – dysfunctional breathing

Young and exhausted, by Filip Olekšák, Peter Ďurdík, Ľubica Jakušová, Tomáš Turčan, Peter Bánovčin in Advances in Respiratory Medicine 2021, vol. 89, no. 1, pages 1-4

 

Letter to the editors extracts:

Dysfunctional breathing (DB) is highly prevalent and is overlooked mainly in adolescents and often attributed to behavioural changes during adolescence [6]. Chronic fatigue might be a symptom of DB in adolescents. We present a case study supporting this claim.

Case report

In the case report, we present a 13-year-old patient with chronic debilitating fatigue who
meets the criteria for CFS/ME. The patient and patient’s parents reported 6 months of fatigue, which was not improved even after an adequate period of sleep and very low physical performance. According to the parents, the patient has difficulty concentrating, is morose most of the day and reports limb twitching and paraesthesia.

The patient was examined in detail by a paediatrician (anamnestic unclear cause, resting tachycardia in the physical examination, laboratory tests within normal limits, serum minerals within normal limits), endocrinologist (normal hormonal profile for a given age, Tanner stage 3), infectologist (serology for typical viruses negative), psychologist (normal cognitive functions).

For a history of resting tachycardia, the patient was examined by a cardiologist, where no cardiogenic cause of fatigue was demonstrated, sinus tachycardia was present, and the patient was recommended head-up-tilt test, which showed the presence of postural orthostatic tachycardia. Due to the idiopathic nature of the difficulties and the excluded secondary cause, a two-day protocol examination by cardiopulmonary exercise testing was indicated.

Conclusions
CPET confirmed the presence of DB in the patient based on the low resting value of ETCO2, the existence of a chaotic pattern of respiration  during resting and exercise with the presence of tachypnoea (with very low ventilatory efficiency) in maximal exertion. Diagnosis of DB using CPET is one of the methods of DB diagnostics. Proper respiratory rehabilitation and psychological guidance resulted in the patient fixing the respiratory pattern and subsequently eliminating the primary cause of the examination — chronic fatigue.

Patients with CFS/ME are a common paediatric problem. The current possibilities of diagnostics are enriched by the possibility of performing CPET, which can be a benefit in differential diagnostics as well as in confirming the diagnosis. Patients with CFS/ME and/or postural orthostatic tachycardia should be checked for the presence of DB as a treatable cause of clinical symptoms.

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