The Impact of a Structured Exercise Programme upon Cognitive Function in Chronic Fatigue Syndrome Patients
by Paweł Zalewski 1,Sławomir Kujawski 1,*,Malwina Tudorowska 2,Karl Morten 3,Małgorzata Tafil-Klawe 4,Jacek J. Klawe 1,James Strong 3,Fernando Estévez-López 5,Modra Murovska 6,Julia L. Newton 7 andthe European Network on ME/CFS (EUROMENE)
1
Department of Hygiene, Epidemiology and Ergonomics, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Poland, M. Sklodowskiej-Curie 9, 85-094 Bydgoszcz, Poland
Brain Sci. 2020, 10(1), 4; https://doi.org/10.3390/brainsci10010004
Received: 29 November 2019 / Accepted: 16 December 2019 / Published: 19 December 2019
(This article belongs to the Section Cognitive Neuroscience)
Abstract
Background: Cognitive function disturbance is a frequently described symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In this study, the effects of a structured exercise programme (SEP) upon cognitive function in ME/CFS patients was examined. Methods: Out of the 53 ME/CFS patients initiating SEP 34 (64%) completed the 16 week programme. Cognitive function was assessed using a computerized battery test consisting of a Simple Reaction Time (SRT) (repeated three times) and Choice Reaction Time (CRT) measurements, a Visual Attention Test (VAT) and a Delayed Matching to Sample (DMS) assessment. Results: Statistically significant improvement was noted in the third attempt to SRT in reaction time for correct answers, p = 0.045, r = 0.24. Moreover, significant improvement was noted in VAT reaction time, number of correct answers and errors committed, p = 0.02, omega = 0.03, p = 0.007, r = 0.34 and p = 0.004, r = 0.35, respectively. Non-significant changes were noted in other cognitive tests. Conclusions: A substantial number of participants were unwilling or unable to complete the exercise programme. ME/CFS patients able to complete the SEP showed improved visual attention both in terms of reaction time and correctness of responses and processing speed of simple visual stimuli.
Keywords: mental function; brain fog; cognitive impairment
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Randomized Controlled Trial Free Radic Res . 2019 Aug;53(8):901-909.
doi: 10.1080/10715762.2019.1645955. Epub 2019 Aug 7.
Coenzyme Q10 supplementation alleviates pain in pregabalin-treated fibromyalgia patients via reducing brain activity and mitochondrial dysfunction
Passakorn Sawaddiruk 1 2 3, Nattayaporn Apaijai 1 2, Sahattaya Paiboonworachat 3, Tawika Kaewchur 4, Nuntana Kasitanon 5, Thidarat Jaiwongkam 1 2, Sasiwan Kerdphoo 1 2, Nipon Chattipakorn 1 2 6, Siriporn C Chattipakorn 1 2 7 PMID: 31387429 DOI: 10.1080/10715762.2019.1645955
Abstract
Although coenzyme Q10 (CoQ10) supplementation has shown to reduce pain levels in chronic pain, the effects of CoQ10 supplementation on pain, anxiety, brain activity, mitochondrial oxidative stress, antioxidants, and inflammation in pregabalin-treated fibromyalgia (FM) patients have not clearly elucidated. We hypothesised that CoQ10 supplementation reduced pain better than pregabalin alone via reducing brain activity, mitochondrial oxidative stress, inflammation, and increasing antioxidant levels in pregabalin-treated FM patients. A double-blind randomised placebo-controlled trial was conducted. Eleven FM patients were enrolled with 2 weeks wash-out then randomly allocated to 2 treatment groups; pregabalin with CoQ10 or pregabalin with placebo for 40 d. Then, patients in CoQ10 group were switched to placebo, and patients in placebo group were switched to CoQ10 for another 40 d. Pain pressure threshold (PPT), FM questionnaire, anxiety, and pain score were examined. Peripheral blood mononuclear cells (PBMCs) were isolated to investigate mitochondrial oxidative stress and inflammation at day 0, 40, and 80. The level of antioxidants and brain positron emission tomography (PET) scan were also determined at these time points. Pregabalin alone reduced pain and anxiety via decreasing brain activity compared with their baseline. However, it did not affect mitochondrial oxidative stress and inflammation. Supplementation with CoQ10 effectively reduced greater pain, anxiety and brain activity, mitochondrial oxidative stress, and inflammation. CoQ10 also increased a reduced glutathione levels and superoxide dismutase (SOD) levels in FM patients. These findings provide new evidence that CoQ10 supplementation provides further benefit for relieving pain sensation in pregabalin-treated FM patients, possibly via improving mitochondrial function, reducing inflammation, and decreasing brain activity.
Keywords: Brain activity; coenzyme Q10; fibromyalgia; oxidative stress; pain; pregabalin.
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Cardiac Dimensions and Function are Not Altered among Females with the Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Per Ole Iversen*,Thomas Gero von Lueder,Kristin Reimers Kardel 1 andKatarina Lien
Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway
Department of Hematology, Oslo University Hospital, 0424 Oslo, Norway
Author to whom correspondence should be addressed.
Healthcare 2020, 8(4), 406; https://doi.org/10.3390/healthcare8040406
Received: 24 September 2020 / Revised: 13 October 2020 / Accepted: 15 October 2020 / Published: 16 October 2020
Abstract
Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition associated with several negative health outcomes. A hallmark of ME/CFS is decreased exercise capacity and often profound exercise intolerance. The causes of ME/CSF and its related symptoms are unknown, but there are indications of a dysregulated metabolism with impaired glycolytic vs oxidative energy balance. In line with this, we recently demonstrated abnormal lactate accumulation among ME/CFS patients compared with healthy controls after exercise testing. Here we examined if cardiac dimensions and function were altered in ME/CFS, as this could lead to increased lactate production. Methods: We studied 16 female ME/CFS patients and 10 healthy controls with supine transthoracic echocardiography, and we assessed cardiac dimensions and function by conventional echocardiographic and Doppler analysis as well as novel tissue Doppler and strain variables. Results: A detailed analyses of key variables of cardiac dimensions and cardiac function revealed no significant differences between the two study groups. Conclusion: In this cohort of well-described ME/CFS patients, we found no significant differences in echocardiographic variables characterizing cardiac dimensions and function compared with healthy controls.
Keywords: cardiac function; echocardiography; myalgic encephalomyelitis/chronic fatigue syndrome
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Plasma proteomic profiling suggests an association between antigen driven clonal B cell expansion and ME/CFS
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is an unexplained chronic, debilitating illness characterized by fatigue, sleep disturbances, cognitive dysfunction, orthostatic intolerance and gastrointestinal problems. Using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), we analyzed the plasma proteomes of 39 ME/CFS patients and 41 healthy controls. Logistic regression models, with both linear and quadratic terms of the protein levels as independent variables, revealed a significant association between ME/CFS and the immunoglobulin heavy variable (IGHV) region 3-23/30. Stratifying the ME/CFS group based on self-reported irritable bowel syndrome (sr-IBS) status revealed a significant quadratic effect of immunoglobulin lambda constant region 7 on its association with ME/CFS with sr-IBS whilst IGHV3-23/30 and immunoglobulin kappa variable region 3–11 were significantly associated with ME/CFS without sr-IBS. In addition, we were able to predict ME/CFS status with a high degree of accuracy (AUC = 0.774–0.838) using a panel of proteins selected by 3 different machine learning algorithms: Lasso, Random Forests, and XGBoost. These algorithms also identified proteomic profiles that predicted the status of ME/CFS patients with sr-IBS (AUC = 0.806–0.846) and ME/CFS without sr-IBS (AUC = 0.754–0.780). Our findings are consistent with a significant association of ME/CFS with immune dysregulation and highlight the potential use of the plasma proteome as a source of biomarkers for disease.
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Substrate utilisation of cultured skeletal muscle cells in patients with CFS
Cara Tomas, Joanna L. Elson, Julia L. Newton & Mark Walker
Scientific Reports volume 10, Article number: 18232 (2020) Cite this article
Abstract
Chronic fatigue syndrome (CFS) patients often suffer from severe muscle pain and an inability to exercise due to muscle fatigue. It has previously been shown that CFS skeletal muscle cells have lower levels of ATP and have AMP-activated protein kinase dysfunction. This study outlines experiments looking at the utilisation of different substrates by skeletal muscle cells from CFS patients (n = 9) and healthy controls (n = 11) using extracellular flux analysis. Results show that CFS skeletal muscle cells are unable to utilise glucose to the same extent as healthy control cells. CFS skeletal muscle cells were shown to oxidise galactose and fatty acids normally, indicating that the bioenergetic dysfunction lies upstream of the TCA cycle. The dysfunction in glucose oxidation is similar to what has previously been shown in blood cells from CFS patients. The consistency of cellular bioenergetic dysfunction in different cell types supports the hypothesis that CFS is a systemic disease. The retention of bioenergetic defects in cultured cells indicates that there is a genetic or epigenetic component to the disease. This is the first study to use cells derived from skeletal muscle biopsies in CFS patients and healthy controls to look at cellular bioenergetic function in whole cells.
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Persistent Symptoms in Patients After Acute COVID-19 - July 9, 2020
Angelo Carfì, MD1; Roberto Bernabei, MD1; Francesco Landi, MD, PhD1; et alfor the Gemelli Against COVID-19 Post-Acute Care Study Group
JAMA. 2020;324(6):603-605. 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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Open Access Published: 24 September 2020
A SWATH-MS analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction
Eiren Sweetman, Torsten Kleffmann, Christina Edgar, Michel de Lange, Rosamund Vallings & Warren Tate
Journal of Translational Medicine volume 18, Article number:
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a serious and complex physical illness that affects all body systems with a multiplicity of symptoms, but key hallmarks of the disease are pervasive fatigue and ‘post-exertional malaise’, exacerbation after physical and/or mental activity of the intrinsic fatigue and other symptoms that can be highly debilitating and last from days to months. Although the disease can vary widely between individuals, common symptoms also include pain, cognitive deficits, sleep dysfunction, as well as immune, neurological and autonomic symptoms. Typically, it is a very isolating illness socially, carrying a stigma because of the lack of understanding of the cause and pathophysiology.
Methods
To gain insight into the pathophysiology of ME/CFS, we examined the proteomes of peripheral blood mononuclear cells (PBMCs) by SWATH-MS analysis in a small well-characterised group of patients and matched controls. A principal component analysis (PCA) was used to stratify groups based on protein abundance patterns, which clearly segregated the majority of the ME/CFS patients (9/11) from the controls. This majority subgroup of ME/CFS patients was then further compared to the control group.
Results
A total of 60 proteins in the ME/CFS patients were differentially expressed (P < 0.01, Log10 (Fold Change) > 0.2 and < −0.2). Comparison of the PCA selected subgroup of ME/CFS patients (9/11) with controls increased the number of proteins differentially expressed to 99. Of particular relevance to the core symptoms of fatigue and post-exertional malaise experienced in ME/CFS, a proportion of the identified proteins in the ME/CFS groups were involved in mitochondrial function, oxidative phosphorylation, electron transport chain complexes, and redox regulation. A significant number were also involved in previously implicated disturbances in ME/CFS, such as the immune inflammatory response, DNA methylation, apoptosis and proteasome activation.
Conclusions
The results from this study support a model of deficient ATP production in ME/CFS, compensated for by upregulation of immediate pathways upstream of Complex V that would suggest an elevation of oxidative stress. This study and others have found evidence of a distinct pathology in ME/CFS that holds promise for developing diagnostic biomarkers.
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Front. Neurol., 28 August 2020 | https://doi.org/10.3389/fneur.2020.00828
Signs of Intracranial Hypertension, Hypermobility, and Craniocervical Obstructions in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Björn Bragée1,2*, Anastasios Michos2, Brandon Drum1,2, Mikael Fahlgren2,3, Robert Szulkin1 and Bo C. Bertilson1,2,3
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Reductions in Cerebral Blood Flow Can Be Provoked by Sitting in Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients
C (Linda) MC van Campen, Peter C. Rowe 2 and Frans C Visser
Stichting CardioZorg, 2132 HN Hoofddorp, The Netherlands
Department of Paediatrics, John Hopkins University School of Medicine, Baltimore, MD 21205, USA
Author to whom correspondence should be addressed.
Healthcare 2020, 8(4), 394; https://doi.org/10.3390/healthcare8040394
Received: 7 September 2020 / Revised: 6 October 2020 / Accepted: 9 October 2020 / Published: 11 October 2020
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Abstract
Introduction: In a large study with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients, we showed that 86% had symptoms of orthostatic intolerance in daily life and that 90% had an abnormal reduction in cerebral blood flow (CBF) during a standard tilt test. A standard head-up tilt test might not be tolerated by the most severely affected bed-ridden ME/CFS patients. Sitting upright is a milder orthostatic stress. The present study examined whether a sitting test, measuring cerebral blood flow by extracranial Doppler, would be sufficient to provoke abnormal reductions in cerebral blood flow in severe ME/CFS patients. Methods and results: 100 severe ME/CFS patients were studied, (88 females) and were compared with 15 healthy controls (HC) (13 females). CBF was measured first while seated for at least one hour, followed by a CBF measurement in the supine position. Fibromyalgia was present in 37 patients. Demographic data as well as supine heart rate and blood pressures were not different between ME/CFS patients and HC. Heart rate and blood pressure did not change significantly between supine and sitting both in patients and HC. Supine CBF was not different between patients and HC. In contrast, absolute CBF during sitting was lower in patients compared to HC: 474 (96) mL/min in patients and 627 (89) mL/min in HC; p < 0.0001. As a result, percent CBF reduction while seated was −24.5 (9.4)% in severe ME/CFS patients and −0.4 (1.2)% in HC (p < 0.0001). In the ten patients who had no orthostatic intolerance complaints in daily life, the CBF reduction was −2.7 (2.1)%, which was not significantly different from HC (p = 0.58). The remaining 90 patients with orthostatic intolerance complaints had a −26.9 (6.2)% CBF reduction. No difference in CBF parameters was found in patients with and without fibromyalgia. Patients with a previous diagnosis of postural orthostatic tachycardia syndrome (POTS) had a significantly larger CBF reduction compared with those without POTS: 28.8 (7.2)% vs. 22.3 (9.7)% (p = 0.0008). Conclusions: A sitting test in severe ME/CFS patients was sufficient to provoke a clinically and statistically significant mean CBF decline of 24.5%. Patients with a previous diagnosis of POTS had a larger CBF reduction while seated, compared to patients without POTS. The magnitude of these CBF reductions is similar to the results in less severely affected ME/CFS patients during head-up tilt, suggesting that a sitting test is adequate for the diagnosis of orthostatic intolerance in severely affected patients.
Keywords: orthostatic intolerance; cerebral blood flow; sitting; myalgic encephalomyelitis; chronic fatigue syndrome; severe disease; ME/CFS
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Letters Covid-19: “Just stay at home”
Long covid: doctors must assess and investigate patients properly
BMJ 2020; 371 doi: https://doi.org/10.1136/bmj.m4583 (Published 02 December 2020)Cite this as: BMJ 2020;371:m4583
Amali U Lokugamage, consultant obstetrician and gynaecologist and honorary associate professor12, Mary-Ann Bowen, general practitioner3, Jennifer Blair, consultant anaesthetist4
[email protected]
Jensen’s article provides a poignant patient perspective and reflects well the experiences of many patients that were very sick at the peak of the first wave of covid-19 but were denied proper medical assessment and told to “stay at home.”1 Of course it is important to “show you care” and empathise with the patient. But, as part of an online group of over 500 doctors (ever growing in number) affected by long covid, we are disappointed that the learning points don’t include “doctors should assess and investigate patients properly.” Before the covid-19 pandemic, symptoms such as low oxygen levels, tachycardia, and shortness of breath would warrant examination and investigation, especially when persistent and in previously fit and healthy patients.
It saddens us to hear such low expectations from general practice and secondary care. This is a new disease, and we are surprised about the lack of professional curiosity to explain new and sometimes seemingly odd symptoms. Numerous BMJ publications support the need for further assessment.234 Pathological consequences such as myocarditis5 or a thromboembolic episode6 may explain symptoms, and these have been noted to occur months after onset in long covid support groups. The medical profession needs to evolve rapid transformative pathways to deal with the long term sequelae of covid-19 that include full investigation of patients. This is becoming urgent, as new covid cases are increasing again and we are already starting to see a new wave of patients with long covid.
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Profile of circulating microRNAs in myalgic encephalomyelitis and their relation to symptom severity, and disease pathophysiology
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex chronic disease, rooted in multi-system dysfunctions characterized by unexplained debilitating fatigue. Post-exertional malaise (PEM), defined as the exacerbation of the patient's symptoms following minimal physical or mental stress, is a hallmark of ME/CFS. While multiple case definitions exist, there is currently no well-established biomarkers or laboratory tests to diagnose ME/CFS. Our study aimed to investigate circulating microRNA expression in severely ill ME/CFS patients before and after an innovative stress challenge that stimulates PEM. Our findings highlight the differential expression of eleven microRNAs associated with a physiological response to PEM. The present study uncovers specific microRNA expression signatures associated with ME/CFS in response to PEM induction and reports microRNA expression patterns associated to specific symptom severities. The identification of distinctive microRNA expression signatures for ME/CFS through a provocation challenge is essential for the elucidation of the ME/CFS pathophysiology, and lead to accurate diagnoses, prevention measures, and effective treatment options.
Accurate and objective determination of myalgic encephalomyelitis/chronic fatigue syndrome disease severity with a wearable sensor
Abstract
Background
Approximately 2.5 million people in the U.S. suffer from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This disease negatively impacts patients’ ability to function, often resulting in difficulty maintaining employment, sustaining financial independence, engaging socially with others, and in particularly severe cases, consistently and adequately performing activities of daily living. The focus of this research was to develop a sensor-based method to measure upright activity defined as time with feet on the floor and referred to as UpTime, as an indicator of ME/CFS disease severity.
Methods
A commercially available inertial measurement unit (IMU), the Shimmer, was selected for this research. A Kalman filter was used to convert IMU data collected by the Shimmer to angle estimates. Angle estimate accuracy was confirmed by comparison to a motion capture system. Leg angle estimates were then converted to personalized daily UpTime scores using a critical angle of 39º from vertical to differentiate between upright (feet on the floor) and not upright. A 6-day, case–control study with 15 subjects (five healthy controls, five moderate-level ME/CFS, and five severe-level ME/CFS) was conducted to determine the utility of UpTime for assessing disease severity.
Results
UpTime was found to be a significant measure of ME/CFS disease severity. Severely ill ME/CFS patients spend less than 20% of each day with feet on the floor. Moderately ill ME/CFS patients spend between 20–30% of each day with feet on the floor. Healthy controls have greater than 30% UpTime. IMU-measured UpTime was more precise than self-reported hours of upright activity which were over-estimated by patients.
Conclusions
UpTime is an accurate and objective measure of upright activity, a measure that can be used to assess disease severity in ME/CFS patients. Due to its ability to accurately monitor upright activity, UpTime can also be used as a reliable endpoint for evaluating ME/CFS treatment efficacy. Future studies with larger samples and extended data collection periods are required to fully confirm the use of UpTime as a measure of disease severity in ME/CFS. With the added perspective of large-scale studies, this sensor-based platform could provide a recovery path for individuals struggling with ME/CFS.
Deep phenotyping of myalgic encephalomyelitis/chronic fatigue syndrome in Japanese population
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex and debilitating disease with no molecular diagnostics and no treatment options. To identify potential markers of this illness, we profiled 48 patients and 52 controls for standard laboratory tests, plasma metabolomics, blood immuno-phenotyping and transcriptomics, and fecal microbiome analysis. Here, we identified a set of 26 potential molecular markers that distinguished ME/CFS patients from healthy controls. Monocyte number, microbiome abundance, and lipoprotein profiles appeared to be the most informative markers. When we correlated these molecular changes to sleep and cognitive measurements of fatigue, we found that lipoprotein and microbiome profiles most closely correlated with sleep disruption while a different set of markers correlated with a cognitive parameter. Sleep, lipoprotein, and microbiome changes occur early during the course of illness suggesting that these markers can be examined in a larger cohort for potential biomarker application. Our study points to a cluster of sleep-related molecular changes as a prominent feature of ME/CFS in our Japanese cohort.
Diverse Functional Autoantibodies in Patients with COVID-19
Eric Y. Wang,1,* Tianyang Mao,1,* Jon Klein,1,* Yile Dai,1,* John D. Huck,1 Feimei Liu,1 Neil S. Zheng,1 Ting Zhou,1 Benjamin Israelow,1 Patrick Wong,1 Carolina Lucas,1 Julio Silva,1 Ji Eun Oh,1 Eric Song,1 Emily S. Perotti,1 Suzanne Fischer,1 Melissa Campbell,5 John B. Fournier,5 Anne L. Wyllie,3 Chantal B. F. Vogels,3 Isabel M. Ott,3 Chaney C. Kalinich,3 Mary E. Petrone,3 Anne E. Watkins,3 Yale IMPACT Team,¶ Charles Dela Cruz,4 Shelli F. Farhadian,5 Wade L. Schulz,6,7 Nathan D. Grubaugh,3 Albert I. Ko,3,5 Akiko Iwasaki,1,3,8,# and Aaron M. Ring1,2,#
Author information Copyright and License information Disclaimer
Version 2. medRxiv. Preprint. 2020 Dec 12.
doi: 10.1101/2020.12.10.20247205 PMCID: PMC7743105 PMID: 33330894
Abstract
COVID-19 manifests with a wide spectrum of clinical phenotypes that are characterized by exaggerated and misdirected host immune responses1–8. While pathological innate immune activation is well documented in severe disease1, the impact of autoantibodies on disease progression is less defined. Here, we used a high-throughput autoantibody discovery technique called Rapid Extracellular Antigen Profiling (REAP) to screen a cohort of 194 SARS-CoV-2 infected COVID-19 patients and healthcare workers for autoantibodies against 2,770 extracellular and secreted proteins (the “exoproteome”). We found that COVID-19 patients exhibit dramatic increases in autoantibody reactivities compared to uninfected controls, with a high prevalence of autoantibodies against immunomodulatory proteins including cytokines, chemokines, complement components, and cell surface proteins. We established that these autoantibodies perturb immune function and impair virological control by inhibiting immunoreceptor signaling and by altering peripheral immune cell composition, and found that murine surrogates of these autoantibodies exacerbate disease severity in a mouse model of SARS-CoV-2 infection. Analysis of autoantibodies against tissue-associated antigens revealed associations with specific clinical characteristics and disease severity. In summary, these findings implicate a pathological role for exoproteome-directed autoantibodies in COVID-19 with diverse impacts on immune functionality and associations with clinical outcomes.
Review
Am J Cardiovasc Drugs . 2018 Jun;18(3):195-204. doi: 10.1007/s40256-017-0252-1.
Ivabradine for the Treatment of Postural Orthostatic Tachycardia Syndrome: A Systematic Review
Megan E Gee 1, Alicia K Watkins 2, Jamie N Brown 3, Emily J A Young 4
Affiliations expand PMID: 29330767 DOI: 10.1007/s40256-017-0252-1
Abstract
Introduction: Postural orthostatic tachycardia syndrome (POTS) impacts millions of patients, but there is currently no gold standard treatment for this condition. Ivabradine is a novel heart rate (HR) lowering agent that acts on the sinoatrial node cells by selectively inhibiting the If-current.
Objective: The objective of this systematic review is to evaluate the evidence for the efficacy and safety of ivabradine for the treatment of POTS.
Methods: MEDLINE (from 1956 to August 2017) and EMBASE (from 1957 to August 2017) were queried with the following search term: "postural orthostatic tachycardia syndrome" OR "postural tachycardia syndrome" OR "chronic orthostatic intolerance" AND "ivabradine." Articles in English with clinical outcomes of human patient(s) treated with ivabradine for POTS were included.
Results: The initial search identified 73 articles. After screening, 13 articles were included. Two prospective open-label trials, three retrospective cohort studies, and eight case reports evaluated the safety and efficacy of ivabradine in a total of 132 patients with postural tachycardia. Overall, ivabradine lowered HR and provided symptomatic relief of POTS without blood pressure lowering. Dizziness, nausea, headache, and fatigue were the most common side effects and often did not lead to discontinuation of treatment.
Conclusion: Based on this small sample, ivabradine appears to be a reasonable option for patients with POTS who have failed or are unable to tolerate other treatment options, however, but a randomized controlled trial in this population is needed.
Cureus. 2020 Apr; 12(4): e7868.
Published online 2020 Apr 28. doi: 10.7759/cureus.7868
PMCID: PMC7255540
Ivabradine in Postural Orthostatic Tachycardia Syndrome: A Review of the Literature
Faryal Tahir,1 Taha Bin Arif,1 Zainab Majid,1 Jawad Ahmed,1 and Muhammad Khalid2,3
Abstract
Introduction and background
The first informal mention of postural orthostatic tachycardia syndrome (POTS) was by Da Costa, in 1871, who referred to it as “soldier’s heart” or “irritable heart” [1]. However, Schondorf and Low, in 1993, first described POTS in the adult population as an increase in the heart rate (HR) in a symptomatic patient by more than 30 beats per min (bpm) when the patient moves from supine to upright position [2]. In 2015, Heart Rhythm Society defined POTS on the basis of three points: (1) a clinical syndrome characterized by symptoms of lightheadedness, blurring of vision, palpitations, intolerance to exercise, and fatigue; (2) an increase of ≥30 bpm (≥40 bpm in those aged 12-19 years) in the HR when the person stands up from a recumbent position; and (3) absence of orthostatic hypotension [3]. Orthostatic hypotension is characterized by a more than 20 mmHg drop in systolic blood pressure (BP) on standing [3]. The incidence of POTS varies globally from 0.2% to 1% in the developed countries with an increased prevalence among females, Caucasian race, and individuals from 13 to 50 years of age [4,5,6-8]. The affected individuals account for 3,000,000 cases alone in the United States of America (USA) [9]. A recent 2019 study has shown that the incidence of POTS has increased fourfold since 2000 [8].
POTS is an autonomic disorder characterized by symptoms such as palpitations, dyspnea, chest discomfort, lightheadedness, nausea, blurred vision, chronic fatigue, sleeping abnormalities, migraines, hypermobile joints, abdominal pain, irritable bowel, and bladder symptoms as well affecting various systems [9,10]. Only 30% of individuals have reported fainting along with the symptoms of POTS [9]. Usually, there is a two-year (median) delay in the diagnosis of disease from the onset of symptoms [7]. The pathophysiology of POTS is not completely understood due to a variety of symptoms showing that the disease is multifactorial [4,9,10]. Chronic fatigue syndrome, inappropriate sinus tachycardia, and vasovagal syncope are few conditions associated with POTS [4].
There is no approved uniform management strategy for POTS and hence, no drug has been approved by the US Food and Drug Administration (FDA) for it [4]. Non-pharmacological therapies include lifestyle modifications such as increased hydration and salt intake, and use of support stockings [11]. Pharmacological therapies include beta-blockers (first line), alpha-agonists (first or second line), mineralocorticoids (second line), selective serotonin reuptake inhibitors (SSRIs), and selective serotonin-norepinephrine reuptake inhibitors (SSNRIs), and rarely used drugs include pyridostigmine, desmopressin, and erythropoietin [4,11]. However, there has been evidence of beneficial outcomes with the use of ivabradine in POTS patients, as seen in prospective and retrospective studies [12-16].
Ivabradine is an FDA-approved drug for stable symptomatic heart failure (HF) and patients with an ejection fraction (EF) of ≤35% [17,18]. European Society of Cardiology recommends ivabradine as second-line therapy for patients whose angina has been poorly controlled by other medications, namely calcium-channel blockers (CCBs), beta-blockers, or nitrates (short-acting) [19].
Ivabradine increases the diastolic time and reduces the HR by inhibiting channels responsible for maintaining cardiac pacemaker current, If (funny current). The selective blocking of these trans-membrane ion channels that conduct the inward depolarizing sodium (Na) and potassium (K) current slows down the HR without affecting systemic vascular resistance and cardiac inotropy [18,20,21]. Ivabradine has been+ associated with many severe side effects such as bradycardia, heart block, sinus arrest, QT prolongation, torsades de pointes, and fetal toxicity. Other less severe side effects include, but are not limited to, vertigo, diplopia, rash, and hypotension [17,18].
Ivabradine is not an FDA-approved drug for POTS but due to its ability to reduce HR, it has shown improvement in POTS patients in many studies [12-16]. This review aims to provide a comprehensive and up-to-date picture of all the studies and case reports that utilized ivabradine for the treatment of POTS along with a precise overview of epidemiology, pathophysiology, and types of POTS.
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. 2020;324(6):603-605. doi:10.1001/jama.2020.12603 July 9, 2020
What Is It Like to Have COVID-19?
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.
Mapping of pathological change in chronic fatigue syndrome using the ratio of T1- and T2-weighted MRI scans
Author links open overlay panelKiranThapaliyaabSonyaMarshall-GradisnikaDonStainesaLeightonBarndena
https://doi.org/10.1016/j.nicl.2020.102366Get rights and content
Neurolmage Clinical Vol 28 2020cc
Highlights
We showed increased T1w/T2w in ME/CFS in contrast to other neurodegenerative diseases.
Higher T1w/T2w occurred in basal ganglia and white matter tracts.
Increased T1w/T2w indicates increased myelin and/or iron levels.
T1w/T2w regressions vs clinical measures were abnormal in cingulate cortex and white matter foci.
Abstract
Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS) subjects suffer from a variety of cognitive complaints indicating that the central nervous system plays a role in its pathophysiology. Recently, the ratio T1w/T2w has been used to study changes in tissue myelin and/or iron levels in neurodegenerative diseases such as multiple sclerosis and schizophrenia. In this study, we applied the T1w/T2w method to detect changes in tissue microstructure in ME/CFS patients relative to healthy controls. We mapped the T1w/T2w signal intensity values in the whole brain for forty-five ME/CFS patients who met Fukuda criteria and twenty-seven healthy controls and applied both region- and voxel-based quantification. We also performed interaction-with-group regressions with clinical measures to test for T1w/T2w relationships that are abnormal in ME/CFS at the population level. Region-based analysis showed significantly elevated T1w/T2w values (increased myelin and/or iron) in ME/CFS in both white matter (WM) and subcortical grey matter. The voxel-based group comparison with sub-millimetre resolution voxels detected very significant clusters with increased T1w/T2w in ME/CFS, mostly in subcortical grey matter, but also in brainstem and projection WM tracts. No areas with decreased T1w/T2w were found in either analysis. ME/CFS T1w/T2w regressions with heart-rate variability, cognitive performance, respiration rate and physical well-being were abnormal in both gray and white matter foci. Our study demonstrates that the T1w/T2w approach is very sensitive and shows increases in myelin and/or iron in WM and basal ganglia in ME/CFS.
A systematic review of mitochondrial abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease
Sean Holden, Rebekah Maksoud, Natalie Eaton-Fitch, Hélène Cabanas, Donald Staines & Sonya Marshall-Gradisnik
Published: 29 July 2020
Journal of Translational Medicine volume 18, Article number: 290 (2020) Cite this article
The Correction to this article has been published in Journal of Translational Medicine 2020 18:407
Abstract
Background
Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) or Systemic Exertion Intolerance Disease (SEID) present with a constellation of symptoms including debilitating fatigue that is unrelieved by rest. The pathomechanisms underlying this illness are not fully understood and the search for a biomarker continues, mitochondrial aberrations have been suggested as a possible candidate. The aim of this systematic review is to collate and appraise current literature on mitochondrial changes in ME/CFS/SEID patients compared to healthy controls.
Methods
Embase, PubMed, Scopus and Medline (EBSCO host) were systematically searched for articles assessing mitochondrial changes in ME/CFS/SEID patients compared to healthy controls published between January 1995 and February 2020. The list of articles was further refined using specific inclusion and exclusion criteria. Quality and bias were measured using the Joanna Briggs Institute Critical Appraisal Checklist for Case Control Studies.
Results
Nineteen studies were included in this review. The included studies investigated mitochondrial structural and functional differences in ME/CFS/SEID patients compared with healthy controls. Outcomes addressed by the papers include changes in mitochondrial structure, deoxyribonucleic acid/ribonucleic acid, respiratory function, metabolites, and coenzymes.
Conclusion
Based on the included articles in the review it is difficult to establish the role of mitochondria in the pathomechanisms of ME/CFS/SEID due to inconsistencies across the studies. Future well-designed studies using the same ME/CFS/SEID diagnostic criteria and analysis methods are required to determine possible mitochondrial involvement in the pathomechanisms of ME/CFS/SEID.
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.
Centre for Applied Health Economics, Griffith University, Nathan, QLD, Australia
Objectives: This study aims to estimate direct and indirect health economic costs associated with government and out-of-pocket (OOP) expenditure based on health care service utilization and lost income of participants and carers, as reported by Australian Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patient survey participants.
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.
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Organic Disease or Psychosomatic Illness? A Re-Examination of the Royal Free Epidemic of 1955
Rosemary Underhill 1,* and Rosemarie Baillod 2
Medicina 2021, 57, 12. https://dx.doi.org/10.3390/ medicina57010012 Received: 20 November 2020 Accepted: 22 December 2020 Published: 26 December 2020
Copyright: © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Correspondence: [email protected]
Abstract:
Background and Objectives: Controversy exists over whether myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an organic disease or a psychosomatic illness. ME/CFS usually occurs as sporadic cases, but epidemics (outbreaks) have occurred worldwide. Myalgic encephalomyelitis was named to describe an outbreak affecting the lymphatic, muscular, and nervous systems that closed the Royal Free hospital for three months in 1955. Fifteen years later, two psychiatrists concluded that epidemic hysteria was the likely cause. ME/CFS research studies show multiple pathophysiological differences between patients and controls and a possible etiological role for infectious organisms, but the belief that ME/CFS is psychosomatic is widespread and has been specifically supported by the epidemic hysteria hypothesis for the Royal Free outbreak. Our objective was to obtain accounts from ex-Royal Free hospital staff who personally experienced the 1955 outbreak and evaluate evidence for it being an infectious illness versus epidemic hysteria.
Materials and Methods: Statements in the newsletters of two organizations for staff who had worked at the Royal Free hospital invited anyone who had experienced the 1955 Royal Free outbreak to contact the authors. Accounts of the outbreak from telephone interviews and letters were evaluated against the “epidemic hysteria hypothesis” paper and original medical staff reports.
Results: Twentyseven ex-Royal Free hospital staff, including six who had developed ME, provided descriptions typical of an infectious illness affecting the lymphatic, muscular, and nervous systems, and were not consistent with epidemic hysteria.
Conclusions: The 1955 Royal Free hospital epidemic of myalgic encephalomyelitis was an organic infectious disease, not psychogenic epidemic hysteria.
Keywords: Chronic fatigue syndrome; epidemic hysteria; mass hysteria; myalgic encephalomyelitis; psychosomatic illness; Royal Free epidemic
Characterizing Long COVID in an International Cohort: 7 Months of Symptoms and Their Impact
medRxiv preprint doi: https://doi.org/10.1101/2020.12.24.20248802; this version posted December 27, 2020
Hannah E. Davis1 *, Gina S. Assaf1 *, Lisa McCorkell1 *, Hannah Wei1 *, Ryan J. Low1,2*, Yochai Re’em1,3*, Signe Redfield1 , Jared P. Austin4 , Athena Akrami1,
Patient-Led Research for COVID-19, 2 Sainsbury Wellcome Centre, University College London, London, UK, 3 NewYork-Presbyterian Hospital / Weill Cornell Medicine, NYC, USA, 4 Oregon Health and Science University, Portland, OR, USA + Corresponding author, email: [email protected]
Abstract Objective. To characterize the symptom profile and time course in patients with Long COVID, along with the impact on daily life, work, and return to baseline health. Design. International web-based survey of suspected and confirmed COVID-19 cases with illness lasting over 28 days and onset prior to June 2020.
Setting. Survey distribution via online COVID-19 support groups and social media
Participants. 3,762 respondents from 56 countries completed the survey. 1166 (33.7%) were 40-49 years old, 937 (27.1%) were 50-59 years old, and 905 (26.1%) were 30-39 years old. 2961 (78.9%) were women, 718 (19.1%) were men, and 63 (1.7%) were nonbinary. 8.4% reported being hospitalized. 27% reported receiving a laboratory-confirmed diagnosis of COVID-19. 96% reported symptoms beyond 90 days.
Results. Prevalence of 205 symptoms in 10 organ systems was estimated in this cohort, with 66 symptoms traced over seven months. Respondents experienced symptoms in an average of 9.08 (95% confidence interval 9.04 to 9.13) organ systems. The most frequent symptoms reported after month 6 were: fatigue (77.7%, 74.9% to 80.3%), post-exertional malaise (72.2%, 69.3% to 75.0%), and cognitive dysfunction (55.4%, 52.4% to 58.8%). These three symptoms were also the three most commonly reported overall. In those who recovered in less than 90 days, the average number of symptoms peaked at week 2 (11.4, 9.4 to 13.6), and in those who did not recover in 90 days, the average number of symptoms peaked at month 2 (17.2, 16.5 to 17.8). Respondents with symptoms over 6 months experienced an average of 13.8 (12.7 to 14.9) symptoms in month 7. 85.9% (84.8% to 87.0%) experienced relapses, with exercise, physical or mental activity, and stress as the main triggers. 86.7% (85.6% to 92.5%) of unrecovered respondents were experiencing fatigue at the time of survey, compared to 44.7% (38.5% to 50.5%) of recovered respondents. 45.2% (42.9% to 47.2%) reported requiring a reduced work schedule compared to pre-illness and 22.3% (20.5% to 24.3%) were not working at the time of survey due to their health conditions.
Conclusions. Patients with Long COVID report prolonged multisystem involvement and significant disability. Most had not returned to previous levels of work by 6 months. Many patients are not recovered by 7 months, and continue to experience significant symptom burden.
Neurology
Coenzyme Q10 supplementation for prophylaxis in adult patients with migraine—a meta-analysis
Abstract
Objective To determine the effects of coenzyme Q10 (CoQ10) for reduction in the severity, frequency of migraine attacks and duration of headache in adult patients with migraine.
Design Systematic review and meta-analysis.
Data sources Cochrane Central Register of Controlled Trials, CENTRAL, MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Psychological Information Database (PsycINFO) from inception till December 2019.
Study selection All randomised control trials comparing CoQ10 with placebo or used as an adjunct treatment included in this meta-analysis. Cross-over designs and controlled clinical trials were excluded.
Data synthesis Heterogeneity at face value by comparing populations, settings, interventions and outcomes were measured and statistical heterogeneity was assessed by means of the I2 statistic. The treatment effect for dichotomous outcomes were using risk ratios and risk difference, and for continuous outcomes, mean differences (MDs) or standardised mean difference; both with 95% CIs were used. Subgroup analyses were carried out for dosage of CoQ10 and if CoQ10 combined with another supplementation. Sensitivity analysis was used to investigate the impact risk of bias for sequence generation and allocation concealment of included studies.
Results Six studies with a total of 371 participants were included in the meta-analysis. There is no statistically significant reduction in severity of migraine headache with CoQ10 supplementation. CoQ10 supplementation reduced the duration of headache attacks compared with the control group (MD: −0.19; 95% CI: −0.27 to −0.11; random effects; I2 statistic=0%; p<0.00001). CoQ10 usage reduced the frequency of migraine headache compared with the control group (MD: −1.52; 95% CI: −2.40 to −0.65; random effects; I2 statistic=0%; p<0.001).
Conclusion CoQ10 appears to have beneficial effects in reducing duration and frequency of migraine attack.
PROSPERO registration number CRD42019126127.
Imaging Jan 5, 2021:Brain Responses to Noxious Stimuli in Patients With Chronic Pain
A Systematic Review and Meta-analysis
Anna Xu, BS1; Bart Larsen, PhD1; Alina Henn, MS2; et alErica B. Baller, MD, MS1,3,4; J. Cobb Scott, PhD1,5; Vaishnavi Sharma, BA1; Azeez Adebimpe, PhD1; Allan I. Basbaum, PhD6; Gregory Corder, PhD1; Robert H. Dworkin, PhD7; Robert R. Edwards, MD8; Clifford J. Woolf, MB, BCh, PhD9,10; Simon B. Eickhoff, MD11,12; Claudia R. Eickhoff, MD12,13; Theodore D. Satterthwaite, MD, MA1
JAMA Netw Open. 2021;4(1):e2032236. doi:10.1001/jamanetworkopen.2020.32236
Key Points: Question Do the brains of patients with chronic pain respond differently to noxious stimuli?
Findings This systematic review and meta-analysis of 37 experiments from 29 unique articles including 944 participants found that patients with chronic pain were not associated with significant differential responses to noxious stimuli that induce pain compared with healthy controls.
Meaning Chronic pain does not appear to be associated with consistent marked alterations in the brain’s response to noxious stimuli.
Abstract: Importance Functional neuroimaging is a valuable tool for understanding how patients with chronic pain respond to painful stimuli. However, past studies have reported heterogenous results, highlighting opportunities for a quantitative meta-analysis to integrate existing data and delineate consistent associations across studies.
Objective To identify differential brain responses to noxious stimuli in patients with chronic pain using functional magnetic resonance imaging (fMRI) while adhering to current best practices for neuroimaging meta-analyses.
Data Sources All fMRI experiments published from January 1, 1990, to May 28, 2019, were identified in a literature search of PubMed/MEDLINE, EMBASE, Web of Science, Cochrane Library, PsycINFO, and SCOPUS.
Study Selection Experiments comparing brain responses to noxious stimuli in fMRI between patients and controls were selected if they reported whole-brain results, included at least 10 patients and 10 healthy control participants, and used adequate statistical thresholding (voxel-height P < .001 or cluster-corrected P < .05). Two independent reviewers evaluated titles and abstracts returned by the search. In total, 3682 abstracts were screened, and 1129 full-text articles were evaluated.
Data Extraction and Synthesis Thirty-seven experiments from 29 articles met inclusion criteria for meta-analysis. Coordinates reporting significant activation differences between patients with chronic pain and healthy controls were extracted. These data were meta-analyzed using activation likelihood estimation. Data were analyzed from December 2019 to February 2020.
Main Outcomes and Measures A whole-brain meta-analysis evaluated whether reported differences in brain activation in response to noxious stimuli between patients and healthy controls were spatially convergent. Follow-up analyses examined the directionality of any differences. Finally, an exploratory (nonpreregistered) region-of-interest analysis examined differences within the pain network.
Results The 37 experiments from 29 unique articles included a total of 511 patients and 433 controls (944 participants). Whole-brain meta-analyses did not reveal significant differences between patients and controls in brain responses to noxious stimuli at the preregistered statistical threshold. However, exploratory analyses restricted to the pain network revealed aberrant activity in patients.
Conclusions and Relevance In this systematic review and meta-analysis, preregistered, whole-brain analyses did not reveal aberrant fMRI activity in patients with chronic pain. Exploratory analyses suggested that subtle, spatially diffuse differences may exist within the pain network. Future work on chronic pain biomarkers may benefit from focus on this core set of pain-responsive areas.
by Paweł Zalewski 1,Sławomir Kujawski 1,*,Malwina Tudorowska 2,Karl Morten 3,Małgorzata Tafil-Klawe 4,Jacek J. Klawe 1,James Strong 3,Fernando Estévez-López 5,Modra Murovska 6,Julia L. Newton 7 andthe European Network on ME/CFS (EUROMENE)
1
Department of Hygiene, Epidemiology and Ergonomics, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Poland, M. Sklodowskiej-Curie 9, 85-094 Bydgoszcz, Poland
Brain Sci. 2020, 10(1), 4; https://doi.org/10.3390/brainsci10010004
Received: 29 November 2019 / Accepted: 16 December 2019 / Published: 19 December 2019
(This article belongs to the Section Cognitive Neuroscience)
Abstract
Background: Cognitive function disturbance is a frequently described symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In this study, the effects of a structured exercise programme (SEP) upon cognitive function in ME/CFS patients was examined. Methods: Out of the 53 ME/CFS patients initiating SEP 34 (64%) completed the 16 week programme. Cognitive function was assessed using a computerized battery test consisting of a Simple Reaction Time (SRT) (repeated three times) and Choice Reaction Time (CRT) measurements, a Visual Attention Test (VAT) and a Delayed Matching to Sample (DMS) assessment. Results: Statistically significant improvement was noted in the third attempt to SRT in reaction time for correct answers, p = 0.045, r = 0.24. Moreover, significant improvement was noted in VAT reaction time, number of correct answers and errors committed, p = 0.02, omega = 0.03, p = 0.007, r = 0.34 and p = 0.004, r = 0.35, respectively. Non-significant changes were noted in other cognitive tests. Conclusions: A substantial number of participants were unwilling or unable to complete the exercise programme. ME/CFS patients able to complete the SEP showed improved visual attention both in terms of reaction time and correctness of responses and processing speed of simple visual stimuli.
Keywords: mental function; brain fog; cognitive impairment
______________________________________________________________________________
Randomized Controlled Trial Free Radic Res . 2019 Aug;53(8):901-909.
doi: 10.1080/10715762.2019.1645955. Epub 2019 Aug 7.
Coenzyme Q10 supplementation alleviates pain in pregabalin-treated fibromyalgia patients via reducing brain activity and mitochondrial dysfunction
Passakorn Sawaddiruk 1 2 3, Nattayaporn Apaijai 1 2, Sahattaya Paiboonworachat 3, Tawika Kaewchur 4, Nuntana Kasitanon 5, Thidarat Jaiwongkam 1 2, Sasiwan Kerdphoo 1 2, Nipon Chattipakorn 1 2 6, Siriporn C Chattipakorn 1 2 7 PMID: 31387429 DOI: 10.1080/10715762.2019.1645955
Abstract
Although coenzyme Q10 (CoQ10) supplementation has shown to reduce pain levels in chronic pain, the effects of CoQ10 supplementation on pain, anxiety, brain activity, mitochondrial oxidative stress, antioxidants, and inflammation in pregabalin-treated fibromyalgia (FM) patients have not clearly elucidated. We hypothesised that CoQ10 supplementation reduced pain better than pregabalin alone via reducing brain activity, mitochondrial oxidative stress, inflammation, and increasing antioxidant levels in pregabalin-treated FM patients. A double-blind randomised placebo-controlled trial was conducted. Eleven FM patients were enrolled with 2 weeks wash-out then randomly allocated to 2 treatment groups; pregabalin with CoQ10 or pregabalin with placebo for 40 d. Then, patients in CoQ10 group were switched to placebo, and patients in placebo group were switched to CoQ10 for another 40 d. Pain pressure threshold (PPT), FM questionnaire, anxiety, and pain score were examined. Peripheral blood mononuclear cells (PBMCs) were isolated to investigate mitochondrial oxidative stress and inflammation at day 0, 40, and 80. The level of antioxidants and brain positron emission tomography (PET) scan were also determined at these time points. Pregabalin alone reduced pain and anxiety via decreasing brain activity compared with their baseline. However, it did not affect mitochondrial oxidative stress and inflammation. Supplementation with CoQ10 effectively reduced greater pain, anxiety and brain activity, mitochondrial oxidative stress, and inflammation. CoQ10 also increased a reduced glutathione levels and superoxide dismutase (SOD) levels in FM patients. These findings provide new evidence that CoQ10 supplementation provides further benefit for relieving pain sensation in pregabalin-treated FM patients, possibly via improving mitochondrial function, reducing inflammation, and decreasing brain activity.
Keywords: Brain activity; coenzyme Q10; fibromyalgia; oxidative stress; pain; pregabalin.
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Cardiac Dimensions and Function are Not Altered among Females with the Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Per Ole Iversen*,Thomas Gero von Lueder,Kristin Reimers Kardel 1 andKatarina Lien
Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway
Department of Hematology, Oslo University Hospital, 0424 Oslo, Norway
Author to whom correspondence should be addressed.
Healthcare 2020, 8(4), 406; https://doi.org/10.3390/healthcare8040406
Received: 24 September 2020 / Revised: 13 October 2020 / Accepted: 15 October 2020 / Published: 16 October 2020
Abstract
Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition associated with several negative health outcomes. A hallmark of ME/CFS is decreased exercise capacity and often profound exercise intolerance. The causes of ME/CSF and its related symptoms are unknown, but there are indications of a dysregulated metabolism with impaired glycolytic vs oxidative energy balance. In line with this, we recently demonstrated abnormal lactate accumulation among ME/CFS patients compared with healthy controls after exercise testing. Here we examined if cardiac dimensions and function were altered in ME/CFS, as this could lead to increased lactate production. Methods: We studied 16 female ME/CFS patients and 10 healthy controls with supine transthoracic echocardiography, and we assessed cardiac dimensions and function by conventional echocardiographic and Doppler analysis as well as novel tissue Doppler and strain variables. Results: A detailed analyses of key variables of cardiac dimensions and cardiac function revealed no significant differences between the two study groups. Conclusion: In this cohort of well-described ME/CFS patients, we found no significant differences in echocardiographic variables characterizing cardiac dimensions and function compared with healthy controls.
Keywords: cardiac function; echocardiography; myalgic encephalomyelitis/chronic fatigue syndrome
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Plasma proteomic profiling suggests an association between antigen driven clonal B cell expansion and ME/CFS
- Milica Milivojevic ,Xiaoyu Che ,Lucinda Bateman,Aaron Cheng,Benjamin A. Garcia,Mady Hornig, Manuel Huber,Nancy G. Klimas,Bohyun Lee,Hyoungjoo Lee,Susan Levine,Jose G. Montoya,
- Daniel L. Peterson,Anthony L. Komaroff,W. Ian Lipkin
- Published: July 21, 2020 https://doi.org/10.1371/journal.pone.0236148
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is an unexplained chronic, debilitating illness characterized by fatigue, sleep disturbances, cognitive dysfunction, orthostatic intolerance and gastrointestinal problems. Using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), we analyzed the plasma proteomes of 39 ME/CFS patients and 41 healthy controls. Logistic regression models, with both linear and quadratic terms of the protein levels as independent variables, revealed a significant association between ME/CFS and the immunoglobulin heavy variable (IGHV) region 3-23/30. Stratifying the ME/CFS group based on self-reported irritable bowel syndrome (sr-IBS) status revealed a significant quadratic effect of immunoglobulin lambda constant region 7 on its association with ME/CFS with sr-IBS whilst IGHV3-23/30 and immunoglobulin kappa variable region 3–11 were significantly associated with ME/CFS without sr-IBS. In addition, we were able to predict ME/CFS status with a high degree of accuracy (AUC = 0.774–0.838) using a panel of proteins selected by 3 different machine learning algorithms: Lasso, Random Forests, and XGBoost. These algorithms also identified proteomic profiles that predicted the status of ME/CFS patients with sr-IBS (AUC = 0.806–0.846) and ME/CFS without sr-IBS (AUC = 0.754–0.780). Our findings are consistent with a significant association of ME/CFS with immune dysregulation and highlight the potential use of the plasma proteome as a source of biomarkers for disease.
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Substrate utilisation of cultured skeletal muscle cells in patients with CFS
Cara Tomas, Joanna L. Elson, Julia L. Newton & Mark Walker
Scientific Reports volume 10, Article number: 18232 (2020) Cite this article
Abstract
Chronic fatigue syndrome (CFS) patients often suffer from severe muscle pain and an inability to exercise due to muscle fatigue. It has previously been shown that CFS skeletal muscle cells have lower levels of ATP and have AMP-activated protein kinase dysfunction. This study outlines experiments looking at the utilisation of different substrates by skeletal muscle cells from CFS patients (n = 9) and healthy controls (n = 11) using extracellular flux analysis. Results show that CFS skeletal muscle cells are unable to utilise glucose to the same extent as healthy control cells. CFS skeletal muscle cells were shown to oxidise galactose and fatty acids normally, indicating that the bioenergetic dysfunction lies upstream of the TCA cycle. The dysfunction in glucose oxidation is similar to what has previously been shown in blood cells from CFS patients. The consistency of cellular bioenergetic dysfunction in different cell types supports the hypothesis that CFS is a systemic disease. The retention of bioenergetic defects in cultured cells indicates that there is a genetic or epigenetic component to the disease. This is the first study to use cells derived from skeletal muscle biopsies in CFS patients and healthy controls to look at cellular bioenergetic function in whole cells.
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Persistent Symptoms in Patients After Acute COVID-19 - July 9, 2020
Angelo Carfì, MD1; Roberto Bernabei, MD1; Francesco Landi, MD, PhD1; et alfor the Gemelli Against COVID-19 Post-Acute Care Study Group
JAMA. 2020;324(6):603-605. 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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Open Access Published: 24 September 2020
A SWATH-MS analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction
Eiren Sweetman, Torsten Kleffmann, Christina Edgar, Michel de Lange, Rosamund Vallings & Warren Tate
Journal of Translational Medicine volume 18, Article number:
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a serious and complex physical illness that affects all body systems with a multiplicity of symptoms, but key hallmarks of the disease are pervasive fatigue and ‘post-exertional malaise’, exacerbation after physical and/or mental activity of the intrinsic fatigue and other symptoms that can be highly debilitating and last from days to months. Although the disease can vary widely between individuals, common symptoms also include pain, cognitive deficits, sleep dysfunction, as well as immune, neurological and autonomic symptoms. Typically, it is a very isolating illness socially, carrying a stigma because of the lack of understanding of the cause and pathophysiology.
Methods
To gain insight into the pathophysiology of ME/CFS, we examined the proteomes of peripheral blood mononuclear cells (PBMCs) by SWATH-MS analysis in a small well-characterised group of patients and matched controls. A principal component analysis (PCA) was used to stratify groups based on protein abundance patterns, which clearly segregated the majority of the ME/CFS patients (9/11) from the controls. This majority subgroup of ME/CFS patients was then further compared to the control group.
Results
A total of 60 proteins in the ME/CFS patients were differentially expressed (P < 0.01, Log10 (Fold Change) > 0.2 and < −0.2). Comparison of the PCA selected subgroup of ME/CFS patients (9/11) with controls increased the number of proteins differentially expressed to 99. Of particular relevance to the core symptoms of fatigue and post-exertional malaise experienced in ME/CFS, a proportion of the identified proteins in the ME/CFS groups were involved in mitochondrial function, oxidative phosphorylation, electron transport chain complexes, and redox regulation. A significant number were also involved in previously implicated disturbances in ME/CFS, such as the immune inflammatory response, DNA methylation, apoptosis and proteasome activation.
Conclusions
The results from this study support a model of deficient ATP production in ME/CFS, compensated for by upregulation of immediate pathways upstream of Complex V that would suggest an elevation of oxidative stress. This study and others have found evidence of a distinct pathology in ME/CFS that holds promise for developing diagnostic biomarkers.
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Front. Neurol., 28 August 2020 | https://doi.org/10.3389/fneur.2020.00828
Signs of Intracranial Hypertension, Hypermobility, and Craniocervical Obstructions in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Björn Bragée1,2*, Anastasios Michos2, Brandon Drum1,2, Mikael Fahlgren2,3, Robert Szulkin1 and Bo C. Bertilson1,2,3
- 1Division of Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Solna, Sweden
- 2ME-center, Bragée Clinics, Stockholm, Sweden
- 3Academic Primary Health Care Center, Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden
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Reductions in Cerebral Blood Flow Can Be Provoked by Sitting in Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients
C (Linda) MC van Campen, Peter C. Rowe 2 and Frans C Visser
Stichting CardioZorg, 2132 HN Hoofddorp, The Netherlands
Department of Paediatrics, John Hopkins University School of Medicine, Baltimore, MD 21205, USA
Author to whom correspondence should be addressed.
Healthcare 2020, 8(4), 394; https://doi.org/10.3390/healthcare8040394
Received: 7 September 2020 / Revised: 6 October 2020 / Accepted: 9 October 2020 / Published: 11 October 2020
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Abstract
Introduction: In a large study with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients, we showed that 86% had symptoms of orthostatic intolerance in daily life and that 90% had an abnormal reduction in cerebral blood flow (CBF) during a standard tilt test. A standard head-up tilt test might not be tolerated by the most severely affected bed-ridden ME/CFS patients. Sitting upright is a milder orthostatic stress. The present study examined whether a sitting test, measuring cerebral blood flow by extracranial Doppler, would be sufficient to provoke abnormal reductions in cerebral blood flow in severe ME/CFS patients. Methods and results: 100 severe ME/CFS patients were studied, (88 females) and were compared with 15 healthy controls (HC) (13 females). CBF was measured first while seated for at least one hour, followed by a CBF measurement in the supine position. Fibromyalgia was present in 37 patients. Demographic data as well as supine heart rate and blood pressures were not different between ME/CFS patients and HC. Heart rate and blood pressure did not change significantly between supine and sitting both in patients and HC. Supine CBF was not different between patients and HC. In contrast, absolute CBF during sitting was lower in patients compared to HC: 474 (96) mL/min in patients and 627 (89) mL/min in HC; p < 0.0001. As a result, percent CBF reduction while seated was −24.5 (9.4)% in severe ME/CFS patients and −0.4 (1.2)% in HC (p < 0.0001). In the ten patients who had no orthostatic intolerance complaints in daily life, the CBF reduction was −2.7 (2.1)%, which was not significantly different from HC (p = 0.58). The remaining 90 patients with orthostatic intolerance complaints had a −26.9 (6.2)% CBF reduction. No difference in CBF parameters was found in patients with and without fibromyalgia. Patients with a previous diagnosis of postural orthostatic tachycardia syndrome (POTS) had a significantly larger CBF reduction compared with those without POTS: 28.8 (7.2)% vs. 22.3 (9.7)% (p = 0.0008). Conclusions: A sitting test in severe ME/CFS patients was sufficient to provoke a clinically and statistically significant mean CBF decline of 24.5%. Patients with a previous diagnosis of POTS had a larger CBF reduction while seated, compared to patients without POTS. The magnitude of these CBF reductions is similar to the results in less severely affected ME/CFS patients during head-up tilt, suggesting that a sitting test is adequate for the diagnosis of orthostatic intolerance in severely affected patients.
Keywords: orthostatic intolerance; cerebral blood flow; sitting; myalgic encephalomyelitis; chronic fatigue syndrome; severe disease; ME/CFS
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Letters Covid-19: “Just stay at home”
Long covid: doctors must assess and investigate patients properly
BMJ 2020; 371 doi: https://doi.org/10.1136/bmj.m4583 (Published 02 December 2020)Cite this as: BMJ 2020;371:m4583
Amali U Lokugamage, consultant obstetrician and gynaecologist and honorary associate professor12, Mary-Ann Bowen, general practitioner3, Jennifer Blair, consultant anaesthetist4
[email protected]
Jensen’s article provides a poignant patient perspective and reflects well the experiences of many patients that were very sick at the peak of the first wave of covid-19 but were denied proper medical assessment and told to “stay at home.”1 Of course it is important to “show you care” and empathise with the patient. But, as part of an online group of over 500 doctors (ever growing in number) affected by long covid, we are disappointed that the learning points don’t include “doctors should assess and investigate patients properly.” Before the covid-19 pandemic, symptoms such as low oxygen levels, tachycardia, and shortness of breath would warrant examination and investigation, especially when persistent and in previously fit and healthy patients.
It saddens us to hear such low expectations from general practice and secondary care. This is a new disease, and we are surprised about the lack of professional curiosity to explain new and sometimes seemingly odd symptoms. Numerous BMJ publications support the need for further assessment.234 Pathological consequences such as myocarditis5 or a thromboembolic episode6 may explain symptoms, and these have been noted to occur months after onset in long covid support groups. The medical profession needs to evolve rapid transformative pathways to deal with the long term sequelae of covid-19 that include full investigation of patients. This is becoming urgent, as new covid cases are increasing again and we are already starting to see a new wave of patients with long covid.
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Profile of circulating microRNAs in myalgic encephalomyelitis and their relation to symptom severity, and disease pathophysiology
- Evguenia Nepotchatykh, et al
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex chronic disease, rooted in multi-system dysfunctions characterized by unexplained debilitating fatigue. Post-exertional malaise (PEM), defined as the exacerbation of the patient's symptoms following minimal physical or mental stress, is a hallmark of ME/CFS. While multiple case definitions exist, there is currently no well-established biomarkers or laboratory tests to diagnose ME/CFS. Our study aimed to investigate circulating microRNA expression in severely ill ME/CFS patients before and after an innovative stress challenge that stimulates PEM. Our findings highlight the differential expression of eleven microRNAs associated with a physiological response to PEM. The present study uncovers specific microRNA expression signatures associated with ME/CFS in response to PEM induction and reports microRNA expression patterns associated to specific symptom severities. The identification of distinctive microRNA expression signatures for ME/CFS through a provocation challenge is essential for the elucidation of the ME/CFS pathophysiology, and lead to accurate diagnoses, prevention measures, and effective treatment options.
Accurate and objective determination of myalgic encephalomyelitis/chronic fatigue syndrome disease severity with a wearable sensor
- Turner Palombo, Andrea Campos, Suzanne D. Vernon & Shad Roundy
Abstract
Background
Approximately 2.5 million people in the U.S. suffer from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This disease negatively impacts patients’ ability to function, often resulting in difficulty maintaining employment, sustaining financial independence, engaging socially with others, and in particularly severe cases, consistently and adequately performing activities of daily living. The focus of this research was to develop a sensor-based method to measure upright activity defined as time with feet on the floor and referred to as UpTime, as an indicator of ME/CFS disease severity.
Methods
A commercially available inertial measurement unit (IMU), the Shimmer, was selected for this research. A Kalman filter was used to convert IMU data collected by the Shimmer to angle estimates. Angle estimate accuracy was confirmed by comparison to a motion capture system. Leg angle estimates were then converted to personalized daily UpTime scores using a critical angle of 39º from vertical to differentiate between upright (feet on the floor) and not upright. A 6-day, case–control study with 15 subjects (five healthy controls, five moderate-level ME/CFS, and five severe-level ME/CFS) was conducted to determine the utility of UpTime for assessing disease severity.
Results
UpTime was found to be a significant measure of ME/CFS disease severity. Severely ill ME/CFS patients spend less than 20% of each day with feet on the floor. Moderately ill ME/CFS patients spend between 20–30% of each day with feet on the floor. Healthy controls have greater than 30% UpTime. IMU-measured UpTime was more precise than self-reported hours of upright activity which were over-estimated by patients.
Conclusions
UpTime is an accurate and objective measure of upright activity, a measure that can be used to assess disease severity in ME/CFS patients. Due to its ability to accurately monitor upright activity, UpTime can also be used as a reliable endpoint for evaluating ME/CFS treatment efficacy. Future studies with larger samples and extended data collection periods are required to fully confirm the use of UpTime as a measure of disease severity in ME/CFS. With the added perspective of large-scale studies, this sensor-based platform could provide a recovery path for individuals struggling with ME/CFS.
Deep phenotyping of myalgic encephalomyelitis/chronic fatigue syndrome in Japanese population
- Toshimori Kitami, et al
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex and debilitating disease with no molecular diagnostics and no treatment options. To identify potential markers of this illness, we profiled 48 patients and 52 controls for standard laboratory tests, plasma metabolomics, blood immuno-phenotyping and transcriptomics, and fecal microbiome analysis. Here, we identified a set of 26 potential molecular markers that distinguished ME/CFS patients from healthy controls. Monocyte number, microbiome abundance, and lipoprotein profiles appeared to be the most informative markers. When we correlated these molecular changes to sleep and cognitive measurements of fatigue, we found that lipoprotein and microbiome profiles most closely correlated with sleep disruption while a different set of markers correlated with a cognitive parameter. Sleep, lipoprotein, and microbiome changes occur early during the course of illness suggesting that these markers can be examined in a larger cohort for potential biomarker application. Our study points to a cluster of sleep-related molecular changes as a prominent feature of ME/CFS in our Japanese cohort.
Diverse Functional Autoantibodies in Patients with COVID-19
Eric Y. Wang,1,* Tianyang Mao,1,* Jon Klein,1,* Yile Dai,1,* John D. Huck,1 Feimei Liu,1 Neil S. Zheng,1 Ting Zhou,1 Benjamin Israelow,1 Patrick Wong,1 Carolina Lucas,1 Julio Silva,1 Ji Eun Oh,1 Eric Song,1 Emily S. Perotti,1 Suzanne Fischer,1 Melissa Campbell,5 John B. Fournier,5 Anne L. Wyllie,3 Chantal B. F. Vogels,3 Isabel M. Ott,3 Chaney C. Kalinich,3 Mary E. Petrone,3 Anne E. Watkins,3 Yale IMPACT Team,¶ Charles Dela Cruz,4 Shelli F. Farhadian,5 Wade L. Schulz,6,7 Nathan D. Grubaugh,3 Albert I. Ko,3,5 Akiko Iwasaki,1,3,8,# and Aaron M. Ring1,2,#
Author information Copyright and License information Disclaimer
Version 2. medRxiv. Preprint. 2020 Dec 12.
doi: 10.1101/2020.12.10.20247205 PMCID: PMC7743105 PMID: 33330894
Abstract
COVID-19 manifests with a wide spectrum of clinical phenotypes that are characterized by exaggerated and misdirected host immune responses1–8. While pathological innate immune activation is well documented in severe disease1, the impact of autoantibodies on disease progression is less defined. Here, we used a high-throughput autoantibody discovery technique called Rapid Extracellular Antigen Profiling (REAP) to screen a cohort of 194 SARS-CoV-2 infected COVID-19 patients and healthcare workers for autoantibodies against 2,770 extracellular and secreted proteins (the “exoproteome”). We found that COVID-19 patients exhibit dramatic increases in autoantibody reactivities compared to uninfected controls, with a high prevalence of autoantibodies against immunomodulatory proteins including cytokines, chemokines, complement components, and cell surface proteins. We established that these autoantibodies perturb immune function and impair virological control by inhibiting immunoreceptor signaling and by altering peripheral immune cell composition, and found that murine surrogates of these autoantibodies exacerbate disease severity in a mouse model of SARS-CoV-2 infection. Analysis of autoantibodies against tissue-associated antigens revealed associations with specific clinical characteristics and disease severity. In summary, these findings implicate a pathological role for exoproteome-directed autoantibodies in COVID-19 with diverse impacts on immune functionality and associations with clinical outcomes.
Review
Am J Cardiovasc Drugs . 2018 Jun;18(3):195-204. doi: 10.1007/s40256-017-0252-1.
Ivabradine for the Treatment of Postural Orthostatic Tachycardia Syndrome: A Systematic Review
Megan E Gee 1, Alicia K Watkins 2, Jamie N Brown 3, Emily J A Young 4
Affiliations expand PMID: 29330767 DOI: 10.1007/s40256-017-0252-1
Abstract
Introduction: Postural orthostatic tachycardia syndrome (POTS) impacts millions of patients, but there is currently no gold standard treatment for this condition. Ivabradine is a novel heart rate (HR) lowering agent that acts on the sinoatrial node cells by selectively inhibiting the If-current.
Objective: The objective of this systematic review is to evaluate the evidence for the efficacy and safety of ivabradine for the treatment of POTS.
Methods: MEDLINE (from 1956 to August 2017) and EMBASE (from 1957 to August 2017) were queried with the following search term: "postural orthostatic tachycardia syndrome" OR "postural tachycardia syndrome" OR "chronic orthostatic intolerance" AND "ivabradine." Articles in English with clinical outcomes of human patient(s) treated with ivabradine for POTS were included.
Results: The initial search identified 73 articles. After screening, 13 articles were included. Two prospective open-label trials, three retrospective cohort studies, and eight case reports evaluated the safety and efficacy of ivabradine in a total of 132 patients with postural tachycardia. Overall, ivabradine lowered HR and provided symptomatic relief of POTS without blood pressure lowering. Dizziness, nausea, headache, and fatigue were the most common side effects and often did not lead to discontinuation of treatment.
Conclusion: Based on this small sample, ivabradine appears to be a reasonable option for patients with POTS who have failed or are unable to tolerate other treatment options, however, but a randomized controlled trial in this population is needed.
Cureus. 2020 Apr; 12(4): e7868.
Published online 2020 Apr 28. doi: 10.7759/cureus.7868
PMCID: PMC7255540
Ivabradine in Postural Orthostatic Tachycardia Syndrome: A Review of the Literature
Faryal Tahir,1 Taha Bin Arif,1 Zainab Majid,1 Jawad Ahmed,1 and Muhammad Khalid2,3
Abstract
Introduction and background
The first informal mention of postural orthostatic tachycardia syndrome (POTS) was by Da Costa, in 1871, who referred to it as “soldier’s heart” or “irritable heart” [1]. However, Schondorf and Low, in 1993, first described POTS in the adult population as an increase in the heart rate (HR) in a symptomatic patient by more than 30 beats per min (bpm) when the patient moves from supine to upright position [2]. In 2015, Heart Rhythm Society defined POTS on the basis of three points: (1) a clinical syndrome characterized by symptoms of lightheadedness, blurring of vision, palpitations, intolerance to exercise, and fatigue; (2) an increase of ≥30 bpm (≥40 bpm in those aged 12-19 years) in the HR when the person stands up from a recumbent position; and (3) absence of orthostatic hypotension [3]. Orthostatic hypotension is characterized by a more than 20 mmHg drop in systolic blood pressure (BP) on standing [3]. The incidence of POTS varies globally from 0.2% to 1% in the developed countries with an increased prevalence among females, Caucasian race, and individuals from 13 to 50 years of age [4,5,6-8]. The affected individuals account for 3,000,000 cases alone in the United States of America (USA) [9]. A recent 2019 study has shown that the incidence of POTS has increased fourfold since 2000 [8].
POTS is an autonomic disorder characterized by symptoms such as palpitations, dyspnea, chest discomfort, lightheadedness, nausea, blurred vision, chronic fatigue, sleeping abnormalities, migraines, hypermobile joints, abdominal pain, irritable bowel, and bladder symptoms as well affecting various systems [9,10]. Only 30% of individuals have reported fainting along with the symptoms of POTS [9]. Usually, there is a two-year (median) delay in the diagnosis of disease from the onset of symptoms [7]. The pathophysiology of POTS is not completely understood due to a variety of symptoms showing that the disease is multifactorial [4,9,10]. Chronic fatigue syndrome, inappropriate sinus tachycardia, and vasovagal syncope are few conditions associated with POTS [4].
There is no approved uniform management strategy for POTS and hence, no drug has been approved by the US Food and Drug Administration (FDA) for it [4]. Non-pharmacological therapies include lifestyle modifications such as increased hydration and salt intake, and use of support stockings [11]. Pharmacological therapies include beta-blockers (first line), alpha-agonists (first or second line), mineralocorticoids (second line), selective serotonin reuptake inhibitors (SSRIs), and selective serotonin-norepinephrine reuptake inhibitors (SSNRIs), and rarely used drugs include pyridostigmine, desmopressin, and erythropoietin [4,11]. However, there has been evidence of beneficial outcomes with the use of ivabradine in POTS patients, as seen in prospective and retrospective studies [12-16].
Ivabradine is an FDA-approved drug for stable symptomatic heart failure (HF) and patients with an ejection fraction (EF) of ≤35% [17,18]. European Society of Cardiology recommends ivabradine as second-line therapy for patients whose angina has been poorly controlled by other medications, namely calcium-channel blockers (CCBs), beta-blockers, or nitrates (short-acting) [19].
Ivabradine increases the diastolic time and reduces the HR by inhibiting channels responsible for maintaining cardiac pacemaker current, If (funny current). The selective blocking of these trans-membrane ion channels that conduct the inward depolarizing sodium (Na) and potassium (K) current slows down the HR without affecting systemic vascular resistance and cardiac inotropy [18,20,21]. Ivabradine has been+ associated with many severe side effects such as bradycardia, heart block, sinus arrest, QT prolongation, torsades de pointes, and fetal toxicity. Other less severe side effects include, but are not limited to, vertigo, diplopia, rash, and hypotension [17,18].
Ivabradine is not an FDA-approved drug for POTS but due to its ability to reduce HR, it has shown improvement in POTS patients in many studies [12-16]. This review aims to provide a comprehensive and up-to-date picture of all the studies and case reports that utilized ivabradine for the treatment of POTS along with a precise overview of epidemiology, pathophysiology, and types of POTS.
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. 2020;324(6):603-605. doi:10.1001/jama.2020.12603 July 9, 2020
What Is It Like to Have COVID-19?
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.
Mapping of pathological change in chronic fatigue syndrome using the ratio of T1- and T2-weighted MRI scans
Author links open overlay panelKiranThapaliyaabSonyaMarshall-GradisnikaDonStainesaLeightonBarndena
https://doi.org/10.1016/j.nicl.2020.102366Get rights and content
Neurolmage Clinical Vol 28 2020cc
Highlights
We showed increased T1w/T2w in ME/CFS in contrast to other neurodegenerative diseases.
Higher T1w/T2w occurred in basal ganglia and white matter tracts.
Increased T1w/T2w indicates increased myelin and/or iron levels.
T1w/T2w regressions vs clinical measures were abnormal in cingulate cortex and white matter foci.
Abstract
Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS) subjects suffer from a variety of cognitive complaints indicating that the central nervous system plays a role in its pathophysiology. Recently, the ratio T1w/T2w has been used to study changes in tissue myelin and/or iron levels in neurodegenerative diseases such as multiple sclerosis and schizophrenia. In this study, we applied the T1w/T2w method to detect changes in tissue microstructure in ME/CFS patients relative to healthy controls. We mapped the T1w/T2w signal intensity values in the whole brain for forty-five ME/CFS patients who met Fukuda criteria and twenty-seven healthy controls and applied both region- and voxel-based quantification. We also performed interaction-with-group regressions with clinical measures to test for T1w/T2w relationships that are abnormal in ME/CFS at the population level. Region-based analysis showed significantly elevated T1w/T2w values (increased myelin and/or iron) in ME/CFS in both white matter (WM) and subcortical grey matter. The voxel-based group comparison with sub-millimetre resolution voxels detected very significant clusters with increased T1w/T2w in ME/CFS, mostly in subcortical grey matter, but also in brainstem and projection WM tracts. No areas with decreased T1w/T2w were found in either analysis. ME/CFS T1w/T2w regressions with heart-rate variability, cognitive performance, respiration rate and physical well-being were abnormal in both gray and white matter foci. Our study demonstrates that the T1w/T2w approach is very sensitive and shows increases in myelin and/or iron in WM and basal ganglia in ME/CFS.
A systematic review of mitochondrial abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease
Sean Holden, Rebekah Maksoud, Natalie Eaton-Fitch, Hélène Cabanas, Donald Staines & Sonya Marshall-Gradisnik
Published: 29 July 2020
Journal of Translational Medicine volume 18, Article number: 290 (2020) Cite this article
The Correction to this article has been published in Journal of Translational Medicine 2020 18:407
Abstract
Background
Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) or Systemic Exertion Intolerance Disease (SEID) present with a constellation of symptoms including debilitating fatigue that is unrelieved by rest. The pathomechanisms underlying this illness are not fully understood and the search for a biomarker continues, mitochondrial aberrations have been suggested as a possible candidate. The aim of this systematic review is to collate and appraise current literature on mitochondrial changes in ME/CFS/SEID patients compared to healthy controls.
Methods
Embase, PubMed, Scopus and Medline (EBSCO host) were systematically searched for articles assessing mitochondrial changes in ME/CFS/SEID patients compared to healthy controls published between January 1995 and February 2020. The list of articles was further refined using specific inclusion and exclusion criteria. Quality and bias were measured using the Joanna Briggs Institute Critical Appraisal Checklist for Case Control Studies.
Results
Nineteen studies were included in this review. The included studies investigated mitochondrial structural and functional differences in ME/CFS/SEID patients compared with healthy controls. Outcomes addressed by the papers include changes in mitochondrial structure, deoxyribonucleic acid/ribonucleic acid, respiratory function, metabolites, and coenzymes.
Conclusion
Based on the included articles in the review it is difficult to establish the role of mitochondria in the pathomechanisms of ME/CFS/SEID due to inconsistencies across the studies. Future well-designed studies using the same ME/CFS/SEID diagnostic criteria and analysis methods are required to determine possible mitochondrial involvement in the pathomechanisms of ME/CFS/SEID.
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.
Centre for Applied Health Economics, Griffith University, Nathan, QLD, Australia
Objectives: This study aims to estimate direct and indirect health economic costs associated with government and out-of-pocket (OOP) expenditure based on health care service utilization and lost income of participants and carers, as reported by Australian Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patient survey participants.
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.
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Organic Disease or Psychosomatic Illness? A Re-Examination of the Royal Free Epidemic of 1955
Rosemary Underhill 1,* and Rosemarie Baillod 2
Medicina 2021, 57, 12. https://dx.doi.org/10.3390/ medicina57010012 Received: 20 November 2020 Accepted: 22 December 2020 Published: 26 December 2020
Copyright: © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Correspondence: [email protected]
Abstract:
Background and Objectives: Controversy exists over whether myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an organic disease or a psychosomatic illness. ME/CFS usually occurs as sporadic cases, but epidemics (outbreaks) have occurred worldwide. Myalgic encephalomyelitis was named to describe an outbreak affecting the lymphatic, muscular, and nervous systems that closed the Royal Free hospital for three months in 1955. Fifteen years later, two psychiatrists concluded that epidemic hysteria was the likely cause. ME/CFS research studies show multiple pathophysiological differences between patients and controls and a possible etiological role for infectious organisms, but the belief that ME/CFS is psychosomatic is widespread and has been specifically supported by the epidemic hysteria hypothesis for the Royal Free outbreak. Our objective was to obtain accounts from ex-Royal Free hospital staff who personally experienced the 1955 outbreak and evaluate evidence for it being an infectious illness versus epidemic hysteria.
Materials and Methods: Statements in the newsletters of two organizations for staff who had worked at the Royal Free hospital invited anyone who had experienced the 1955 Royal Free outbreak to contact the authors. Accounts of the outbreak from telephone interviews and letters were evaluated against the “epidemic hysteria hypothesis” paper and original medical staff reports.
Results: Twentyseven ex-Royal Free hospital staff, including six who had developed ME, provided descriptions typical of an infectious illness affecting the lymphatic, muscular, and nervous systems, and were not consistent with epidemic hysteria.
Conclusions: The 1955 Royal Free hospital epidemic of myalgic encephalomyelitis was an organic infectious disease, not psychogenic epidemic hysteria.
Keywords: Chronic fatigue syndrome; epidemic hysteria; mass hysteria; myalgic encephalomyelitis; psychosomatic illness; Royal Free epidemic
Characterizing Long COVID in an International Cohort: 7 Months of Symptoms and Their Impact
medRxiv preprint doi: https://doi.org/10.1101/2020.12.24.20248802; this version posted December 27, 2020
Hannah E. Davis1 *, Gina S. Assaf1 *, Lisa McCorkell1 *, Hannah Wei1 *, Ryan J. Low1,2*, Yochai Re’em1,3*, Signe Redfield1 , Jared P. Austin4 , Athena Akrami1,
Patient-Led Research for COVID-19, 2 Sainsbury Wellcome Centre, University College London, London, UK, 3 NewYork-Presbyterian Hospital / Weill Cornell Medicine, NYC, USA, 4 Oregon Health and Science University, Portland, OR, USA + Corresponding author, email: [email protected]
Abstract Objective. To characterize the symptom profile and time course in patients with Long COVID, along with the impact on daily life, work, and return to baseline health. Design. International web-based survey of suspected and confirmed COVID-19 cases with illness lasting over 28 days and onset prior to June 2020.
Setting. Survey distribution via online COVID-19 support groups and social media
Participants. 3,762 respondents from 56 countries completed the survey. 1166 (33.7%) were 40-49 years old, 937 (27.1%) were 50-59 years old, and 905 (26.1%) were 30-39 years old. 2961 (78.9%) were women, 718 (19.1%) were men, and 63 (1.7%) were nonbinary. 8.4% reported being hospitalized. 27% reported receiving a laboratory-confirmed diagnosis of COVID-19. 96% reported symptoms beyond 90 days.
Results. Prevalence of 205 symptoms in 10 organ systems was estimated in this cohort, with 66 symptoms traced over seven months. Respondents experienced symptoms in an average of 9.08 (95% confidence interval 9.04 to 9.13) organ systems. The most frequent symptoms reported after month 6 were: fatigue (77.7%, 74.9% to 80.3%), post-exertional malaise (72.2%, 69.3% to 75.0%), and cognitive dysfunction (55.4%, 52.4% to 58.8%). These three symptoms were also the three most commonly reported overall. In those who recovered in less than 90 days, the average number of symptoms peaked at week 2 (11.4, 9.4 to 13.6), and in those who did not recover in 90 days, the average number of symptoms peaked at month 2 (17.2, 16.5 to 17.8). Respondents with symptoms over 6 months experienced an average of 13.8 (12.7 to 14.9) symptoms in month 7. 85.9% (84.8% to 87.0%) experienced relapses, with exercise, physical or mental activity, and stress as the main triggers. 86.7% (85.6% to 92.5%) of unrecovered respondents were experiencing fatigue at the time of survey, compared to 44.7% (38.5% to 50.5%) of recovered respondents. 45.2% (42.9% to 47.2%) reported requiring a reduced work schedule compared to pre-illness and 22.3% (20.5% to 24.3%) were not working at the time of survey due to their health conditions.
Conclusions. Patients with Long COVID report prolonged multisystem involvement and significant disability. Most had not returned to previous levels of work by 6 months. Many patients are not recovered by 7 months, and continue to experience significant symptom burden.
Neurology
Coenzyme Q10 supplementation for prophylaxis in adult patients with migraine—a meta-analysis
- Suhairul Sazali, http://orcid.org/0000-0002-7353-2839
- Salziyan Badrin, http://orcid.org/0000-0002-6372-1476
- Mohd Noor Norhayati, Nur Suhaila Idris
Abstract
Objective To determine the effects of coenzyme Q10 (CoQ10) for reduction in the severity, frequency of migraine attacks and duration of headache in adult patients with migraine.
Design Systematic review and meta-analysis.
Data sources Cochrane Central Register of Controlled Trials, CENTRAL, MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Psychological Information Database (PsycINFO) from inception till December 2019.
Study selection All randomised control trials comparing CoQ10 with placebo or used as an adjunct treatment included in this meta-analysis. Cross-over designs and controlled clinical trials were excluded.
Data synthesis Heterogeneity at face value by comparing populations, settings, interventions and outcomes were measured and statistical heterogeneity was assessed by means of the I2 statistic. The treatment effect for dichotomous outcomes were using risk ratios and risk difference, and for continuous outcomes, mean differences (MDs) or standardised mean difference; both with 95% CIs were used. Subgroup analyses were carried out for dosage of CoQ10 and if CoQ10 combined with another supplementation. Sensitivity analysis was used to investigate the impact risk of bias for sequence generation and allocation concealment of included studies.
Results Six studies with a total of 371 participants were included in the meta-analysis. There is no statistically significant reduction in severity of migraine headache with CoQ10 supplementation. CoQ10 supplementation reduced the duration of headache attacks compared with the control group (MD: −0.19; 95% CI: −0.27 to −0.11; random effects; I2 statistic=0%; p<0.00001). CoQ10 usage reduced the frequency of migraine headache compared with the control group (MD: −1.52; 95% CI: −2.40 to −0.65; random effects; I2 statistic=0%; p<0.001).
Conclusion CoQ10 appears to have beneficial effects in reducing duration and frequency of migraine attack.
PROSPERO registration number CRD42019126127.
Imaging Jan 5, 2021:Brain Responses to Noxious Stimuli in Patients With Chronic Pain
A Systematic Review and Meta-analysis
Anna Xu, BS1; Bart Larsen, PhD1; Alina Henn, MS2; et alErica B. Baller, MD, MS1,3,4; J. Cobb Scott, PhD1,5; Vaishnavi Sharma, BA1; Azeez Adebimpe, PhD1; Allan I. Basbaum, PhD6; Gregory Corder, PhD1; Robert H. Dworkin, PhD7; Robert R. Edwards, MD8; Clifford J. Woolf, MB, BCh, PhD9,10; Simon B. Eickhoff, MD11,12; Claudia R. Eickhoff, MD12,13; Theodore D. Satterthwaite, MD, MA1
JAMA Netw Open. 2021;4(1):e2032236. doi:10.1001/jamanetworkopen.2020.32236
Key Points: Question Do the brains of patients with chronic pain respond differently to noxious stimuli?
Findings This systematic review and meta-analysis of 37 experiments from 29 unique articles including 944 participants found that patients with chronic pain were not associated with significant differential responses to noxious stimuli that induce pain compared with healthy controls.
Meaning Chronic pain does not appear to be associated with consistent marked alterations in the brain’s response to noxious stimuli.
Abstract: Importance Functional neuroimaging is a valuable tool for understanding how patients with chronic pain respond to painful stimuli. However, past studies have reported heterogenous results, highlighting opportunities for a quantitative meta-analysis to integrate existing data and delineate consistent associations across studies.
Objective To identify differential brain responses to noxious stimuli in patients with chronic pain using functional magnetic resonance imaging (fMRI) while adhering to current best practices for neuroimaging meta-analyses.
Data Sources All fMRI experiments published from January 1, 1990, to May 28, 2019, were identified in a literature search of PubMed/MEDLINE, EMBASE, Web of Science, Cochrane Library, PsycINFO, and SCOPUS.
Study Selection Experiments comparing brain responses to noxious stimuli in fMRI between patients and controls were selected if they reported whole-brain results, included at least 10 patients and 10 healthy control participants, and used adequate statistical thresholding (voxel-height P < .001 or cluster-corrected P < .05). Two independent reviewers evaluated titles and abstracts returned by the search. In total, 3682 abstracts were screened, and 1129 full-text articles were evaluated.
Data Extraction and Synthesis Thirty-seven experiments from 29 articles met inclusion criteria for meta-analysis. Coordinates reporting significant activation differences between patients with chronic pain and healthy controls were extracted. These data were meta-analyzed using activation likelihood estimation. Data were analyzed from December 2019 to February 2020.
Main Outcomes and Measures A whole-brain meta-analysis evaluated whether reported differences in brain activation in response to noxious stimuli between patients and healthy controls were spatially convergent. Follow-up analyses examined the directionality of any differences. Finally, an exploratory (nonpreregistered) region-of-interest analysis examined differences within the pain network.
Results The 37 experiments from 29 unique articles included a total of 511 patients and 433 controls (944 participants). Whole-brain meta-analyses did not reveal significant differences between patients and controls in brain responses to noxious stimuli at the preregistered statistical threshold. However, exploratory analyses restricted to the pain network revealed aberrant activity in patients.
Conclusions and Relevance In this systematic review and meta-analysis, preregistered, whole-brain analyses did not reveal aberrant fMRI activity in patients with chronic pain. Exploratory analyses suggested that subtle, spatially diffuse differences may exist within the pain network. Future work on chronic pain biomarkers may benefit from focus on this core set of pain-responsive areas.
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