Epidemiological and clinical factors associated with post-exertional malaise severity in patients with myalgic encephalomyelitis/chronic fatigue syndrome
Alaa Ghali, ï Paul Richa, ï Carole Lacout, ï Aline Gury, ï Anne-Berengere Beucher, Chadi Homedan, ï Christian Lavigne & ï Geoffrey Urbanski
Journal of Translational Medicine volume 18, Article number: 246 (2020) Abstract
Background
Post-exertional malaise (PEM), the cardinal feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), occurs generally after exposure to a stressor. It is characterized by the worsening of ME/CFS symptoms and results in aggravating the course of the disease and the quality of life of patients. Due to its unpredictable onset, severity, and recovery time, identifying patients with higher risk for severe PEM would allow preventing or reducing its occurrence. We thus aimed at defining possible factors that could be associated with PEM severity.
Methods
Adult patients fulfilling ME international consensus criteria who attended the internal medicine department of University hospital Angers-France between October 2011 and December 2019 were included retrospectively. All patients were systematically hospitalized for an etiological workup and overall assessment. We reviewed their medical records for data related to the assessment: epidemiological data, fatigue features, clinical manifestations, and ME/CFS precipitants. PEM severity was appreciated by the Center for Disease Control self-reported questionnaire. The study population was classified into quartiles according to PEM severity scores. Analyses were performed with ordinal logistic regression to compare quartile groups.
Results
197 patients were included. PEM severity was found to be positively associated with age at disease onset ≥ 32 years (OR 1.8 [95% CI 1.1–3.0] (p = 0.03)), recurrent infections during the course of the disease (OR 2.1 [95% CI 1.2–3.7] (p = 0.009)), and when ME/CFS was elicited by a gastrointestinal infectious precipitant (OR 5.7 [1.7–19.3] (p = 0.006)).
Conclusion
We identified some epidemiological and clinical features, which were positively associated with PEM severity in subsets of ME/CFS patients. This could help improving disease management and patients’ quality of life.
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Predicting GP visits: A multinomial logistic regression investigating GP visits amongst a cohort of UK patients living with Myalgic encephalomyelitis
Abstract
Background
Myalgic Encephalomyelitis (ME) is a chronic condition whose status within medicine is the subject of on-going debate. Some medical professionals regard it as a contentious illness. Others report a lack of confidence with diagnosis and management of the condition. The genesis of this paper was a complaint, made by an ME patient, about their treatment by a general practitioner. In response to the complaint, Healthwatch Trafford ran a patient experience-gathering project.
Method
Data was collected from 476 participants (411 women and 65 men), living with ME from across the UK. Multinomial logistic regression investigated the predictive utility of length of time with ME; geographic location (i.e. Manchester vs. rest of UK); trust in GP; whether the patient had received a formal diagnosis; time taken to diagnosis; and gender. The outcome variable was number of GP visits per year.
Results
All variables, with the exception of whether the patient had received a formal diagnosis, were significant predictors.
Conclusions
Relationships between ME patients and their GPs are discussed and argued to be key to the effective delivery of care to this patient cohort. Identifying potential barriers to doctor patient interactions in the context of ME is crucial.
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International Journal of Cardiology, Hypertension. Volume 5, June 2020, 100032
Paradigm shift to disequilibrium in the genesis of orthostatic intolerance in patients with myalgic encephalomyelitis and chronic fatigue syndrome
Author links open overlay panel KunihisaMiwaa1YukichiInoueb1
https://doi.org/10.1016/j.ijchy.2020.100032Get rights and content
Highlights Most patients with chronic fatigue syndrome suffers from orthostatic intolerance (OI).
OI significantly restricts daily functional capacity.
Circulatory and autonomic nervous dysregulation is not the sole cause of OI.
Disequilibrium should be recognized as the important cause of OI.
Disequilibrium is more influential cause of OI than postural orthostatic tachycardia.
Abstract
Background
Orthostatic intolerance (OI) markedly impairs activities of daily living in patients with myalgic encephalomyelitis (ME) or chronic fatigue syndrome. OI is surmised to be a cardiovascular symptom correlated with cerebral hypo-perfusion and exaggerated sympathetic activation. Postural instability or disequilibrium may be part of the etiology of OI.
Methods The study comprised 72 patients with ME (18 men, 54 women; mean age, 37 ± 10 years) who underwent neurological examinations and the 10 min standing test. We quantified disequilibrium (instability upon standing with feet together and eyes shut), ability to complete the 10 min standing test, and postural orthostatic tachycardia (POT) during the test.
Results Disequilibrium was detected in 23/72 (32%) patients and POT in 16 (22%). Nineteen (26%) patients failed to complete the 10 min standing test; disequilibrium was significantly more common in the 19- patient subgroup than in the 53-patient test-completing subgroup (89% vs. 11%, p < 0.01). However, the rate of POT was not different between the groups (21% vs. 23%, p = 1.00). Compared with the 49 (68%) patients without disequilibrium, the 23 (32%) patients with disequilibrium were significantly more likely to have failed to complete the test (74% vs. 4%, p < 0.01). The rate of POT was comparable between the groups (23% vs. 22%, p = 1.00). Among patients with disequilibrium who failed to complete the 10 min standing test and had a previous record, 6/8 had completed the test 6–24 months earlier when all six had reported no disequilibrium.
Conclusion
Disequilibrium should be recognized as an important cause of OI in patients with ME.
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Journal of Experimental Neurology Commentary
https://www.scientificarchives.com/journal/journal-of-experimental-neurology Skeletal
Muscle Weakness Often Occurs in Patients with Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS)
Yves Jammes1,2, Frédérique Retornaz2*
1 C2VN UMR Inra Inserm, Faculty of Medicine, Aix-Marseille University, France 2 Department of Internal Medicine, European Hospital, Marseille, France fr
Received date: April 16, 2020, Accepted date: May 14, 2020 Copyright: © 2020 Jammes Y, et al.
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
This commentary considers the occurrence of skeletal muscle weakness in patients with myalgic encephalomyelitis / chronic fatigue syndrome (ME/ CFS), already reported by Jammes et al. in the last issue of Clinical Biomechanics [1]. These authors showed that numerous patients with severe body fatigue and clinical criteria of ME/CFS had reduced values of maximal handgrip strength in proportion of their lowered maximal performance at work measured on a cycloergometer. Here, we discuss these data in terms of pathophysiological mechanisms of muscle failure. Remember that ME/CFS is a multisystem disease characterized by an intense fatigue worsened by physical/ mental activity [2-4], often associated with postexertional malaise (PEM) [3,5]. Several body systems including the muscular and nervous systems are affected in ME/CFS. The symptoms combine fatigue, loss of memory and/or concentration, headaches, unrefreshing sleep, unexplained muscle or joint pain, sore throat and sometimes enlarged lymph nodes in neck or armpits [6]. ME/CFS pathogenesis appears to have a number of factors; different stressors (such as physical exertion, Highlights • Altered muscle function often occurs in ME/CFS patients. • Reduced handgrip strength is proportional to lowered physical performance • Muscle fatigue could result from altered muscle excitability at work • Reduced central motor command is also documented in relation of encephalomyelitis • Subgroups of ME/CFS patients without muscle weakness are documented Abstract This commentary complements data reported in Clinical Biomechanics [1] reporting reduced maximal handgrip strength in numerous patients with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) in proportion to their lowered maximal physical performances. The causes of muscle weakness in these patients are open to discussion. Literature data reveal a reduction of central command to skeletal muscles in some ME/CFS patients, related to encephalomyelitis. Altered muscle membrane excitability, that is “peripheral fatigue”, is also described in relation with an imbalance of the oxidant / anti-oxidant status. On the other hand, subgroups of chronically fatigued patients with clinical criteria of ME/CFS do not suffer from any muscle weakness. Thus, clinical data do not sufficiently clarify homogeneous ME/CFS pathology.
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Persistent Symptoms in Patients After Acute COVID-19 In Italy,
2020 American Medical Association JAMA Published online July 9, 2020
A large proportion of patients with coronavirus disease 2019 (COVID-19) presented with symptoms (71.4% of 31 845 confirmed cases as of June 3, 2020).1 Common symptoms include cough, fever, dyspnea, musculoskeletal symptoms (myalgia, joint pain, fatigue), gastrointestinal symptoms, and anosmia/dysgeusia.2-4 However, information is lacking on symptoms that persist after recovery. We assessed persistent symptoms in patients who were discharged from the hospital after recovery from COVID-19.
Methods | In the waning phase of the pandemic, beginning on April 21, 2020, the Fondazione Policlinico Universitario Agostino Gemelli IRCCS in Rome, Italy, established a postacute outpatient service for individuals discharged from the hospital after recovery from COVID-19. All patients who met World Health Organization criteria for discontinuation of quarantine (no fever for 3 consecutive days, improvement in other symptoms, and 2 negative test results for severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] 24 hours apart) were followed up. At enrollment in the study, real-time reverse transcriptase–polymerase chain reaction for SARS-CoV-2 was performed and patients with a negative test result were included. Patients were offered a comprehensive medical assessment with detailed history and physical examination. Data on all clinical characteristics, including clinical and pharmacological history, lifestyle factors, vaccination status, and body measurements, were collected in a structured electronic data collection system. The COVID-19 postacute outpatient service is currently active, and further details about the patient evaluation protocol are described elsewhere.5 In particular, data on specific symptoms potentially correlated with COVID-19 were obtained using a standardized questionnaire administered at enrollment. Patients were asked to retrospectively recount the presence or absence of symptoms during the acute phase of COVID-19 and whether each symptom persisted at the time of the visit. More than 1 symptom could be reported. The EuroQol visual analog scale was used to ask patients to score their quality of life from 0 (worst imaginable health) to 100 (best imaginable health) before COVID-19 and at the time of the visit. A difference of 10 points defined worsened quality of life. All analyses were performed using R version 3.6.3 (R Foundation).
This study was approved by the Università Cattolica and Fondazione Policlinico Gemelli IRCCS Institutional Ethics Committee. Written informed consent was obtained from all participants.
Results | From April 21 to May 29, 2020, 179 patients were potentially eligible for the follow-up post–acute care assessment; 14 individuals (8%) refused to participate and 22 had a positive test result. Thus, 143 patients were included. Themean age was 56.5 (SD, 14.6) years (range, 19-84 years), and 53 (37%) were women. During hospitalization, 72.7% of participants had evidence of interstitial pneumonia. The mean length of hospital stay was 13.5 (SD, 9.7) days; 21 patients (15%) received noninvasive ventilation and 7 patients (5%) received invasive ventilation. Patients were assessed a mean of 60.3 (SD, 13.6) days after onset of the first COVID-19 symptom; at the time of the evaluation, only 18 (12.6%) were completely free of any COVID19–related symptom, while 32% had 1 or 2 symptoms and 55% had 3 or more. None of the patients had fever or any signs or symptoms of acute illness. Worsened quality of life was observed among 44.1% of patients. A high proportion of individuals still reported fatigue (53.1%), dyspnea (43.4%), joint pain, (27.3%) and chest pain (21.7%).
Discussion This study found that in patients who had recovered from COVID-19, 87.4% reported persistence of at least 1 symptom, particularly fatigue and dyspnea. Limitations of the study include the lack of information on symptom history before acute COVID-19 illness and the lack of details on symptom severity. Furthermore, this is a single-center study with a relatively small number of patients and without a control group of patients discharged for other reasons. Patients with community-acquired pneumonia can also have persistent symptoms, suggesting that these findings may not be exclusive to COVID-19.6 Clinicians and researchers have focused on the acute phase of COVID-19, but continuedmonitoring after discharge for longlasting effects is needed.
Angelo Carfì, MD Roberto Bernabei, MD Francesco Landi, MD, PhD
Corresponding Author: Angelo Carfì, MD, Centro Medicina dell’Invecchiamento, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo Francesco Vito 1, 00168 Rome, Italy (angelo.carfi@ policlinicogemelli.it).
Accepted for Publication: June 23, 2020. Published Online: July 9, 2020. doi:10.1001/jama.2020.12603
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J Med Virol. 2020 Mar 4. doi: 10.1002/jmv.25744. Online ahead of print.
Cytomegalovirus, Epstein-Barr virus, and human herpesvirus-6 infections in patients with myalgic еncephalomyelitis/chronic fatigue syndrome
Evelina Shikova 1 2, Valentina Reshkova 3, Аntoniya Kumanova 1, Sevdalina Raleva 1, Dora Alexandrova 2, Natasa Capo 4 5, Modra Murovska 6, European Network on ME/CFS (EUROMENE)
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling multisystem chronic disease. The etiology and pathogenesis of ME/CFS are unknown. Infections of cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus-6 (HHV-6) are suspected as etiological agents for ME/CFS. This study aims to estimate prevalence and type (active/latent) of EBV, CMV, and HHV-6 infections in Bulgarian ME/CFS patients. In the study were included 58 patients with ME/CFS and 50 healthy controls. Virus-specific antibodies were detected by enzyme-linked immunosorbent assay and viral genomic sequences in peripheral blood mononuclear cell (PBMCs) and plasma samples by nested polymerase chain reaction (PCR). We did not observe any significant differences in virus-specific immunoglobulin G and immunoglobulin M positivity rates between patients with ME/CFS and control group. In ME/CFS plasma samples, EBV DNA was found in 24.1%, CMV DNA in 3.4%, and HHV-6 DNA in 1.7% of samples. EBV DNA was detected in 4%, and CMV and HHV-6 DNA were not found in plasma samples of controls. The frequency of viral genome detection in PBMCs of patients and controls was 74% vs 78% for CMV, 81% vs 84% for EBV, and 82.8% vs 82% for HHV-6. The difference in frequency of EBV active infection in ME/CFS and control group was statistically significant (P = .0027). No ME/CFS and control individuals with active CMV and HHV-6 infection were observed. In conclusion, this study using both serological and PCR-based techniques for distinguishing between active and latent infection showed high rate of active EBV infection among patients with ME/CFS indicating that at least in a subset of cases, EBV is important factor for the development of disease.
Keywords: CMV; EBV; ELISA; HHV-6 infection; PCR; active infection; myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
© 2020 The Authors. Journal of Medical Virology published by Wiley Periodicals, Inc.
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· Hypothesis · March 2020 ·
“Neither dying, nor recovering”:
Learning from Intensive Care Units to Solve Chronic Fatigue Syndrome (ME/CFS)
Dominic Stanculescu* Independent, Belgium
Introduction
Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a debilitating, multi-system disease of unclear etiology and without reliable treatments. Some researchers consider ME/CFS to be a maladaptive response to stressors (physical, infectious, or emotional) [1]. Similarly, the failure of a subset of intensive care unit (ICU) patients to begin recovery is also increasingly considered the result of maladaptive responses to the stress of severe injury or infection [2;3;4]. Irrespective of the initial critical illness, these “chronic” ICU patients experience severe ME/CFSlike symptoms that include profound muscular weakness, cognitive impairment, pain, and vulnerability to infection [5]. Here the hypothesis is advanced that maladaptive mechanisms that prevent recovery in some ICU patients also underlie ME/CFS. Specifically, these mechanisms are: (a) suppression of the pituitary gland’s pulsatile secretion of tropic hormones, and (b) "vicious cycles" between cytokines, oxidative and nitrosative stress (O&NS), and low thyroid hormone function.
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Adv Rheumatol 2020 Jun 29;60(1):34. doi: 10.1186/s42358-020-00135-7.
Repetitive transcranial magnetic stimulation of the prefrontal cortex for fibromyalgia syndrome: a randomised controlled trial with 6-months follow up
Suman Tanwar 1 2, Bhawna Mattoo 1, Uma Kumar 3, Renu Bhatia 4
PMID: 32600394
Abstract
Objectives: Fibromyalgia Syndrome (FMS), is a chronic pain disorder with poorly understood pathophysiology. In recent years, repetitive transcranial magnetic stimulation (rTMS) has been recommended for pain relief in various chronic pain disorders. The objective of the present research was to study the effect of low frequency rTMS over the right dorsolateral prefrontal cortex (DLPFC) on pain status in FMS.
Methods: Ninety diagnosed cases of FMS were randomized into Sham-rTMS and Real-rTMS groups. Real rTMS (1 Hz/1200 pulses/8 trains/90% resting motor threshold) was delivered over the right DLPFC for 5 consecutive days/week for 4 weeks. Pain was assessed by subjective and objective methods along with oxidative stress markers. Patients were followed up for 6 months (post-rTMS;15 days, 3 months and 6 months).
Results: In Real-rTMS group, average pain ratings and associated symptoms showed significant improvement post rTMS. The beneficial effects of rTMS lasted up to 6 months in the follow-up phase. In Sham-rTMS group, no significant change in pain ratings was observed.
Conclusion: Right DLPFC rTMS can significantly reduce pain and associated symptoms of FMS probably through targeting spinal pain circuits and top-down pain modulation .
Trial registration: Ref No: CTRI/2013/12/004228.
Keywords: Chronic pain; Dorsolateral prefrontal cortex; Neuromodulation; Nociceptive flexion reflex; Non-invasive therapy; Oxidative stress.
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May 26, 2020; 94 (21) ARTICLE - Neurology
Effect of yoga as add-on therapy in migraine (CONTAIN)
A randomized clinical trial
View ORCID ProfileAnand Kumar, Rohit Bhatia, Gautam Sharma, Dhanlika Dhanlika, Sreenivas Vishnubhatla, Rajesh Kumar Singh, Deepa Dash, Manjari Tripathi, M.V. Padma Srivastava
First published May 6, 2020, DOI: https://doi.org/10.1212/WNL.0000000000009473
Abstract
Objective To evaluate the effectiveness of yoga as an adjuvant to conventional medical management on clinical outcomes in patients with migraine.
Methods CONTAIN was a prospective, randomized, open-label superiority trial with blinded endpoint assessment carried out at a single tertiary care academic hospital in New Delhi, India. Patients enrolled were aged 18–50 years with a diagnosis of episodic migraine and were randomized into medical and yoga groups (1:1). Randomization was computer-generated with a variable block size and concealed. A predesigned yoga intervention was given for 3 months. Outcomes were recorded by a blinded assessor. The primary endpoint was a decrease in headache frequency, headache intensity, and Headache Impact Test (HIT)–6 score. Secondary outcomes included change in Migraine Disability Assessment (MIDAS) score, pill count, and proportion of headache free patients.
Results Between April 2017 and August 2018, 160 patients with episodic migraine were randomly assigned to medical and yoga groups. A total of 114 patients completed the trial. Baseline measures were comparable except for a higher mean headache frequency in the yoga group. Compared to medical therapy, the yoga group showed a significant mean delta value reduction in headache frequency (delta difference 3.53 [95% confidence interval 2.52–4.54]; p < 0.0001), headache intensity (1.31 [0.60–2.01]; p = 0.0004), HIT score (8.0 [4.78–11.22]; p < 0.0001), MIDAS score (7.85 [4.98–10.97]; p < 0.0001), and pill count (2.28 [1.06–3.51]; p < 0.0003).
Conclusion Yoga as an add-on therapy in migraine is superior to medical therapy alone. It may be useful to integrate a cost-effective and safe intervention like yoga into the management of migraine.
Clinicaltrials.gov identifier CTRI/2017/03/008041.
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NICE advises against using graded exercise therapy for patients recovering from covid-19
BMJ 2020; 370 doi: https://doi.org/10.1136/bmj.m2912 (Published 21 July 2020)Cite this as: BMJ 2020;370:m2912
In a statement NICE said that it was aware of concerns related to the impact of graded exercise therapy (GET) for managing post-viral fatigue in patients recovering from covid-19. It noted that its current advice on managing chronic fatigue may not be appropriate for this group of patients and acknowledged that it could also be out of date for other groups.1
“NICE’s guideline on ME/CFS [chronic fatigue syndrome] (CG53) was published in 2007,2 many years before the current pandemic, and it should not be assumed that the recommendations apply to people with fatigue following covid-19,” the statement said.
It emphasised that the recommendations on GET in this guideline applied only to patients with a diagnosis of chronic fatigue syndrome as part of specialist care, where it should be part of an individualised, person centred programme of care, where GET is recommended only for people with mild to moderate symptoms.
NICE added, “As the guideline is currently being updated, it is possible that these recommendations may change. The evidence for and against graded exercise therapy is one of the important issues the guideline committee is considering.”
NICE plans to consult on its updated guidance in November 2020. In the interim it advises doctors to use recent guidance from NHS England on the aftercare needs of inpatients recovering from covid-19, which includes advice on managing fatigue.3 That guidance says that “it is important to ensure a gradual return to activities and exercise and to teach pacing methods.”
Much of the support for GET comes from a study published in the Lancet in 2011, which concluded that patients with chronic fatigue syndrome benefited more from cognitive behavioural therapy and GET than from pacing therapy.4 Many patients reported that GET made them feel worse and that pacing was more effective,5 and the study’s methodology was heavily criticised.6 A review conducted by the Health Research Authority concluded that the study was properly conducted,7 but the review focused on the research process, not the conclusions.
Post-exertional malaise
The large number of patients experiencing post-viral fatigue after covid-19 has now shone a spotlight on the controversial technique again.
Among this number is Paul Garner, professor of infectious disease at the Liverpool School of Tropical Medicine and director of the Centre for Evidence Synthesis in Global Health. Early in his recovery Garner realised that he was experiencing post-exertional malaise, as every time he did any exercise that increased his heart rate, such as cycling or yoga, he found himself back in bed.89
Garner, who is coordinating editor of the Cochrane Infectious Diseases Group and one of the founders of the Cochrane Collaboration, said that he was “furious” when he read the 2007 NICE advice and the conclusions of the Cochrane review, which also support exercise therapy and mention uncertainty about the side effects of adaptive pacing.10
“Obviously, I know that if I increase my exercise I will be thrown back to bed,” he said. “What I struggle with as a highly driven medic is stopping myself overdoing it. That’s what I need help with—I don’t need help to increase my exercise.”
Garner researched and started using pacing, finding the approach helpful. However, he emphasised that the technique was complex and that there was very little information in the medical literature. “GPs need some really practical guidance on how they rehabilitate these patients. People are having to search out techniques or generate them themselves,” he said.
He added that, while some charities and health authorities had put out guidance, it was “difficult to negotiate” and that a centralised approach coordinated by NICE or the Royal College of General Practitioners, involving medical professionals and patients, was needed quickly.
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Proc Natl Acad Sci U S A . 2020 Jun 9;117(23):13044-13055.
doi: 10.1073/pnas.2000625117. Epub 2020 May 20.
Epstein-Barr virus co-opts TFIIH component XPB to specifically activate essential viral lytic promoters
Dinesh Verma 1, Trenton Mel Church 1, Sankar Swaminathan 2 3
Epstein-Barr virus (EBV) is associated with epithelial and lymphoid malignancies, establishes latent infection in memory B cells, and intermittently produces infectious virions through lytic replication. Released virions play a key role in latent reservoir maintenance and transmission. Lytic EBV transcription differs from cellular transcription in requiring a virus-encoded preinitiation complex that binds to TATT motifs unique to EBV late lytic promoters. Expression of 15 late lytic genes that are important for virion production and infectivity is particularly dependent on the EBV SM protein, a nuclear protein expressed early during lytic reactivation that binds to viral RNAs and enhances RNA stability. We recently discovered that spironolactone blocks EBV virion production by inhibiting EBV SM function. Since spironolactone causes degradation of xeroderma pigmentosum group B-complementing protein (XPB), a component of human transcription factor TFIIH, in both B lymphocytes and epithelial cells, we hypothesized that SM utilizes XPB to specifically activate transcription of SM target promoters. While EBV SM has been thought to act posttranscriptionally, we provide evidence that SM also facilitates EBV gene transcription. We demonstrate that SM binds and recruits XPB to EBV promoters during lytic replication. Depletion of XPB protein, by spironolactone treatment or by siRNA transfection, inhibits SM-dependent late lytic gene transcription but not transcription of other EBV genes or cellular genes. These data indicate that SM acts as a transcriptional activator that has co-opted XPB to specifically target 15 EBV promoters that have uniquely evolved to require XPB for activity, providing an additional mechanism to differentially regulate EBV gene expression.
Keywords: Epstein–Barr virus; XPB; herpesvirus; transcription.
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Proc Natl Acad Sci U S A. 2016 Mar 29;113(13):3609-14. doi: 10.1073/pnas.1523686113. Epub 2016 Mar 14.
Spironolactone blocks Epstein-Barr virus production by inhibiting EBV SM protein function
Dinesh Verma 1, Jacob Thompson 1, Sankar Swaminathan 2
Clinically available drugs active against Epstein-Barr virus (EBV) and other human herpesviruses are limited to those targeting viral DNA replication. To identify compounds directed against other steps in the viral life cycle, we searched for drugs active against the EBV SM protein, which is essential for infectious virus production. SM has a highly gene-specific mode of action and preferentially enhances expression of several late lytic cycle EBV genes. Here we demonstrate that spironolactone, a mineralocorticoid receptor antagonist approved for clinical use, inhibits SM function and infectious EBV production. Expression of EBV viral capsid antigen is highly SM dependent, and spironolactone inhibits viral capsid antigen synthesis and capsid formation, blocking EBV virion production at a step subsequent to viral DNA replication. In addition, spironolactone inhibits expression of other SM-dependent genes necessary for infectious virion formation. We further demonstrate that molecules structurally related to spironolactone with similar antimineralocorticoid blocking activity do not inhibit EBV production. These findings pave the way for development of antiherpesvirus drugs with new mechanisms of action directed against SM and homologous essential proteins in other herpesviruses.
Keywords: Epstein–Barr virus; antiviral; herpesvirus; posttranscriptional regulation; spironolactone.
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Persistent Symptoms in Patients After Acute COVID-19
Angelo Carfì, MD1; Roberto Bernabei, MD1; Francesco Landi, MD, PhD1; et alfor the Gemelli Against COVID-19 Post-Acute Care Study Group
JAMA. Published online July 9, 2020. doi:10.1001/jama.2020.12603
In Italy, a large proportion of patients with coronavirus disease 2019 (COVID-19) presented with symptoms (71.4% of 31 845 confirmed cases as of June 3, 2020).1 Common symptoms include cough, fever, dyspnea, musculoskeletal symptoms (myalgia, joint pain, fatigue), gastrointestinal symptoms, and anosmia/dysgeusia.2-4 However, information is lacking on symptoms that persist after recovery. We assessed persistent symptoms in patients who were discharged from the hospital after recovery from COVID-19.
Methods
In the waning phase of the pandemic, beginning on April 21, 2020, the Fondazione Policlinico Universitario Agostino Gemelli IRCCS in Rome, Italy, established a postacute outpatient service for individuals discharged from the hospital after recovery from COVID-19. All patients who met World Health Organization criteria for discontinuation of quarantine (no fever for 3 consecutive days, improvement in other symptoms, and 2 negative test results for severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] 24 hours apart) were followed up. At enrollment in the study, real-time reverse transcriptase–polymerase chain reaction for SARS-CoV-2 was performed and patients with a negative test result were included.
Patients were offered a comprehensive medical assessment with detailed history and physical examination. Data on all clinical characteristics, including clinical and pharmacological history, lifestyle factors, vaccination status, and body measurements, were collected in a structured electronic data collection system. The COVID-19 postacute outpatient service is currently active, and further details about the patient evaluation protocol are described elsewhere.5
In particular, data on specific symptoms potentially correlated with COVID-19 were obtained using a standardized questionnaire administered at enrollment. Patients were asked to retrospectively recount the presence or absence of symptoms during the acute phase of COVID-19 and whether each symptom persisted at the time of the visit. More than 1 symptom could be reported. The EuroQol visual analog scale was used to ask patients to score their quality of life from 0 (worst imaginable health) to 100 (best imaginable health) before COVID-19 and at the time of the visit. A difference of 10 points defined worsened quality of life. All analyses were performed using R version 3.6.3 (R Foundation).
This study was approved by the Università Cattolica and Fondazione Policlinico Gemelli IRCCS Institutional Ethics Committee. Written informed consent was obtained from all participants.
Results
From April 21 to May 29, 2020, 179 patients were potentially eligible for the follow-up post–acute care assessment; 14 individuals (8%) refused to participate and 22 had a positive test result. Thus, 143 patients were included. The mean age was 56.5 (SD, 14.6) years (range, 19-84 years), and 53 (37%) were women. During hospitalization, 72.7% of participants had evidence of interstitial pneumonia. The mean length of hospital stay was 13.5 (SD, 9.7) days; 21 patients (15%) received noninvasive ventilation and 7 patients (5%) received invasive ventilation. The characteristics of the study population are summarized in the Table.
Patients were assessed a mean of 60.3 (SD, 13.6) days after onset of the first COVID-19 symptom; at the time of the evaluation, only 18 (12.6%) were completely free of any COVID-19–related symptom, while 32% had 1 or 2 symptoms and 55% had 3 or more. None of the patients had fever or any signs or symptoms of acute illness. Worsened quality of life was observed among 44.1% of patients. The Figure shows that a high proportion of individuals still reported fatigue (53.1%), dyspnea (43.4%), joint pain, (27.3%) and chest pain (21.7%).
Discussion
This study found that in patients who had recovered from COVID-19, 87.4% reported persistence of at least 1 symptom, particularly fatigue and dyspnea. Limitations of the study include the lack of information on symptom history before acute COVID-19 illness and the lack of details on symptom severity. Furthermore, this is a single-center study with a relatively small number of patients and without a control group of patients discharged for other reasons. Patients with community-acquired pneumonia can also have persistent symptoms, suggesting that these findings may not be exclusive to COVID-19.6
Clinicians and researchers have focused on the acute phase of COVID-19, but continued monitoring after discharge for long-lasting effects is needed.
Section Editor: Jody W. Zylke, MD, Deputy Editor.
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Cerebral Blood Flow Is Reduced in Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients During Mild Orthostatic Stress Testing: An Exploratory Study at 20 Degrees of Head-Up Tilt Testing
by C (Linda) M.C. van Campen 1,*,Peter C. Rowe 2 andFrans C. Visser 1
Stichting CardioZorg, 2132 HN Hoofddorp, The Netherlands
Department of Paediatrics, John Hopkins University School of Medicine, Baltimore, MD 21205, USA
Healthcare 2020, 8(2), 169; https://doi.org/10.3390/healthcare8020169
Received: 5 May 2020 / Revised: 1 June 2020 / Accepted: 10 June 2020 / Published: 13 June 2020
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Abstract
Introduction: In a study of 429 adults with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), we demonstrated that 86% had symptoms of orthostatic intolerance in daily life. Using extracranial Doppler measurements of the internal carotid and vertebral arteries during a 30-min head-up tilt to 70 degrees, 90% had an abnormal reduction in cerebral blood flow (CBF). A standard head-up tilt test of this duration might not be tolerated by the most severely affected bed-ridden ME/CFS patients. This study examined whether a shorter 15-min test at a lower 20 degree tilt angle would be sufficient to provoke reductions in cerebral blood flow in severe ME/CFS patients. Methods and results: Nineteen severe ME/CFS patients with orthostatic intolerance complaints in daily life were studied: 18 females. The mean (SD) age was 35(14) years, body surface area (BSA) was 1.8(0.2) m2 and BMI was 24.0(5.4) kg/m2. The median disease duration was 14 (IQR 5–18) years. Heart rate increased, and stroke volume index and end-tidal CO2 decreased significantly during the test (p ranging from <0.001 to <0.0001). The cardiac index decreased by 26(7)%: p < 0.0001. CBF decreased from 617(72) to 452(63) mL/min, a 27(5)% decline. All 19 severely affected ME/CFS patients met the criteria for an abnormal CBF reduction. Conclusions: Using a less demanding 20 degree tilt test for 15 min in severe ME/CFS patients resulted in a mean CBF decline of 27%. This is comparable to the mean 26% decline previously noted in less severely affected patients studied during a 30-min 70 degree head-up tilt. These observations have implications for the evaluation and treatment of severely affected individuals with ME/CFS. View Full-Text
Keywords: orthostatic intolerance; cerebral blood flow; 20 degree tilt table testing; myalgic encephalomyelitis; chronic fatigue syndrome; postural orthostatic tachycardia syndrome; stroke volume index; cardiac index
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Health Care Responsibility and Compassion-Visiting the Housebound Patient Severely Affected by ME/CFS
by Caroline Kingdon *,Dionysius Giotas,Luis Nacul andEliana Lacerda
Department of Clinical Research, London School of Hygiene & Tropical Medicine, Faculty of Infectious and Tropical Diseases, London WC1E 7HT, UK
Healthcare 2020, 8(3), 197; https://doi.org/10.3390/healthcare8030197
Received: 9 June 2020 / Revised: 1 July 2020 / Accepted: 2 July 2020 / Published: 4 July 2020
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Abstract
Many people with severe Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) commonly receive no care from healthcare professionals, while some have become distanced from all statutory medical services. Paradoxically, it is often the most seriously ill and needy who are the most neglected by those responsible for their healthcare. Reasons for this include tensions around the complexity of making an accurate diagnosis in the absence of a biomarker, the bitter debate about the effectiveness of the few available treatments, and the very real stigma associated with the diagnosis. Illness severity often precludes attendance at healthcare facilities, and if an individual is well enough to be able to attend an appointment, the presentation will not be typical; by definition, patients who are severely affected are home-bound and often confined to bed. We argue that a holistic model, such as ‘‘Compassion in Practice’’, can help with planning appointments and caring for people severely affected by ME/CFS. We show how this can be used to frame meaningful interactions between the healthcare practitioners (HCPs) and the homebound patient.
Keywords: ME/CFS; severe ME/CFS; validation; engagement; health encounters; housebound; bedbound
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Two-Day Cardiopulmonary Exercise Testing in Females with a Severe Grade of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Comparison with Patients with Mild and Moderate Disease
by C (Linda) M. C. van Campen 1,*,Peter C. Rowe 2
Healthcare 2020, 8(3), 192; https://doi.org/10.3390/healthcare8030192
Received: 28 April 2020 / Revised: 17 June 2020 / Accepted: 25 June 2020 / Published: 30 June 2020
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Abstract
Introduction: Effort intolerance along with a prolonged recovery from exercise and post-exertional exacerbation of symptoms are characteristic features of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The gold standard to measure the degree of physical activity intolerance is cardiopulmonary exercise testing (CPET). Multiple studies have shown that peak oxygen consumption is reduced in the majority of ME/CFS patients, and that a 2-day CPET protocol further discriminates between ME/CFS patients and sedentary controls. Limited information is present on ME/CFS patients with a severe form of the disease. Therefore, the aim of this study was to compare the effects of a 2-day CPET protocol in female ME/CFS patients with a severe grade of the disease to mildly and moderately affected ME/CFS patients. Methods and results: We studied 82 female patients who had undergone a 2-day CPET protocol. Measures of oxygen consumption (VO2), heart rate (HR) and workload both at peak exercise and at the ventilatory threshold (VT) were collected. ME/CFS disease severity was graded according to the International Consensus Criteria. Thirty-one patients were clinically graded as having mild disease, 31 with moderate and 20 with severe disease. Baseline characteristics did not differ between the 3 groups. Within each severity group, all analyzed CPET parameters (peak VO2, VO2 at VT, peak workload and the workload at VT) decreased significantly from day-1 to day-2 (p-Value between 0.003 and <0.0001). The magnitude of the change in CPET parameters from day-1 to day-2 was similar between mild, moderate, and severe groups, except for the difference in peak workload between mild and severe patients (p = 0.019). The peak workload decreases from day-1 to day-2 was largest in the severe ME/CFS group (−19 (11) %). Conclusion: This relatively large 2-day CPET protocol study confirms previous findings of the reduction of various exercise variables in ME/CFS patients on day-2 testing. This is the first study to demonstrate that disease severity negatively influences exercise capacity in female ME/CFS patients. Finally, this study shows that the deterioration in peak workload from day-1 to day-2 is largest in the severe ME/CFS patient group. View Full-Text
Keywords: chronic fatigue syndrome; cardiopulmonary exercise testing; oxygen consumption; VO2 peak; ventilatory threshold; VO2 VT; myalgic encephalitis; workload; ME/CFS severity grade
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Risk factors for suicide in chronic fatigue syndrome
Madeline L. Johnson,Joseph Cotler,Julia M. Terman &Leonard A. Jason
Published online: 12 Jun 2020 – Journal of Death Studies
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) includes symptoms such as post-exertional malaise, unrefreshing sleep, and cognitive impairments. Several studies suggest these patients have an increased risk of suicidal ideation and early mortality, although few have published in this area. This study explores risk factors for suicide among 64 individuals with ME/CFS using archival data, 17 of which died from suicide. Results indicated an increased risk of suicide for those for those utilizing the label CFS, for those with limited overall functioning, and for those without comorbid illnesses. Findings suggest that stigma and functional impairments limit access to care and social supports.
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Pain. 2020 Jul 10. doi: 10.1097/j.pain.0000000000001996. Online ahead of print.
A genetic polymorphism that is associated with mitochondrial energy metabolism increases risk of fibromyalgia
Miranda Al van Tilburg 1 2 3, Marc Parisien 4, Richard G Boles 5, Gillian L Drury 4, Julian Smith-Voudouris 4, Vivek Verma 4, Samar Khoury 4, Anne-Julie Chabot-Doré 4, Andrea G Nackley 6 7, Shad B Smith 6, William E Whitehead 8, Denniz A Zolnoun 9, Gary D Slade 10 11 12, Inna Tchivileva 10, William Maixner 6, Luda Diatchenko 4
Abstract
Alterations in cellular energy metabolism have been implicated in chronic pain suggesting a role for mitochondrial DNA (mtDNA). Previous studies reported associations of a limited number of mtDNA polymorphisms with specific pain conditions. In this study, we examined the full mitochondrial genomes of people with a variety of chronic pain conditions. A discovery cohort consisting of 609 participants either with or without a complex persistent pain conditions (CPPC) was examined. mtDNA was subjected to deep sequencing for identification of rare mutations, common variants, haplogroups, and heteroplasmy associated with five CPPCs: episodic migraine, irritable bowel syndrome, fibromyalgia, vulvar vestibulitis, or temporomandibular disorders. The strongest association found was the presence of the C allele at the single nucleotide polymorphism (SNP) m.2352T>C (rs28358579) that significantly increased the risk for fibromyalgia (OR=4.6, P=4.3x10). This relationship was even stronger in women (OR=5.1, P=2.8x10), and m.2352T>C was associated with all other CPPCs in a consistent risk-increasing fashion. This finding was replicated in another cohort (OR=4.3, P=2.6x10) of the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study consisting of 1754 female participants. To gain insight into the cellular consequences of the associated genetic variability, we conducted an assay testing metabolic reprogramming in human cell lines with defined genotypes. The minor allele C was associated with decreased mitochondrial membrane potential under conditions where oxidative phosphorylation is required, indicating a role of oxidative phosphorylation in pathophysiology of chronic pain. Our results suggest that cellular energy metabolism, modulated by m.2352T>C, contributes to fibromyalgia and possibly other chronic pain conditions.
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Autoantibodies to beta-adrenergic and muscarinic cholinergic receptors in Myalgic Encephalomyelitis (ME) patients – A validation study in plasma and cerebrospinal fluid from two Swedish cohorts
Brain, Behaviour and Immunity Volume 7, August 2020, 10010
AnnieBynkeabPerJulincdCarl-GerhardGottfrieseHaraldHeideckefCarmenScheibenbogengJonasBergquistab
https://doi.org/10.1016/j.bbih.2020.100107Get rights and content
Highlights
Myalgic Encephalomyelitis (ME) is a devastating disorder (with millions of patients worldwide) with unclear aetiology and no clear diagnostic biomarker available.
This study support the existance of a general pattern of increased antibody levels to adrenergic and muscarinic receptors within the ME patient group.
No evidence for intrathecal antibody production was found in cerebrospinal fluid. The role of increased autoantibodies in the pathogenesis of ME is still uncertain and further research is needed to evaluate their clinical significance.
Abstract
Myalgic encephalomyelitis (ME) also known as ME/CFS (Chronic Fatigue Syndrome) or ME/SEID (Systemic Exertion Intolerance Disorder), is a disabling and often long-lasting disease that can drastically impair quality of life and physical/social functioning of the patients. Underlying pathological mechanisms are to a large extent unknown, but the presence of autoantibodies, cytokine pattern deviations and the presentation of cognitive and autonomic nervous system related symptoms provide evidence for ME being an immunological disorder with elements of autoimmunity. Increased levels of autoantibodies binding to adrenergic and muscarinic receptors in ME-patients have been reported. It is hypothesized that these autoantibodies have pathological significance and contribute to the ME-specific symptoms, however, these observations need to be validated.
This study was designed to investigate potential differences in adrenergic and muscarinic receptor autoantibody levels in plasma and cerebrospinal fluid (CSF) samples between ME patients and gender and age-matched healthy controls, and to correlate the autoantibody levels to disease severity.
We collected bodyfluids and health-related questionnaires from two Swedish ME cohorts, plasma and CSF from one of the cohorts (n = 24), only plasma from the second cohort (n = 24) together with plasma samples (n = 24) and CSF (n = 6) from healthy controls.
All samples were analysed for IgG autoantibodies directed against Alpha- (α1, α2) and Beta- (β1-3) adrenergic receptors and Muscarinic (M) 1–5 acetylcholine receptors using an ELISA technique. The questionnaires were used as measures of disease severity.
Significant increases in autoantibody levels in ME patients compared to controls were found for M3 and M4 -receptors in both cohorts and β1, β2, M3 and M4-receptors in one cohort. No significant correlations were found between autoantibody levels and disease severity. No significant levels of autoantibodies were detected in the CSF samples. These findings support previous findings that there exists a general pattern of increased antibody levels to adrenergic and muscarinic receptors within the ME patient group. However, the role of increased adrenergic and muscarinic receptor autoantibodies in the pathogenesis of ME is still uncertain and further research is needed to evaluate the clinical significance of these findings.
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Front. Public Health, 21 August 2020 | https://doi.org/10.3389/fpubh.2020.00420
The Economic Impacts of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in an Australian Cohort
Shara Close1, Sonya Marshall-Gradisnik2*, Joshua Byrnes3, Peter Smith2, Son Nghiem3 and Don Staines2
Design: A cost of illness study was conducted to estimate Australian cost data for individuals with a ME/CFS diagnosis as determined by the Canadian Consensus Criteria (CCC), International Consensus Criteria (ICC), and the 1994 CDC Criteria (Fukuda).
Setting and participants: Survey participants identified from a research registry database provided self-report of expenditure associated with ME/CFS related healthcare across a 1-month timeframe between 2017 and 2019.
Main outcome measures: ME/CFS related direct annual government health care costs, OOP health expenditure costs, indirect costs associated with lost income and health care service use patterns.
Results: The mean annual cost of health care related expenditure and associated income loss among survey participants meeting diagnostic criteria for ME/CFS was estimated at $14.5 billion. For direct OOP and Government health care expenditure, high average costs were related to medical practitioner attendance, diagnostics, natural medicines, and device expenditure, with an average attendance of 10.6 referred attendances per annum and 12.1 GP visits per annum related specifically to managing ME/CFS.
Conclusions: The economic impacts of ME/CFS in Australia are significant. Improved understanding of the illness pathology, diagnosis, and management, may reduce costs, improve patient prognosis and decrease the burden of ME/CFS in Australia.
Clin neurophysiological Prac. 2020; 5: 50–58.
Published online 2020 Feb 8. doi: 10.1016/j.cnp.2020.01.003 PMCID: PMC7044650 PMID: 32140630
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Cerebral blood flow is reduced in ME/CFS during head-up tilt testing even in the absence of hypotension or tachycardia: A quantitative, controlled study using Doppler echography
C. (Linda) M.C. van Campen,a,⁎ Freek W.A. Verheugt,b Peter C. Rowe,c and Frans C. Vissera
Abstract
Objective
The underlying hypothesis in orthostatic intolerance (OI) syndromes is that symptoms are associated with cerebral blood flow (CBF) reduction. Indirect CBF measurements (transcranial Doppler flow velocities), provide inconsistent support of this hypothesis. The aim of the study was to measure CBF during a 30 min head-up tilt test (HUT), using Doppler flow imaging of carotid and vertebral arteries, in individuals with chronic fatigue syndrome/myalgic encephalomyelitis (ME/CFS), a condition with a high prevalence of OI.
Methods
429 ME/CFS patients were studied: 247 had a normal heart rate (HR) and blood pressure (BP) response to HUT, 62 had delayed orthostatic hypotension (dOH), and 120 had postural orthostatic tachycardia syndrome (POTS). We also studied 44 healthy controls (HC). CBF measurements were made at mid-tilt and end-tilt. Before mid-tilt, we administered a verbal questionnaire to ascertain for 15 OI symptoms.
Results
End-tilt CBF reduction was 7% in HC versus 26% in the overall ME/CFS group, 24% in patients with a normal HR/BP response, 28% in those with dOH, and 29% in POTS patients (all P < .0005). Using a lower limit of normal of 2SD of CBF reduction in HC (13% reduction), 82% of patients with normal HR/BP response, 98% with dOH and 100% with POTS showed an abnormal CBF reduction. There was a linear correlation of summed OI symptoms with the degree of CBF reduction at mid-tilt (P < .0005).
Conclusions
During HUT, extracranial Doppler measurements demonstrate that CBF is reduced in ME/CFS patients with POTS, dOH, and even in those without HR/BP abnormalities.
Significance
This study shows that orthostatic intolerance symptoms are related to CBF reduction, and that the majority of ME/CFS patients (90%) show an abnormal cerebral flow reduction during orthostatic stress testing. This may have implications for the diagnosis and treatment of ME/CFS patients.
Transl Med. 2020 Aug 15;18(1):314. doi: 10.1186/s12967-020-02481-y.
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Hemodynamics during the 10-minute NASA Lean Test: evidence of circulatory decompensation in a subset of ME/CFS patients
Jihyun Lee 1, Suzanne D Vernon 2, Patricia Jeys 1, Weam Ali 1, Andrea Campos 1, Derya Unutmaz 3, Brayden Yellman 1, Lucinda Bateman 1
Background: Lightheadedness, fatigue, weakness, heart palpitations, cognitive dysfunction, muscle pain, and exercise intolerance are some of the symptoms of orthostatic intolerance (OI). There is substantial comorbidity of OI in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome). The 10-minute NASA Lean Test (NLT) is a simple, point-of-care method that can aid ME/CFS diagnosis and guide management and treatment of OI. The objective of this study was to understand the hemodynamic changes that occur in ME/CFS patients during the 10-minute NLT.
Methods: A total of 150 ME/CFS patients and 75 age, gender and race matched healthy controls (HCs) were enrolled. We recruited 75 ME/CFS patients who had been sick for less than 4 years (< 4 ME/CFS) and 75 ME/CFS patients sick for more than 10 years (> 10 ME/CFS). The 10-minute NLT involves measurement of blood pressure and heart rate while resting supine and every minute for 10 min while standing with shoulder-blades on the wall for a relaxed stance. Spontaneously reported symptoms are recorded during the test. ANOVA and regression analysis were used to test for differences and relationships in hemodynamics, symptoms and upright activity between groups.
Results: At least 5 min of the 10-minute NLT were required to detect hemodynamic changes. The < 4 ME/CFS group had significantly higher heart rate and abnormally narrowed pulse pressure compared to > 10 ME/CFS and HCs. The < 4 ME/CFS group experienced significantly more OI symptoms compared to > 10 ME/CFS and HCs. The circulatory decompensation observed in the < 4 ME/CFS group was not related to age or medication use.
Conclusions: Circulatory decompensation characterized by increased heart rate and abnormally narrow pulse pressure was identified in a subgroup of ME/CFS patients who have been sick for < 4 years. This suggests inadequate ventricular filling from low venous pressure. The 10-minute NLT can be used to diagnose and treat the circulatory decompensation in this newly recognized subgroup of ME/CFS patients. The > 10 ME/CFS group had less pronounced hemodynamic changes during the NLT possibly from adaptation and compensation that occurs over time. The 10-minute NLT is a simple and clinically useful point-of-care method that can be used for early diagnosis of ME/CFS and help guide OI treatment.
Keywords: 10-minute NASA lean test; Circulatory decompensation; ME/CFS; Orthostatic intolerance; Point-of-care.
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Long covid”: the Dutch response
BMJ 2020; 370 doi: https://doi.org/10.1136/bmj.m3202 (Published 14 August 2020)Cite this as: BMJ 2020;370:m3202
We have undertaken a series of actions to tackle this problem.
Firstly, we have developed rapid guidance to support clinicians in primary and secondary care in decision making about diagnosis and treatment. Because of a lack of evidence, most recommendations are based on expert opinion.
Secondly, the Dutch government has decided to reimburse physiotherapy, exercise therapy, ergotherapy, and dietetics in primary care to a maximum of six months. The results of individual treatment will be monitored and evaluated systematically.
Thirdly, research has started on follow-up of patients with covid-19 funded by the Netherlands Organisation for Health Research and Development. One of the research aims is to identify predictors of chronicity.
We hope that more evidence will soon become available on the large group of patients with covid-19 that have not been admitted to hospital. This will help to develop evidence based guidelines and to contribute to effective management of patients with persistent symptoms.
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Covid-19 and chronic fatigue
BMJ 2020; 370 doi: https://doi.org/10.1136/bmj.m2922 (Published 30 July 2020)Cite this as: BMJ 2020;370:m2922
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DR Clin Trans Res. 2020 Jul;5(3):224-232. doi: 10.1177/2380084419872135. Epub 2019 Aug 28.
Brain Responses in CFS and TMD to Autonomic Challenges: An Exploratory fMRI Study
Q C Vuong 1, J R Allison 2, A Finkelmeyer 1, J Newton 3 4, J Durham 2 5 6 PMID: 31461628
Abstract
Introduction: Dysfunction of the autonomic nervous system (ANS) is seen in chronic fatigue syndrome (CFS) and temporomandibular disorders (TMDs). Both conditions have poorly understood pathophysiology. Several brain structures that play a role in pain and fatigue, such as the insular cortex and basal ganglia, are also implicated in autonomic function.
Objectives: ANS dysfunction may point to common neurophysiologic mechanisms underlying the predominant symptoms for CFS and TMD. No studies to date have investigated the combination of both conditions. Thus, our aim was to test whether patients with CFS with or without TMD show differences in brain responses to autonomic challenges.
Methods: In this exploratory functional imaging study, patients with CFS who screened positive for TMD (n = 26), patients who screened negative for TMD (n = 16), and age-matched control participants (n = 10) performed the Valsalva maneuver while in a 3-T magnetic resonance imaging scanner. This maneuver is known to activate the ANS.
Results: For all 3 groups, whole-brain F test showed increased brain activation during the maneuver in the superior and inferior frontal gyri, the left and right putamen and thalamus, and the insular cortex. Furthermore, group contrasts with small-volume correction showed that patients with CFS who screened positive for TMD showed greater activity in the left insular cortex as compared with patients who screened negative and in the left caudate nucleus as compared with controls.
Conclusion: Our results suggest that increased activity in the cortical and subcortical regions observed during autonomic challenges may be modulated by fatigue and pain. ANS dysfunction may be a contributing factor to these findings, and further work is required to tease apart the complex relationship among CFS, TMD, and autonomic functions.
Knowledge transfer statement: Brain activity related to activation of the autonomic nervous system in patients with chronic fatigue syndrome who screened positive for painful temporomandibular disorder was greater than in patients who screened negative; activity was seen in brain regions associated with autonomic functions and pain. These findings suggest that autonomic dysfunction may play a role in the pathophysiology of both conditions, explain some of the apparent comorbidity between them, and offer avenues to help with treatment.
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Living with covid-19
Fiona Godlee, The BMJ Aug 2020
“Death is not the only adverse outcome of covid-19,” writes Nisreen Alwan, an epidemiologist who is experiencing a range of prolonged, fluctuating, and debilitating symptoms several months after her initial mild illness.1 Like a growing number of people around the world, she has what is being called post-acute or long covid.
While most people recover quickly and completely from the virus, stories of persistent and troubling symptoms have now moved from anecdote to the evidence of crowd sourced cohorts. Reports suggest that one in three people have not fully recovered several weeks after initial illness. A smaller but still substantial proportion have symptoms and difficulties that persist for months. These are not people who have been seriously ill in hospital, whose difficult journey to recovery is better understood.2 These are often physically fit, younger people who report persistent exercise intolerance, breathlessness and cough,3 anxiety, palpitations, and poor concentration. Paul Garner describes boom and bust—the illusion of recovery only to fall back into mental and physical exhaustion.4 These false dawns add to the burden for “long haulers,” he says, which for him includes intense fatigue, mood swings, muscle and joint pains, headaches, and brain fog.
One of the most distressing aspects of living with long covid, says Garner, is the dismissive attitude of some doctors. This may change as more doctors find themselves affected. So how should doctors respond to their patients struggling with this complex and worrying multisystem disorder? Trish Greenhalgh and colleagues recommend taking a whole person, pragmatic approach with symptom management that avoids overinvestigation.5 With so much uncertainty about the cause and course of long covid, a doctor’s key role is to be a witness, they say, “‘honouring the story’ of the patient whose protracted recovery is unexpected, alarming, and does not make sense.”
The challenge for those in charge of our public health response to covid-19 is to make sense of this emergent information. Policies and messaging must now reflect the risks to younger people of developing prolonged illness and multiple organ damage, especially in light of other new information about the risks of airborne transmission.67 For this, we need to be able to quantify the risks through proper population surveillance and to mitigate them with effective systems of rapid testing, tracing, isolation, and support.8 In the UK, at least, such crucial traditional public health approaches still seem a long way off.9
Follow BMJ Editor Fiona Godlee on Twitter @fgodlee and the BMJ @bmj_latest
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Brain, Behaviour and Immunity Vol:7 Aug 2020 100107
Autoantibodies to beta-adrenergic and muscarinic cholinergic receptors in Myalgic Encephalomyelitis (ME) patients – A validation study in plasma and cerebrospinal fluid from two Swedish cohorts
Author links open overlay panel AnnieBynkeabPerJulincdCarl-GerhardGottfrieseHaraldHeideckefCarmenScheibenbogengJonasBergquistab
https://doi.org/10.1016/j.bbih.2020.100107Get rights and content
Highlights
Myalgic Encephalomyelitis (ME) is a devastating disorder (with millions of patients worldwide) with unclear aetiology and no clear diagnostic biomarker available.
This study support the existance of a general pattern of increased antibody levels to adrenergic and muscarinic receptors within the ME patient group.
No evidence for intrathecal antibody production was found in cerebrospinal fluid. The role of increased autoantibodies in the pathogenesis of ME is still uncertain and further research is needed to evaluate their clinical significance.
Abstract
Myalgic encephalomyelitis (ME) also known as ME/CFS (Chronic Fatigue Syndrome) or ME/SEID (Systemic Exertion Intolerance Disorder), is a disabling and often long-lasting disease that can drastically impair quality of life and physical/social functioning of the patients. Underlying pathological mechanisms are to a large extent unknown, but the presence of autoantibodies, cytokine pattern deviations and the presentation of cognitive and autonomic nervous system related symptoms provide evidence for ME being an immunological disorder with elements of autoimmunity. Increased levels of autoantibodies binding to adrenergic and muscarinic receptors in ME-patients have been reported. It is hypothesized that these autoantibodies have pathological significance and contribute to the ME-specific symptoms, however, these observations need to be validated.
This study was designed to investigate potential differences in adrenergic and muscarinic receptor autoantibody levels in plasma and cerebrospinal fluid (CSF) samples between ME patients and gender and age-matched healthy controls, and to correlate the autoantibody levels to disease severity.
We collected bodyfluids and health-related questionnaires from two Swedish ME cohorts, plasma and CSF from one of the cohorts (n = 24), only plasma from the second cohort (n = 24) together with plasma samples (n = 24) and CSF (n = 6) from healthy controls.
All samples were analysed for IgG autoantibodies directed against Alpha- (α1, α2) and Beta- (β1-3) adrenergic receptors and Muscarinic (M) 1–5 acetylcholine receptors using an ELISA technique. The questionnaires were used as measures of disease severity.
Significant increases in autoantibody levels in ME patients compared to controls were found for M3 and M4 -receptors in both cohorts and β1, β2, M3 and M4-receptors in one cohort. No significant correlations were found between autoantibody levels and disease severity. No significant levels of autoantibodies were detected in the CSF samples. These findings support previous findings that there exists a general pattern of increased antibody levels to adrenergic and muscarinic receptors within the ME patient group. However, the role of increased adrenergic and muscarinic receptor autoantibodies in the pathogenesis of ME is still uncertain and further research is needed to evaluate the clinical significance of these findings.
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Review of case definitions for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) Eun-Jin Lim & Chang-Gue Son
Journal of Translational Medicine volume 18, Article number: 289 (2020)
Abstract
Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease with unknown causes. From the perspectives on the etiology and pathophysiology, ME/CFS has been labeled differently, which influenced changes in case definitions and terminologies. This review sought to feature aspects of the history, developments, and differential symptoms in the case definitions.
Methods
A search was conducted through PubMed published to February 2020 using the following search keywords: case definition AND chronic fatigue syndrome [MeSH Terms]. All reference lists of the included studies were checked. Of the included studies, the number of citations and the visibility in the literatures of the definitions were considered for comparisons of the criteria.
Results
Since the first 'ME' case definition was developed in 1986, 25 case definitions/diagnostic criteria were created based on three conceptual factors (etiology, pathophysiology, and exclusionary disorders). These factors can be categorized into four categories (ME, ME/CFS, CFS, and SEID) and broadly characterized according to primary disorder (ME-viral, CFS-unknown, ME/CFS-inflammatory, SEID-multisystemic), compulsory symptoms (ME and ME/CFS-neuroinflammatory, CFS and SEID-fatigue and/or malaise), and required conditions (ME-infective agent, ME/CFS, CFS, SEID-symptoms associated with fatigue, e.g., duration of illness). ME and ME/CFS widely cover all symptom categories, while CFS mainly covers neurologic and neurocognitive symptoms. Fatigue, cognitive impairment, PEM, sleep disorder, and orthostatic intolerance were the overlapping symptoms of the 4 categories, which were included as SEID criteria.
Conclusions
This study comprehensively described the journey of the development of case definitions and compared the symptom criteria. This review provides broader insights and explanations to understand the complexity of ME/CFS for clinicians and researchers.
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Front Neurosci : 2020 Jun 26;14:688. doi: 10.3389/fnins.2020.00688. eCollection 2020.
Cognitive Function Declines Following Orthostatic Stress in Adults With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
C Linda M C van Campen 1, Peter C Rowe 2, Freek W A Verheugt 3, Frans C Visser 1
PMID: 32670016 PMCID: PMC7332734 DOI: 10.3389/fnins.2020.00688
Abstract
Introduction: Orthostatic intolerance (OI) is common among individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Cognitive dysfunction has been demonstrated during head-up tilt testing (HUT) in those with ME/CFS: worse scores on cognitive tests occur with increasing tilt angles and increasing complexity of the cognitive challenge. The aim of our study was to determine whether cognitive impairment persists after completion of HUT.
Methods and results: Eligible participants were consecutive individuals satisfying criteria for ME/CFS who underwent HUT because of OI. The 2- and 3-back tests were performed before the start of HUT and within 5 min after completion of HUT. We measured the percentage of correct responses and raw reaction times before and after HUT for both the 2- and 3-back tests. We studied 128 ME/CFS patients who underwent HUT and had a complete set of N-back data before and after HUT. Compared to pre-tilt responses, the percentage of correct responses on the 2-back test decreased post-HUT from 77(18) to 62(21) and of the 3-back test from 57(17) to 41(17) (both p < 0.0001). The raw reaction time of the 2-back test increased post-HUT from 783(190) to 941(234) m/s and of the 3-back test from 950(170) to 1102(176) (both p < 0.0001). There was no difference in the N-back test data for subgroups dichotomized based on disease severity, the presence of co-morbid fibromyalgia, or the presence of postural orthostatic tachycardia syndrome.
Conclusion: As measured by the N-back test, working memory remains impaired in adults with ME/CFS following a 30-min head-up tilt test.
Alaa Ghali, ï Paul Richa, ï Carole Lacout, ï Aline Gury, ï Anne-Berengere Beucher, Chadi Homedan, ï Christian Lavigne & ï Geoffrey Urbanski
Journal of Translational Medicine volume 18, Article number: 246 (2020) Abstract
Background
Post-exertional malaise (PEM), the cardinal feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), occurs generally after exposure to a stressor. It is characterized by the worsening of ME/CFS symptoms and results in aggravating the course of the disease and the quality of life of patients. Due to its unpredictable onset, severity, and recovery time, identifying patients with higher risk for severe PEM would allow preventing or reducing its occurrence. We thus aimed at defining possible factors that could be associated with PEM severity.
Methods
Adult patients fulfilling ME international consensus criteria who attended the internal medicine department of University hospital Angers-France between October 2011 and December 2019 were included retrospectively. All patients were systematically hospitalized for an etiological workup and overall assessment. We reviewed their medical records for data related to the assessment: epidemiological data, fatigue features, clinical manifestations, and ME/CFS precipitants. PEM severity was appreciated by the Center for Disease Control self-reported questionnaire. The study population was classified into quartiles according to PEM severity scores. Analyses were performed with ordinal logistic regression to compare quartile groups.
Results
197 patients were included. PEM severity was found to be positively associated with age at disease onset ≥ 32 years (OR 1.8 [95% CI 1.1–3.0] (p = 0.03)), recurrent infections during the course of the disease (OR 2.1 [95% CI 1.2–3.7] (p = 0.009)), and when ME/CFS was elicited by a gastrointestinal infectious precipitant (OR 5.7 [1.7–19.3] (p = 0.006)).
Conclusion
We identified some epidemiological and clinical features, which were positively associated with PEM severity in subsets of ME/CFS patients. This could help improving disease management and patients’ quality of life.
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Predicting GP visits: A multinomial logistic regression investigating GP visits amongst a cohort of UK patients living with Myalgic encephalomyelitis
- R. Stephen Walsh, Andrew Denovan, Kenneth Drinkwater, &, Reddington S
- Neil Dagnall
Abstract
Background
Myalgic Encephalomyelitis (ME) is a chronic condition whose status within medicine is the subject of on-going debate. Some medical professionals regard it as a contentious illness. Others report a lack of confidence with diagnosis and management of the condition. The genesis of this paper was a complaint, made by an ME patient, about their treatment by a general practitioner. In response to the complaint, Healthwatch Trafford ran a patient experience-gathering project.
Method
Data was collected from 476 participants (411 women and 65 men), living with ME from across the UK. Multinomial logistic regression investigated the predictive utility of length of time with ME; geographic location (i.e. Manchester vs. rest of UK); trust in GP; whether the patient had received a formal diagnosis; time taken to diagnosis; and gender. The outcome variable was number of GP visits per year.
Results
All variables, with the exception of whether the patient had received a formal diagnosis, were significant predictors.
Conclusions
Relationships between ME patients and their GPs are discussed and argued to be key to the effective delivery of care to this patient cohort. Identifying potential barriers to doctor patient interactions in the context of ME is crucial.
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International Journal of Cardiology, Hypertension. Volume 5, June 2020, 100032
Paradigm shift to disequilibrium in the genesis of orthostatic intolerance in patients with myalgic encephalomyelitis and chronic fatigue syndrome
Author links open overlay panel KunihisaMiwaa1YukichiInoueb1
https://doi.org/10.1016/j.ijchy.2020.100032Get rights and content
Highlights Most patients with chronic fatigue syndrome suffers from orthostatic intolerance (OI).
OI significantly restricts daily functional capacity.
Circulatory and autonomic nervous dysregulation is not the sole cause of OI.
Disequilibrium should be recognized as the important cause of OI.
Disequilibrium is more influential cause of OI than postural orthostatic tachycardia.
Abstract
Background
Orthostatic intolerance (OI) markedly impairs activities of daily living in patients with myalgic encephalomyelitis (ME) or chronic fatigue syndrome. OI is surmised to be a cardiovascular symptom correlated with cerebral hypo-perfusion and exaggerated sympathetic activation. Postural instability or disequilibrium may be part of the etiology of OI.
Methods The study comprised 72 patients with ME (18 men, 54 women; mean age, 37 ± 10 years) who underwent neurological examinations and the 10 min standing test. We quantified disequilibrium (instability upon standing with feet together and eyes shut), ability to complete the 10 min standing test, and postural orthostatic tachycardia (POT) during the test.
Results Disequilibrium was detected in 23/72 (32%) patients and POT in 16 (22%). Nineteen (26%) patients failed to complete the 10 min standing test; disequilibrium was significantly more common in the 19- patient subgroup than in the 53-patient test-completing subgroup (89% vs. 11%, p < 0.01). However, the rate of POT was not different between the groups (21% vs. 23%, p = 1.00). Compared with the 49 (68%) patients without disequilibrium, the 23 (32%) patients with disequilibrium were significantly more likely to have failed to complete the test (74% vs. 4%, p < 0.01). The rate of POT was comparable between the groups (23% vs. 22%, p = 1.00). Among patients with disequilibrium who failed to complete the 10 min standing test and had a previous record, 6/8 had completed the test 6–24 months earlier when all six had reported no disequilibrium.
Conclusion
Disequilibrium should be recognized as an important cause of OI in patients with ME.
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Journal of Experimental Neurology Commentary
https://www.scientificarchives.com/journal/journal-of-experimental-neurology Skeletal
Muscle Weakness Often Occurs in Patients with Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS)
Yves Jammes1,2, Frédérique Retornaz2*
1 C2VN UMR Inra Inserm, Faculty of Medicine, Aix-Marseille University, France 2 Department of Internal Medicine, European Hospital, Marseille, France fr
Received date: April 16, 2020, Accepted date: May 14, 2020 Copyright: © 2020 Jammes Y, et al.
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
This commentary considers the occurrence of skeletal muscle weakness in patients with myalgic encephalomyelitis / chronic fatigue syndrome (ME/ CFS), already reported by Jammes et al. in the last issue of Clinical Biomechanics [1]. These authors showed that numerous patients with severe body fatigue and clinical criteria of ME/CFS had reduced values of maximal handgrip strength in proportion of their lowered maximal performance at work measured on a cycloergometer. Here, we discuss these data in terms of pathophysiological mechanisms of muscle failure. Remember that ME/CFS is a multisystem disease characterized by an intense fatigue worsened by physical/ mental activity [2-4], often associated with postexertional malaise (PEM) [3,5]. Several body systems including the muscular and nervous systems are affected in ME/CFS. The symptoms combine fatigue, loss of memory and/or concentration, headaches, unrefreshing sleep, unexplained muscle or joint pain, sore throat and sometimes enlarged lymph nodes in neck or armpits [6]. ME/CFS pathogenesis appears to have a number of factors; different stressors (such as physical exertion, Highlights • Altered muscle function often occurs in ME/CFS patients. • Reduced handgrip strength is proportional to lowered physical performance • Muscle fatigue could result from altered muscle excitability at work • Reduced central motor command is also documented in relation of encephalomyelitis • Subgroups of ME/CFS patients without muscle weakness are documented Abstract This commentary complements data reported in Clinical Biomechanics [1] reporting reduced maximal handgrip strength in numerous patients with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) in proportion to their lowered maximal physical performances. The causes of muscle weakness in these patients are open to discussion. Literature data reveal a reduction of central command to skeletal muscles in some ME/CFS patients, related to encephalomyelitis. Altered muscle membrane excitability, that is “peripheral fatigue”, is also described in relation with an imbalance of the oxidant / anti-oxidant status. On the other hand, subgroups of chronically fatigued patients with clinical criteria of ME/CFS do not suffer from any muscle weakness. Thus, clinical data do not sufficiently clarify homogeneous ME/CFS pathology.
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Persistent Symptoms in Patients After Acute COVID-19 In Italy,
2020 American Medical Association JAMA Published online July 9, 2020
A large proportion of patients with coronavirus disease 2019 (COVID-19) presented with symptoms (71.4% of 31 845 confirmed cases as of June 3, 2020).1 Common symptoms include cough, fever, dyspnea, musculoskeletal symptoms (myalgia, joint pain, fatigue), gastrointestinal symptoms, and anosmia/dysgeusia.2-4 However, information is lacking on symptoms that persist after recovery. We assessed persistent symptoms in patients who were discharged from the hospital after recovery from COVID-19.
Methods | In the waning phase of the pandemic, beginning on April 21, 2020, the Fondazione Policlinico Universitario Agostino Gemelli IRCCS in Rome, Italy, established a postacute outpatient service for individuals discharged from the hospital after recovery from COVID-19. All patients who met World Health Organization criteria for discontinuation of quarantine (no fever for 3 consecutive days, improvement in other symptoms, and 2 negative test results for severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] 24 hours apart) were followed up. At enrollment in the study, real-time reverse transcriptase–polymerase chain reaction for SARS-CoV-2 was performed and patients with a negative test result were included. Patients were offered a comprehensive medical assessment with detailed history and physical examination. Data on all clinical characteristics, including clinical and pharmacological history, lifestyle factors, vaccination status, and body measurements, were collected in a structured electronic data collection system. The COVID-19 postacute outpatient service is currently active, and further details about the patient evaluation protocol are described elsewhere.5 In particular, data on specific symptoms potentially correlated with COVID-19 were obtained using a standardized questionnaire administered at enrollment. Patients were asked to retrospectively recount the presence or absence of symptoms during the acute phase of COVID-19 and whether each symptom persisted at the time of the visit. More than 1 symptom could be reported. The EuroQol visual analog scale was used to ask patients to score their quality of life from 0 (worst imaginable health) to 100 (best imaginable health) before COVID-19 and at the time of the visit. A difference of 10 points defined worsened quality of life. All analyses were performed using R version 3.6.3 (R Foundation).
This study was approved by the Università Cattolica and Fondazione Policlinico Gemelli IRCCS Institutional Ethics Committee. Written informed consent was obtained from all participants.
Results | From April 21 to May 29, 2020, 179 patients were potentially eligible for the follow-up post–acute care assessment; 14 individuals (8%) refused to participate and 22 had a positive test result. Thus, 143 patients were included. Themean age was 56.5 (SD, 14.6) years (range, 19-84 years), and 53 (37%) were women. During hospitalization, 72.7% of participants had evidence of interstitial pneumonia. The mean length of hospital stay was 13.5 (SD, 9.7) days; 21 patients (15%) received noninvasive ventilation and 7 patients (5%) received invasive ventilation. Patients were assessed a mean of 60.3 (SD, 13.6) days after onset of the first COVID-19 symptom; at the time of the evaluation, only 18 (12.6%) were completely free of any COVID19–related symptom, while 32% had 1 or 2 symptoms and 55% had 3 or more. None of the patients had fever or any signs or symptoms of acute illness. Worsened quality of life was observed among 44.1% of patients. A high proportion of individuals still reported fatigue (53.1%), dyspnea (43.4%), joint pain, (27.3%) and chest pain (21.7%).
Discussion This study found that in patients who had recovered from COVID-19, 87.4% reported persistence of at least 1 symptom, particularly fatigue and dyspnea. Limitations of the study include the lack of information on symptom history before acute COVID-19 illness and the lack of details on symptom severity. Furthermore, this is a single-center study with a relatively small number of patients and without a control group of patients discharged for other reasons. Patients with community-acquired pneumonia can also have persistent symptoms, suggesting that these findings may not be exclusive to COVID-19.6 Clinicians and researchers have focused on the acute phase of COVID-19, but continuedmonitoring after discharge for longlasting effects is needed.
Angelo Carfì, MD Roberto Bernabei, MD Francesco Landi, MD, PhD
Corresponding Author: Angelo Carfì, MD, Centro Medicina dell’Invecchiamento, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo Francesco Vito 1, 00168 Rome, Italy (angelo.carfi@ policlinicogemelli.it).
Accepted for Publication: June 23, 2020. Published Online: July 9, 2020. doi:10.1001/jama.2020.12603
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J Med Virol. 2020 Mar 4. doi: 10.1002/jmv.25744. Online ahead of print.
Cytomegalovirus, Epstein-Barr virus, and human herpesvirus-6 infections in patients with myalgic еncephalomyelitis/chronic fatigue syndrome
Evelina Shikova 1 2, Valentina Reshkova 3, Аntoniya Kumanova 1, Sevdalina Raleva 1, Dora Alexandrova 2, Natasa Capo 4 5, Modra Murovska 6, European Network on ME/CFS (EUROMENE)
- PMID: 32129496
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling multisystem chronic disease. The etiology and pathogenesis of ME/CFS are unknown. Infections of cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus-6 (HHV-6) are suspected as etiological agents for ME/CFS. This study aims to estimate prevalence and type (active/latent) of EBV, CMV, and HHV-6 infections in Bulgarian ME/CFS patients. In the study were included 58 patients with ME/CFS and 50 healthy controls. Virus-specific antibodies were detected by enzyme-linked immunosorbent assay and viral genomic sequences in peripheral blood mononuclear cell (PBMCs) and plasma samples by nested polymerase chain reaction (PCR). We did not observe any significant differences in virus-specific immunoglobulin G and immunoglobulin M positivity rates between patients with ME/CFS and control group. In ME/CFS plasma samples, EBV DNA was found in 24.1%, CMV DNA in 3.4%, and HHV-6 DNA in 1.7% of samples. EBV DNA was detected in 4%, and CMV and HHV-6 DNA were not found in plasma samples of controls. The frequency of viral genome detection in PBMCs of patients and controls was 74% vs 78% for CMV, 81% vs 84% for EBV, and 82.8% vs 82% for HHV-6. The difference in frequency of EBV active infection in ME/CFS and control group was statistically significant (P = .0027). No ME/CFS and control individuals with active CMV and HHV-6 infection were observed. In conclusion, this study using both serological and PCR-based techniques for distinguishing between active and latent infection showed high rate of active EBV infection among patients with ME/CFS indicating that at least in a subset of cases, EBV is important factor for the development of disease.
Keywords: CMV; EBV; ELISA; HHV-6 infection; PCR; active infection; myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
© 2020 The Authors. Journal of Medical Virology published by Wiley Periodicals, Inc.
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· Hypothesis · March 2020 ·
“Neither dying, nor recovering”:
Learning from Intensive Care Units to Solve Chronic Fatigue Syndrome (ME/CFS)
Dominic Stanculescu* Independent, Belgium
Introduction
Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a debilitating, multi-system disease of unclear etiology and without reliable treatments. Some researchers consider ME/CFS to be a maladaptive response to stressors (physical, infectious, or emotional) [1]. Similarly, the failure of a subset of intensive care unit (ICU) patients to begin recovery is also increasingly considered the result of maladaptive responses to the stress of severe injury or infection [2;3;4]. Irrespective of the initial critical illness, these “chronic” ICU patients experience severe ME/CFSlike symptoms that include profound muscular weakness, cognitive impairment, pain, and vulnerability to infection [5]. Here the hypothesis is advanced that maladaptive mechanisms that prevent recovery in some ICU patients also underlie ME/CFS. Specifically, these mechanisms are: (a) suppression of the pituitary gland’s pulsatile secretion of tropic hormones, and (b) "vicious cycles" between cytokines, oxidative and nitrosative stress (O&NS), and low thyroid hormone function.
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Adv Rheumatol 2020 Jun 29;60(1):34. doi: 10.1186/s42358-020-00135-7.
Repetitive transcranial magnetic stimulation of the prefrontal cortex for fibromyalgia syndrome: a randomised controlled trial with 6-months follow up
Suman Tanwar 1 2, Bhawna Mattoo 1, Uma Kumar 3, Renu Bhatia 4
PMID: 32600394
Abstract
Objectives: Fibromyalgia Syndrome (FMS), is a chronic pain disorder with poorly understood pathophysiology. In recent years, repetitive transcranial magnetic stimulation (rTMS) has been recommended for pain relief in various chronic pain disorders. The objective of the present research was to study the effect of low frequency rTMS over the right dorsolateral prefrontal cortex (DLPFC) on pain status in FMS.
Methods: Ninety diagnosed cases of FMS were randomized into Sham-rTMS and Real-rTMS groups. Real rTMS (1 Hz/1200 pulses/8 trains/90% resting motor threshold) was delivered over the right DLPFC for 5 consecutive days/week for 4 weeks. Pain was assessed by subjective and objective methods along with oxidative stress markers. Patients were followed up for 6 months (post-rTMS;15 days, 3 months and 6 months).
Results: In Real-rTMS group, average pain ratings and associated symptoms showed significant improvement post rTMS. The beneficial effects of rTMS lasted up to 6 months in the follow-up phase. In Sham-rTMS group, no significant change in pain ratings was observed.
Conclusion: Right DLPFC rTMS can significantly reduce pain and associated symptoms of FMS probably through targeting spinal pain circuits and top-down pain modulation .
Trial registration: Ref No: CTRI/2013/12/004228.
Keywords: Chronic pain; Dorsolateral prefrontal cortex; Neuromodulation; Nociceptive flexion reflex; Non-invasive therapy; Oxidative stress.
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May 26, 2020; 94 (21) ARTICLE - Neurology
Effect of yoga as add-on therapy in migraine (CONTAIN)
A randomized clinical trial
View ORCID ProfileAnand Kumar, Rohit Bhatia, Gautam Sharma, Dhanlika Dhanlika, Sreenivas Vishnubhatla, Rajesh Kumar Singh, Deepa Dash, Manjari Tripathi, M.V. Padma Srivastava
First published May 6, 2020, DOI: https://doi.org/10.1212/WNL.0000000000009473
Abstract
Objective To evaluate the effectiveness of yoga as an adjuvant to conventional medical management on clinical outcomes in patients with migraine.
Methods CONTAIN was a prospective, randomized, open-label superiority trial with blinded endpoint assessment carried out at a single tertiary care academic hospital in New Delhi, India. Patients enrolled were aged 18–50 years with a diagnosis of episodic migraine and were randomized into medical and yoga groups (1:1). Randomization was computer-generated with a variable block size and concealed. A predesigned yoga intervention was given for 3 months. Outcomes were recorded by a blinded assessor. The primary endpoint was a decrease in headache frequency, headache intensity, and Headache Impact Test (HIT)–6 score. Secondary outcomes included change in Migraine Disability Assessment (MIDAS) score, pill count, and proportion of headache free patients.
Results Between April 2017 and August 2018, 160 patients with episodic migraine were randomly assigned to medical and yoga groups. A total of 114 patients completed the trial. Baseline measures were comparable except for a higher mean headache frequency in the yoga group. Compared to medical therapy, the yoga group showed a significant mean delta value reduction in headache frequency (delta difference 3.53 [95% confidence interval 2.52–4.54]; p < 0.0001), headache intensity (1.31 [0.60–2.01]; p = 0.0004), HIT score (8.0 [4.78–11.22]; p < 0.0001), MIDAS score (7.85 [4.98–10.97]; p < 0.0001), and pill count (2.28 [1.06–3.51]; p < 0.0003).
Conclusion Yoga as an add-on therapy in migraine is superior to medical therapy alone. It may be useful to integrate a cost-effective and safe intervention like yoga into the management of migraine.
Clinicaltrials.gov identifier CTRI/2017/03/008041.
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NICE advises against using graded exercise therapy for patients recovering from covid-19
BMJ 2020; 370 doi: https://doi.org/10.1136/bmj.m2912 (Published 21 July 2020)Cite this as: BMJ 2020;370:m2912
- Ingrid Torjesen
In a statement NICE said that it was aware of concerns related to the impact of graded exercise therapy (GET) for managing post-viral fatigue in patients recovering from covid-19. It noted that its current advice on managing chronic fatigue may not be appropriate for this group of patients and acknowledged that it could also be out of date for other groups.1
“NICE’s guideline on ME/CFS [chronic fatigue syndrome] (CG53) was published in 2007,2 many years before the current pandemic, and it should not be assumed that the recommendations apply to people with fatigue following covid-19,” the statement said.
It emphasised that the recommendations on GET in this guideline applied only to patients with a diagnosis of chronic fatigue syndrome as part of specialist care, where it should be part of an individualised, person centred programme of care, where GET is recommended only for people with mild to moderate symptoms.
NICE added, “As the guideline is currently being updated, it is possible that these recommendations may change. The evidence for and against graded exercise therapy is one of the important issues the guideline committee is considering.”
NICE plans to consult on its updated guidance in November 2020. In the interim it advises doctors to use recent guidance from NHS England on the aftercare needs of inpatients recovering from covid-19, which includes advice on managing fatigue.3 That guidance says that “it is important to ensure a gradual return to activities and exercise and to teach pacing methods.”
Much of the support for GET comes from a study published in the Lancet in 2011, which concluded that patients with chronic fatigue syndrome benefited more from cognitive behavioural therapy and GET than from pacing therapy.4 Many patients reported that GET made them feel worse and that pacing was more effective,5 and the study’s methodology was heavily criticised.6 A review conducted by the Health Research Authority concluded that the study was properly conducted,7 but the review focused on the research process, not the conclusions.
Post-exertional malaise
The large number of patients experiencing post-viral fatigue after covid-19 has now shone a spotlight on the controversial technique again.
Among this number is Paul Garner, professor of infectious disease at the Liverpool School of Tropical Medicine and director of the Centre for Evidence Synthesis in Global Health. Early in his recovery Garner realised that he was experiencing post-exertional malaise, as every time he did any exercise that increased his heart rate, such as cycling or yoga, he found himself back in bed.89
Garner, who is coordinating editor of the Cochrane Infectious Diseases Group and one of the founders of the Cochrane Collaboration, said that he was “furious” when he read the 2007 NICE advice and the conclusions of the Cochrane review, which also support exercise therapy and mention uncertainty about the side effects of adaptive pacing.10
“Obviously, I know that if I increase my exercise I will be thrown back to bed,” he said. “What I struggle with as a highly driven medic is stopping myself overdoing it. That’s what I need help with—I don’t need help to increase my exercise.”
Garner researched and started using pacing, finding the approach helpful. However, he emphasised that the technique was complex and that there was very little information in the medical literature. “GPs need some really practical guidance on how they rehabilitate these patients. People are having to search out techniques or generate them themselves,” he said.
He added that, while some charities and health authorities had put out guidance, it was “difficult to negotiate” and that a centralised approach coordinated by NICE or the Royal College of General Practitioners, involving medical professionals and patients, was needed quickly.
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Proc Natl Acad Sci U S A . 2020 Jun 9;117(23):13044-13055.
doi: 10.1073/pnas.2000625117. Epub 2020 May 20.
Epstein-Barr virus co-opts TFIIH component XPB to specifically activate essential viral lytic promoters
Dinesh Verma 1, Trenton Mel Church 1, Sankar Swaminathan 2 3
- PMID: 32434920 PMCID: PMC7293708 (available on 2020-11-20) DOI: 10.1073/pnas.2000625117
Epstein-Barr virus (EBV) is associated with epithelial and lymphoid malignancies, establishes latent infection in memory B cells, and intermittently produces infectious virions through lytic replication. Released virions play a key role in latent reservoir maintenance and transmission. Lytic EBV transcription differs from cellular transcription in requiring a virus-encoded preinitiation complex that binds to TATT motifs unique to EBV late lytic promoters. Expression of 15 late lytic genes that are important for virion production and infectivity is particularly dependent on the EBV SM protein, a nuclear protein expressed early during lytic reactivation that binds to viral RNAs and enhances RNA stability. We recently discovered that spironolactone blocks EBV virion production by inhibiting EBV SM function. Since spironolactone causes degradation of xeroderma pigmentosum group B-complementing protein (XPB), a component of human transcription factor TFIIH, in both B lymphocytes and epithelial cells, we hypothesized that SM utilizes XPB to specifically activate transcription of SM target promoters. While EBV SM has been thought to act posttranscriptionally, we provide evidence that SM also facilitates EBV gene transcription. We demonstrate that SM binds and recruits XPB to EBV promoters during lytic replication. Depletion of XPB protein, by spironolactone treatment or by siRNA transfection, inhibits SM-dependent late lytic gene transcription but not transcription of other EBV genes or cellular genes. These data indicate that SM acts as a transcriptional activator that has co-opted XPB to specifically target 15 EBV promoters that have uniquely evolved to require XPB for activity, providing an additional mechanism to differentially regulate EBV gene expression.
Keywords: Epstein–Barr virus; XPB; herpesvirus; transcription.
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Proc Natl Acad Sci U S A. 2016 Mar 29;113(13):3609-14. doi: 10.1073/pnas.1523686113. Epub 2016 Mar 14.
Spironolactone blocks Epstein-Barr virus production by inhibiting EBV SM protein function
Dinesh Verma 1, Jacob Thompson 1, Sankar Swaminathan 2
- PMID: 26976570 PMCID: PMC4822607 DOI: 10.1073/pnas.1523686113
Clinically available drugs active against Epstein-Barr virus (EBV) and other human herpesviruses are limited to those targeting viral DNA replication. To identify compounds directed against other steps in the viral life cycle, we searched for drugs active against the EBV SM protein, which is essential for infectious virus production. SM has a highly gene-specific mode of action and preferentially enhances expression of several late lytic cycle EBV genes. Here we demonstrate that spironolactone, a mineralocorticoid receptor antagonist approved for clinical use, inhibits SM function and infectious EBV production. Expression of EBV viral capsid antigen is highly SM dependent, and spironolactone inhibits viral capsid antigen synthesis and capsid formation, blocking EBV virion production at a step subsequent to viral DNA replication. In addition, spironolactone inhibits expression of other SM-dependent genes necessary for infectious virion formation. We further demonstrate that molecules structurally related to spironolactone with similar antimineralocorticoid blocking activity do not inhibit EBV production. These findings pave the way for development of antiherpesvirus drugs with new mechanisms of action directed against SM and homologous essential proteins in other herpesviruses.
Keywords: Epstein–Barr virus; antiviral; herpesvirus; posttranscriptional regulation; spironolactone.
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Persistent Symptoms in Patients After Acute COVID-19
Angelo Carfì, MD1; Roberto Bernabei, MD1; Francesco Landi, MD, PhD1; et alfor the Gemelli Against COVID-19 Post-Acute Care Study Group
JAMA. Published online July 9, 2020. doi:10.1001/jama.2020.12603
In Italy, a large proportion of patients with coronavirus disease 2019 (COVID-19) presented with symptoms (71.4% of 31 845 confirmed cases as of June 3, 2020).1 Common symptoms include cough, fever, dyspnea, musculoskeletal symptoms (myalgia, joint pain, fatigue), gastrointestinal symptoms, and anosmia/dysgeusia.2-4 However, information is lacking on symptoms that persist after recovery. We assessed persistent symptoms in patients who were discharged from the hospital after recovery from COVID-19.
Methods
In the waning phase of the pandemic, beginning on April 21, 2020, the Fondazione Policlinico Universitario Agostino Gemelli IRCCS in Rome, Italy, established a postacute outpatient service for individuals discharged from the hospital after recovery from COVID-19. All patients who met World Health Organization criteria for discontinuation of quarantine (no fever for 3 consecutive days, improvement in other symptoms, and 2 negative test results for severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] 24 hours apart) were followed up. At enrollment in the study, real-time reverse transcriptase–polymerase chain reaction for SARS-CoV-2 was performed and patients with a negative test result were included.
Patients were offered a comprehensive medical assessment with detailed history and physical examination. Data on all clinical characteristics, including clinical and pharmacological history, lifestyle factors, vaccination status, and body measurements, were collected in a structured electronic data collection system. The COVID-19 postacute outpatient service is currently active, and further details about the patient evaluation protocol are described elsewhere.5
In particular, data on specific symptoms potentially correlated with COVID-19 were obtained using a standardized questionnaire administered at enrollment. Patients were asked to retrospectively recount the presence or absence of symptoms during the acute phase of COVID-19 and whether each symptom persisted at the time of the visit. More than 1 symptom could be reported. The EuroQol visual analog scale was used to ask patients to score their quality of life from 0 (worst imaginable health) to 100 (best imaginable health) before COVID-19 and at the time of the visit. A difference of 10 points defined worsened quality of life. All analyses were performed using R version 3.6.3 (R Foundation).
This study was approved by the Università Cattolica and Fondazione Policlinico Gemelli IRCCS Institutional Ethics Committee. Written informed consent was obtained from all participants.
Results
From April 21 to May 29, 2020, 179 patients were potentially eligible for the follow-up post–acute care assessment; 14 individuals (8%) refused to participate and 22 had a positive test result. Thus, 143 patients were included. The mean age was 56.5 (SD, 14.6) years (range, 19-84 years), and 53 (37%) were women. During hospitalization, 72.7% of participants had evidence of interstitial pneumonia. The mean length of hospital stay was 13.5 (SD, 9.7) days; 21 patients (15%) received noninvasive ventilation and 7 patients (5%) received invasive ventilation. The characteristics of the study population are summarized in the Table.
Patients were assessed a mean of 60.3 (SD, 13.6) days after onset of the first COVID-19 symptom; at the time of the evaluation, only 18 (12.6%) were completely free of any COVID-19–related symptom, while 32% had 1 or 2 symptoms and 55% had 3 or more. None of the patients had fever or any signs or symptoms of acute illness. Worsened quality of life was observed among 44.1% of patients. The Figure shows that a high proportion of individuals still reported fatigue (53.1%), dyspnea (43.4%), joint pain, (27.3%) and chest pain (21.7%).
Discussion
This study found that in patients who had recovered from COVID-19, 87.4% reported persistence of at least 1 symptom, particularly fatigue and dyspnea. Limitations of the study include the lack of information on symptom history before acute COVID-19 illness and the lack of details on symptom severity. Furthermore, this is a single-center study with a relatively small number of patients and without a control group of patients discharged for other reasons. Patients with community-acquired pneumonia can also have persistent symptoms, suggesting that these findings may not be exclusive to COVID-19.6
Clinicians and researchers have focused on the acute phase of COVID-19, but continued monitoring after discharge for long-lasting effects is needed.
Section Editor: Jody W. Zylke, MD, Deputy Editor.
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Cerebral Blood Flow Is Reduced in Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients During Mild Orthostatic Stress Testing: An Exploratory Study at 20 Degrees of Head-Up Tilt Testing
by C (Linda) M.C. van Campen 1,*,Peter C. Rowe 2 andFrans C. Visser 1
Stichting CardioZorg, 2132 HN Hoofddorp, The Netherlands
Department of Paediatrics, John Hopkins University School of Medicine, Baltimore, MD 21205, USA
Healthcare 2020, 8(2), 169; https://doi.org/10.3390/healthcare8020169
Received: 5 May 2020 / Revised: 1 June 2020 / Accepted: 10 June 2020 / Published: 13 June 2020
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Abstract
Introduction: In a study of 429 adults with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), we demonstrated that 86% had symptoms of orthostatic intolerance in daily life. Using extracranial Doppler measurements of the internal carotid and vertebral arteries during a 30-min head-up tilt to 70 degrees, 90% had an abnormal reduction in cerebral blood flow (CBF). A standard head-up tilt test of this duration might not be tolerated by the most severely affected bed-ridden ME/CFS patients. This study examined whether a shorter 15-min test at a lower 20 degree tilt angle would be sufficient to provoke reductions in cerebral blood flow in severe ME/CFS patients. Methods and results: Nineteen severe ME/CFS patients with orthostatic intolerance complaints in daily life were studied: 18 females. The mean (SD) age was 35(14) years, body surface area (BSA) was 1.8(0.2) m2 and BMI was 24.0(5.4) kg/m2. The median disease duration was 14 (IQR 5–18) years. Heart rate increased, and stroke volume index and end-tidal CO2 decreased significantly during the test (p ranging from <0.001 to <0.0001). The cardiac index decreased by 26(7)%: p < 0.0001. CBF decreased from 617(72) to 452(63) mL/min, a 27(5)% decline. All 19 severely affected ME/CFS patients met the criteria for an abnormal CBF reduction. Conclusions: Using a less demanding 20 degree tilt test for 15 min in severe ME/CFS patients resulted in a mean CBF decline of 27%. This is comparable to the mean 26% decline previously noted in less severely affected patients studied during a 30-min 70 degree head-up tilt. These observations have implications for the evaluation and treatment of severely affected individuals with ME/CFS. View Full-Text
Keywords: orthostatic intolerance; cerebral blood flow; 20 degree tilt table testing; myalgic encephalomyelitis; chronic fatigue syndrome; postural orthostatic tachycardia syndrome; stroke volume index; cardiac index
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Health Care Responsibility and Compassion-Visiting the Housebound Patient Severely Affected by ME/CFS
by Caroline Kingdon *,Dionysius Giotas,Luis Nacul andEliana Lacerda
Department of Clinical Research, London School of Hygiene & Tropical Medicine, Faculty of Infectious and Tropical Diseases, London WC1E 7HT, UK
Healthcare 2020, 8(3), 197; https://doi.org/10.3390/healthcare8030197
Received: 9 June 2020 / Revised: 1 July 2020 / Accepted: 2 July 2020 / Published: 4 July 2020
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Abstract
Many people with severe Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) commonly receive no care from healthcare professionals, while some have become distanced from all statutory medical services. Paradoxically, it is often the most seriously ill and needy who are the most neglected by those responsible for their healthcare. Reasons for this include tensions around the complexity of making an accurate diagnosis in the absence of a biomarker, the bitter debate about the effectiveness of the few available treatments, and the very real stigma associated with the diagnosis. Illness severity often precludes attendance at healthcare facilities, and if an individual is well enough to be able to attend an appointment, the presentation will not be typical; by definition, patients who are severely affected are home-bound and often confined to bed. We argue that a holistic model, such as ‘‘Compassion in Practice’’, can help with planning appointments and caring for people severely affected by ME/CFS. We show how this can be used to frame meaningful interactions between the healthcare practitioners (HCPs) and the homebound patient.
Keywords: ME/CFS; severe ME/CFS; validation; engagement; health encounters; housebound; bedbound
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Two-Day Cardiopulmonary Exercise Testing in Females with a Severe Grade of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Comparison with Patients with Mild and Moderate Disease
by C (Linda) M. C. van Campen 1,*,Peter C. Rowe 2
Healthcare 2020, 8(3), 192; https://doi.org/10.3390/healthcare8030192
Received: 28 April 2020 / Revised: 17 June 2020 / Accepted: 25 June 2020 / Published: 30 June 2020
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Abstract
Introduction: Effort intolerance along with a prolonged recovery from exercise and post-exertional exacerbation of symptoms are characteristic features of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The gold standard to measure the degree of physical activity intolerance is cardiopulmonary exercise testing (CPET). Multiple studies have shown that peak oxygen consumption is reduced in the majority of ME/CFS patients, and that a 2-day CPET protocol further discriminates between ME/CFS patients and sedentary controls. Limited information is present on ME/CFS patients with a severe form of the disease. Therefore, the aim of this study was to compare the effects of a 2-day CPET protocol in female ME/CFS patients with a severe grade of the disease to mildly and moderately affected ME/CFS patients. Methods and results: We studied 82 female patients who had undergone a 2-day CPET protocol. Measures of oxygen consumption (VO2), heart rate (HR) and workload both at peak exercise and at the ventilatory threshold (VT) were collected. ME/CFS disease severity was graded according to the International Consensus Criteria. Thirty-one patients were clinically graded as having mild disease, 31 with moderate and 20 with severe disease. Baseline characteristics did not differ between the 3 groups. Within each severity group, all analyzed CPET parameters (peak VO2, VO2 at VT, peak workload and the workload at VT) decreased significantly from day-1 to day-2 (p-Value between 0.003 and <0.0001). The magnitude of the change in CPET parameters from day-1 to day-2 was similar between mild, moderate, and severe groups, except for the difference in peak workload between mild and severe patients (p = 0.019). The peak workload decreases from day-1 to day-2 was largest in the severe ME/CFS group (−19 (11) %). Conclusion: This relatively large 2-day CPET protocol study confirms previous findings of the reduction of various exercise variables in ME/CFS patients on day-2 testing. This is the first study to demonstrate that disease severity negatively influences exercise capacity in female ME/CFS patients. Finally, this study shows that the deterioration in peak workload from day-1 to day-2 is largest in the severe ME/CFS patient group. View Full-Text
Keywords: chronic fatigue syndrome; cardiopulmonary exercise testing; oxygen consumption; VO2 peak; ventilatory threshold; VO2 VT; myalgic encephalitis; workload; ME/CFS severity grade
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Risk factors for suicide in chronic fatigue syndrome
Madeline L. Johnson,Joseph Cotler,Julia M. Terman &Leonard A. Jason
Published online: 12 Jun 2020 – Journal of Death Studies
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) includes symptoms such as post-exertional malaise, unrefreshing sleep, and cognitive impairments. Several studies suggest these patients have an increased risk of suicidal ideation and early mortality, although few have published in this area. This study explores risk factors for suicide among 64 individuals with ME/CFS using archival data, 17 of which died from suicide. Results indicated an increased risk of suicide for those for those utilizing the label CFS, for those with limited overall functioning, and for those without comorbid illnesses. Findings suggest that stigma and functional impairments limit access to care and social supports.
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Pain. 2020 Jul 10. doi: 10.1097/j.pain.0000000000001996. Online ahead of print.
A genetic polymorphism that is associated with mitochondrial energy metabolism increases risk of fibromyalgia
Miranda Al van Tilburg 1 2 3, Marc Parisien 4, Richard G Boles 5, Gillian L Drury 4, Julian Smith-Voudouris 4, Vivek Verma 4, Samar Khoury 4, Anne-Julie Chabot-Doré 4, Andrea G Nackley 6 7, Shad B Smith 6, William E Whitehead 8, Denniz A Zolnoun 9, Gary D Slade 10 11 12, Inna Tchivileva 10, William Maixner 6, Luda Diatchenko 4
- PMID: 32658146
Abstract
Alterations in cellular energy metabolism have been implicated in chronic pain suggesting a role for mitochondrial DNA (mtDNA). Previous studies reported associations of a limited number of mtDNA polymorphisms with specific pain conditions. In this study, we examined the full mitochondrial genomes of people with a variety of chronic pain conditions. A discovery cohort consisting of 609 participants either with or without a complex persistent pain conditions (CPPC) was examined. mtDNA was subjected to deep sequencing for identification of rare mutations, common variants, haplogroups, and heteroplasmy associated with five CPPCs: episodic migraine, irritable bowel syndrome, fibromyalgia, vulvar vestibulitis, or temporomandibular disorders. The strongest association found was the presence of the C allele at the single nucleotide polymorphism (SNP) m.2352T>C (rs28358579) that significantly increased the risk for fibromyalgia (OR=4.6, P=4.3x10). This relationship was even stronger in women (OR=5.1, P=2.8x10), and m.2352T>C was associated with all other CPPCs in a consistent risk-increasing fashion. This finding was replicated in another cohort (OR=4.3, P=2.6x10) of the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study consisting of 1754 female participants. To gain insight into the cellular consequences of the associated genetic variability, we conducted an assay testing metabolic reprogramming in human cell lines with defined genotypes. The minor allele C was associated with decreased mitochondrial membrane potential under conditions where oxidative phosphorylation is required, indicating a role of oxidative phosphorylation in pathophysiology of chronic pain. Our results suggest that cellular energy metabolism, modulated by m.2352T>C, contributes to fibromyalgia and possibly other chronic pain conditions.
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Autoantibodies to beta-adrenergic and muscarinic cholinergic receptors in Myalgic Encephalomyelitis (ME) patients – A validation study in plasma and cerebrospinal fluid from two Swedish cohorts
Brain, Behaviour and Immunity Volume 7, August 2020, 10010
AnnieBynkeabPerJulincdCarl-GerhardGottfrieseHaraldHeideckefCarmenScheibenbogengJonasBergquistab
https://doi.org/10.1016/j.bbih.2020.100107Get rights and content
Highlights
Myalgic Encephalomyelitis (ME) is a devastating disorder (with millions of patients worldwide) with unclear aetiology and no clear diagnostic biomarker available.
This study support the existance of a general pattern of increased antibody levels to adrenergic and muscarinic receptors within the ME patient group.
No evidence for intrathecal antibody production was found in cerebrospinal fluid. The role of increased autoantibodies in the pathogenesis of ME is still uncertain and further research is needed to evaluate their clinical significance.
Abstract
Myalgic encephalomyelitis (ME) also known as ME/CFS (Chronic Fatigue Syndrome) or ME/SEID (Systemic Exertion Intolerance Disorder), is a disabling and often long-lasting disease that can drastically impair quality of life and physical/social functioning of the patients. Underlying pathological mechanisms are to a large extent unknown, but the presence of autoantibodies, cytokine pattern deviations and the presentation of cognitive and autonomic nervous system related symptoms provide evidence for ME being an immunological disorder with elements of autoimmunity. Increased levels of autoantibodies binding to adrenergic and muscarinic receptors in ME-patients have been reported. It is hypothesized that these autoantibodies have pathological significance and contribute to the ME-specific symptoms, however, these observations need to be validated.
This study was designed to investigate potential differences in adrenergic and muscarinic receptor autoantibody levels in plasma and cerebrospinal fluid (CSF) samples between ME patients and gender and age-matched healthy controls, and to correlate the autoantibody levels to disease severity.
We collected bodyfluids and health-related questionnaires from two Swedish ME cohorts, plasma and CSF from one of the cohorts (n = 24), only plasma from the second cohort (n = 24) together with plasma samples (n = 24) and CSF (n = 6) from healthy controls.
All samples were analysed for IgG autoantibodies directed against Alpha- (α1, α2) and Beta- (β1-3) adrenergic receptors and Muscarinic (M) 1–5 acetylcholine receptors using an ELISA technique. The questionnaires were used as measures of disease severity.
Significant increases in autoantibody levels in ME patients compared to controls were found for M3 and M4 -receptors in both cohorts and β1, β2, M3 and M4-receptors in one cohort. No significant correlations were found between autoantibody levels and disease severity. No significant levels of autoantibodies were detected in the CSF samples. These findings support previous findings that there exists a general pattern of increased antibody levels to adrenergic and muscarinic receptors within the ME patient group. However, the role of increased adrenergic and muscarinic receptor autoantibodies in the pathogenesis of ME is still uncertain and further research is needed to evaluate the clinical significance of these findings.
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Front. Public Health, 21 August 2020 | https://doi.org/10.3389/fpubh.2020.00420
The Economic Impacts of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in an Australian Cohort
Shara Close1, Sonya Marshall-Gradisnik2*, Joshua Byrnes3, Peter Smith2, Son Nghiem3 and Don Staines2
- 1Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia
- 2National Centre for Neuroimmunology and Emerging Diseases, Griffith University, Gold Coast, QLD, Australia
- 3Centre for Applied Health Economics, Griffith University, Nathan, QLD, Australia
Design: A cost of illness study was conducted to estimate Australian cost data for individuals with a ME/CFS diagnosis as determined by the Canadian Consensus Criteria (CCC), International Consensus Criteria (ICC), and the 1994 CDC Criteria (Fukuda).
Setting and participants: Survey participants identified from a research registry database provided self-report of expenditure associated with ME/CFS related healthcare across a 1-month timeframe between 2017 and 2019.
Main outcome measures: ME/CFS related direct annual government health care costs, OOP health expenditure costs, indirect costs associated with lost income and health care service use patterns.
Results: The mean annual cost of health care related expenditure and associated income loss among survey participants meeting diagnostic criteria for ME/CFS was estimated at $14.5 billion. For direct OOP and Government health care expenditure, high average costs were related to medical practitioner attendance, diagnostics, natural medicines, and device expenditure, with an average attendance of 10.6 referred attendances per annum and 12.1 GP visits per annum related specifically to managing ME/CFS.
Conclusions: The economic impacts of ME/CFS in Australia are significant. Improved understanding of the illness pathology, diagnosis, and management, may reduce costs, improve patient prognosis and decrease the burden of ME/CFS in Australia.
Clin neurophysiological Prac. 2020; 5: 50–58.
Published online 2020 Feb 8. doi: 10.1016/j.cnp.2020.01.003 PMCID: PMC7044650 PMID: 32140630
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Cerebral blood flow is reduced in ME/CFS during head-up tilt testing even in the absence of hypotension or tachycardia: A quantitative, controlled study using Doppler echography
C. (Linda) M.C. van Campen,a,⁎ Freek W.A. Verheugt,b Peter C. Rowe,c and Frans C. Vissera
Abstract
Objective
The underlying hypothesis in orthostatic intolerance (OI) syndromes is that symptoms are associated with cerebral blood flow (CBF) reduction. Indirect CBF measurements (transcranial Doppler flow velocities), provide inconsistent support of this hypothesis. The aim of the study was to measure CBF during a 30 min head-up tilt test (HUT), using Doppler flow imaging of carotid and vertebral arteries, in individuals with chronic fatigue syndrome/myalgic encephalomyelitis (ME/CFS), a condition with a high prevalence of OI.
Methods
429 ME/CFS patients were studied: 247 had a normal heart rate (HR) and blood pressure (BP) response to HUT, 62 had delayed orthostatic hypotension (dOH), and 120 had postural orthostatic tachycardia syndrome (POTS). We also studied 44 healthy controls (HC). CBF measurements were made at mid-tilt and end-tilt. Before mid-tilt, we administered a verbal questionnaire to ascertain for 15 OI symptoms.
Results
End-tilt CBF reduction was 7% in HC versus 26% in the overall ME/CFS group, 24% in patients with a normal HR/BP response, 28% in those with dOH, and 29% in POTS patients (all P < .0005). Using a lower limit of normal of 2SD of CBF reduction in HC (13% reduction), 82% of patients with normal HR/BP response, 98% with dOH and 100% with POTS showed an abnormal CBF reduction. There was a linear correlation of summed OI symptoms with the degree of CBF reduction at mid-tilt (P < .0005).
Conclusions
During HUT, extracranial Doppler measurements demonstrate that CBF is reduced in ME/CFS patients with POTS, dOH, and even in those without HR/BP abnormalities.
Significance
This study shows that orthostatic intolerance symptoms are related to CBF reduction, and that the majority of ME/CFS patients (90%) show an abnormal cerebral flow reduction during orthostatic stress testing. This may have implications for the diagnosis and treatment of ME/CFS patients.
Transl Med. 2020 Aug 15;18(1):314. doi: 10.1186/s12967-020-02481-y.
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Hemodynamics during the 10-minute NASA Lean Test: evidence of circulatory decompensation in a subset of ME/CFS patients
Jihyun Lee 1, Suzanne D Vernon 2, Patricia Jeys 1, Weam Ali 1, Andrea Campos 1, Derya Unutmaz 3, Brayden Yellman 1, Lucinda Bateman 1
- PMID: 32799889 PMCID: PMC7429890 DOI: 10.1186/s12967-020-02481-y
Background: Lightheadedness, fatigue, weakness, heart palpitations, cognitive dysfunction, muscle pain, and exercise intolerance are some of the symptoms of orthostatic intolerance (OI). There is substantial comorbidity of OI in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome). The 10-minute NASA Lean Test (NLT) is a simple, point-of-care method that can aid ME/CFS diagnosis and guide management and treatment of OI. The objective of this study was to understand the hemodynamic changes that occur in ME/CFS patients during the 10-minute NLT.
Methods: A total of 150 ME/CFS patients and 75 age, gender and race matched healthy controls (HCs) were enrolled. We recruited 75 ME/CFS patients who had been sick for less than 4 years (< 4 ME/CFS) and 75 ME/CFS patients sick for more than 10 years (> 10 ME/CFS). The 10-minute NLT involves measurement of blood pressure and heart rate while resting supine and every minute for 10 min while standing with shoulder-blades on the wall for a relaxed stance. Spontaneously reported symptoms are recorded during the test. ANOVA and regression analysis were used to test for differences and relationships in hemodynamics, symptoms and upright activity between groups.
Results: At least 5 min of the 10-minute NLT were required to detect hemodynamic changes. The < 4 ME/CFS group had significantly higher heart rate and abnormally narrowed pulse pressure compared to > 10 ME/CFS and HCs. The < 4 ME/CFS group experienced significantly more OI symptoms compared to > 10 ME/CFS and HCs. The circulatory decompensation observed in the < 4 ME/CFS group was not related to age or medication use.
Conclusions: Circulatory decompensation characterized by increased heart rate and abnormally narrow pulse pressure was identified in a subgroup of ME/CFS patients who have been sick for < 4 years. This suggests inadequate ventricular filling from low venous pressure. The 10-minute NLT can be used to diagnose and treat the circulatory decompensation in this newly recognized subgroup of ME/CFS patients. The > 10 ME/CFS group had less pronounced hemodynamic changes during the NLT possibly from adaptation and compensation that occurs over time. The 10-minute NLT is a simple and clinically useful point-of-care method that can be used for early diagnosis of ME/CFS and help guide OI treatment.
Keywords: 10-minute NASA lean test; Circulatory decompensation; ME/CFS; Orthostatic intolerance; Point-of-care.
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Long covid”: the Dutch response
BMJ 2020; 370 doi: https://doi.org/10.1136/bmj.m3202 (Published 14 August 2020)Cite this as: BMJ 2020;370:m3202
- Jako Burgers, general practitioner
- [email protected]
We have undertaken a series of actions to tackle this problem.
Firstly, we have developed rapid guidance to support clinicians in primary and secondary care in decision making about diagnosis and treatment. Because of a lack of evidence, most recommendations are based on expert opinion.
Secondly, the Dutch government has decided to reimburse physiotherapy, exercise therapy, ergotherapy, and dietetics in primary care to a maximum of six months. The results of individual treatment will be monitored and evaluated systematically.
Thirdly, research has started on follow-up of patients with covid-19 funded by the Netherlands Organisation for Health Research and Development. One of the research aims is to identify predictors of chronicity.
We hope that more evidence will soon become available on the large group of patients with covid-19 that have not been admitted to hospital. This will help to develop evidence based guidelines and to contribute to effective management of patients with persistent symptoms.
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Covid-19 and chronic fatigue
BMJ 2020; 370 doi: https://doi.org/10.1136/bmj.m2922 (Published 30 July 2020)Cite this as: BMJ 2020;370:m2922
- Article Frances M K Williams, professor of genomic epidemiology and honorary consultant rheumatologist1,
- Nina Muirhead, dermatology surgeon2,
- Carmine Pariante, professor of biological psychiatry3
- [email protected]
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DR Clin Trans Res. 2020 Jul;5(3):224-232. doi: 10.1177/2380084419872135. Epub 2019 Aug 28.
Brain Responses in CFS and TMD to Autonomic Challenges: An Exploratory fMRI Study
Q C Vuong 1, J R Allison 2, A Finkelmeyer 1, J Newton 3 4, J Durham 2 5 6 PMID: 31461628
Abstract
Introduction: Dysfunction of the autonomic nervous system (ANS) is seen in chronic fatigue syndrome (CFS) and temporomandibular disorders (TMDs). Both conditions have poorly understood pathophysiology. Several brain structures that play a role in pain and fatigue, such as the insular cortex and basal ganglia, are also implicated in autonomic function.
Objectives: ANS dysfunction may point to common neurophysiologic mechanisms underlying the predominant symptoms for CFS and TMD. No studies to date have investigated the combination of both conditions. Thus, our aim was to test whether patients with CFS with or without TMD show differences in brain responses to autonomic challenges.
Methods: In this exploratory functional imaging study, patients with CFS who screened positive for TMD (n = 26), patients who screened negative for TMD (n = 16), and age-matched control participants (n = 10) performed the Valsalva maneuver while in a 3-T magnetic resonance imaging scanner. This maneuver is known to activate the ANS.
Results: For all 3 groups, whole-brain F test showed increased brain activation during the maneuver in the superior and inferior frontal gyri, the left and right putamen and thalamus, and the insular cortex. Furthermore, group contrasts with small-volume correction showed that patients with CFS who screened positive for TMD showed greater activity in the left insular cortex as compared with patients who screened negative and in the left caudate nucleus as compared with controls.
Conclusion: Our results suggest that increased activity in the cortical and subcortical regions observed during autonomic challenges may be modulated by fatigue and pain. ANS dysfunction may be a contributing factor to these findings, and further work is required to tease apart the complex relationship among CFS, TMD, and autonomic functions.
Knowledge transfer statement: Brain activity related to activation of the autonomic nervous system in patients with chronic fatigue syndrome who screened positive for painful temporomandibular disorder was greater than in patients who screened negative; activity was seen in brain regions associated with autonomic functions and pain. These findings suggest that autonomic dysfunction may play a role in the pathophysiology of both conditions, explain some of the apparent comorbidity between them, and offer avenues to help with treatment.
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Living with covid-19
Fiona Godlee, The BMJ Aug 2020
“Death is not the only adverse outcome of covid-19,” writes Nisreen Alwan, an epidemiologist who is experiencing a range of prolonged, fluctuating, and debilitating symptoms several months after her initial mild illness.1 Like a growing number of people around the world, she has what is being called post-acute or long covid.
While most people recover quickly and completely from the virus, stories of persistent and troubling symptoms have now moved from anecdote to the evidence of crowd sourced cohorts. Reports suggest that one in three people have not fully recovered several weeks after initial illness. A smaller but still substantial proportion have symptoms and difficulties that persist for months. These are not people who have been seriously ill in hospital, whose difficult journey to recovery is better understood.2 These are often physically fit, younger people who report persistent exercise intolerance, breathlessness and cough,3 anxiety, palpitations, and poor concentration. Paul Garner describes boom and bust—the illusion of recovery only to fall back into mental and physical exhaustion.4 These false dawns add to the burden for “long haulers,” he says, which for him includes intense fatigue, mood swings, muscle and joint pains, headaches, and brain fog.
One of the most distressing aspects of living with long covid, says Garner, is the dismissive attitude of some doctors. This may change as more doctors find themselves affected. So how should doctors respond to their patients struggling with this complex and worrying multisystem disorder? Trish Greenhalgh and colleagues recommend taking a whole person, pragmatic approach with symptom management that avoids overinvestigation.5 With so much uncertainty about the cause and course of long covid, a doctor’s key role is to be a witness, they say, “‘honouring the story’ of the patient whose protracted recovery is unexpected, alarming, and does not make sense.”
The challenge for those in charge of our public health response to covid-19 is to make sense of this emergent information. Policies and messaging must now reflect the risks to younger people of developing prolonged illness and multiple organ damage, especially in light of other new information about the risks of airborne transmission.67 For this, we need to be able to quantify the risks through proper population surveillance and to mitigate them with effective systems of rapid testing, tracing, isolation, and support.8 In the UK, at least, such crucial traditional public health approaches still seem a long way off.9
Follow BMJ Editor Fiona Godlee on Twitter @fgodlee and the BMJ @bmj_latest
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Brain, Behaviour and Immunity Vol:7 Aug 2020 100107
Autoantibodies to beta-adrenergic and muscarinic cholinergic receptors in Myalgic Encephalomyelitis (ME) patients – A validation study in plasma and cerebrospinal fluid from two Swedish cohorts
Author links open overlay panel AnnieBynkeabPerJulincdCarl-GerhardGottfrieseHaraldHeideckefCarmenScheibenbogengJonasBergquistab
https://doi.org/10.1016/j.bbih.2020.100107Get rights and content
Highlights
Myalgic Encephalomyelitis (ME) is a devastating disorder (with millions of patients worldwide) with unclear aetiology and no clear diagnostic biomarker available.
This study support the existance of a general pattern of increased antibody levels to adrenergic and muscarinic receptors within the ME patient group.
No evidence for intrathecal antibody production was found in cerebrospinal fluid. The role of increased autoantibodies in the pathogenesis of ME is still uncertain and further research is needed to evaluate their clinical significance.
Abstract
Myalgic encephalomyelitis (ME) also known as ME/CFS (Chronic Fatigue Syndrome) or ME/SEID (Systemic Exertion Intolerance Disorder), is a disabling and often long-lasting disease that can drastically impair quality of life and physical/social functioning of the patients. Underlying pathological mechanisms are to a large extent unknown, but the presence of autoantibodies, cytokine pattern deviations and the presentation of cognitive and autonomic nervous system related symptoms provide evidence for ME being an immunological disorder with elements of autoimmunity. Increased levels of autoantibodies binding to adrenergic and muscarinic receptors in ME-patients have been reported. It is hypothesized that these autoantibodies have pathological significance and contribute to the ME-specific symptoms, however, these observations need to be validated.
This study was designed to investigate potential differences in adrenergic and muscarinic receptor autoantibody levels in plasma and cerebrospinal fluid (CSF) samples between ME patients and gender and age-matched healthy controls, and to correlate the autoantibody levels to disease severity.
We collected bodyfluids and health-related questionnaires from two Swedish ME cohorts, plasma and CSF from one of the cohorts (n = 24), only plasma from the second cohort (n = 24) together with plasma samples (n = 24) and CSF (n = 6) from healthy controls.
All samples were analysed for IgG autoantibodies directed against Alpha- (α1, α2) and Beta- (β1-3) adrenergic receptors and Muscarinic (M) 1–5 acetylcholine receptors using an ELISA technique. The questionnaires were used as measures of disease severity.
Significant increases in autoantibody levels in ME patients compared to controls were found for M3 and M4 -receptors in both cohorts and β1, β2, M3 and M4-receptors in one cohort. No significant correlations were found between autoantibody levels and disease severity. No significant levels of autoantibodies were detected in the CSF samples. These findings support previous findings that there exists a general pattern of increased antibody levels to adrenergic and muscarinic receptors within the ME patient group. However, the role of increased adrenergic and muscarinic receptor autoantibodies in the pathogenesis of ME is still uncertain and further research is needed to evaluate the clinical significance of these findings.
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Review of case definitions for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) Eun-Jin Lim & Chang-Gue Son
Journal of Translational Medicine volume 18, Article number: 289 (2020)
Abstract
Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease with unknown causes. From the perspectives on the etiology and pathophysiology, ME/CFS has been labeled differently, which influenced changes in case definitions and terminologies. This review sought to feature aspects of the history, developments, and differential symptoms in the case definitions.
Methods
A search was conducted through PubMed published to February 2020 using the following search keywords: case definition AND chronic fatigue syndrome [MeSH Terms]. All reference lists of the included studies were checked. Of the included studies, the number of citations and the visibility in the literatures of the definitions were considered for comparisons of the criteria.
Results
Since the first 'ME' case definition was developed in 1986, 25 case definitions/diagnostic criteria were created based on three conceptual factors (etiology, pathophysiology, and exclusionary disorders). These factors can be categorized into four categories (ME, ME/CFS, CFS, and SEID) and broadly characterized according to primary disorder (ME-viral, CFS-unknown, ME/CFS-inflammatory, SEID-multisystemic), compulsory symptoms (ME and ME/CFS-neuroinflammatory, CFS and SEID-fatigue and/or malaise), and required conditions (ME-infective agent, ME/CFS, CFS, SEID-symptoms associated with fatigue, e.g., duration of illness). ME and ME/CFS widely cover all symptom categories, while CFS mainly covers neurologic and neurocognitive symptoms. Fatigue, cognitive impairment, PEM, sleep disorder, and orthostatic intolerance were the overlapping symptoms of the 4 categories, which were included as SEID criteria.
Conclusions
This study comprehensively described the journey of the development of case definitions and compared the symptom criteria. This review provides broader insights and explanations to understand the complexity of ME/CFS for clinicians and researchers.
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Front Neurosci : 2020 Jun 26;14:688. doi: 10.3389/fnins.2020.00688. eCollection 2020.
Cognitive Function Declines Following Orthostatic Stress in Adults With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
C Linda M C van Campen 1, Peter C Rowe 2, Freek W A Verheugt 3, Frans C Visser 1
PMID: 32670016 PMCID: PMC7332734 DOI: 10.3389/fnins.2020.00688
Abstract
Introduction: Orthostatic intolerance (OI) is common among individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Cognitive dysfunction has been demonstrated during head-up tilt testing (HUT) in those with ME/CFS: worse scores on cognitive tests occur with increasing tilt angles and increasing complexity of the cognitive challenge. The aim of our study was to determine whether cognitive impairment persists after completion of HUT.
Methods and results: Eligible participants were consecutive individuals satisfying criteria for ME/CFS who underwent HUT because of OI. The 2- and 3-back tests were performed before the start of HUT and within 5 min after completion of HUT. We measured the percentage of correct responses and raw reaction times before and after HUT for both the 2- and 3-back tests. We studied 128 ME/CFS patients who underwent HUT and had a complete set of N-back data before and after HUT. Compared to pre-tilt responses, the percentage of correct responses on the 2-back test decreased post-HUT from 77(18) to 62(21) and of the 3-back test from 57(17) to 41(17) (both p < 0.0001). The raw reaction time of the 2-back test increased post-HUT from 783(190) to 941(234) m/s and of the 3-back test from 950(170) to 1102(176) (both p < 0.0001). There was no difference in the N-back test data for subgroups dichotomized based on disease severity, the presence of co-morbid fibromyalgia, or the presence of postural orthostatic tachycardia syndrome.
Conclusion: As measured by the N-back test, working memory remains impaired in adults with ME/CFS following a 30-min head-up tilt test.
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