Cognitive assessment in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a cognitive substudy of the multi-site clinical assessment of ME/CFS (MCAM)

Abstract:

Introduction: Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) experience cognitive problems with attention, information processing speed, working memory, learning efficiency, and executive function. Commonly, patients report worsening of cognitive symptoms over time after physical and/or cognitive challenges. To determine, monitor, and manage longitudinal decrements in cognitive function after such exposures, it is important to be able to screen for cognitive dysfunction and changes over time in clinic and also remotely at home. The primary objectives of this paper were: (1) to determine whether a brief computerized cognitive screening battery will detect differences in cognitive function between ME/CFS and Healthy Controls (HC), (2) to monitor the impact of a full-day study visit on cognitive function over time, and (3) to evaluate the impact of exercise testing on cognitive dysfunction.

Methods: This cognitive sub-study was conducted between 2013 and 2019 across seven U.S. ME/CFS clinics as part of the Multi-Site Clinical Assessment of ME/CFS (MCAM) study. The analysis included 426 participants (261 ME/CFS and 165 HC), who completed cognitive assessments including a computerized CogState Brief Screening Battery (CBSB) administered across five timepoints (T0-T4) at the start of and following a full day in-clinic visit that included exercise testing for a subset of participants (182 ME/CFS and 160 HC). Exercise testing consisted of ramped cycle ergometry to volitional exhaustion. The primary outcomes are performance accuracy and latency (performance speed) on the computerized CBSB administered online in clinic (T0 and T1) and at home (T2-T4).

Results: No difference was found in performance accuracy between ME/CFS and HCs whereas information processing speed was significantly slower for ME/CFS at most timepoints with Cohen’s d effect sizes ranging from 0.3-0.5 (p < 0.01). The cognitive decline over time on all CBSB tasks was similar for patients with ME/CFS independent of whether exercise testing was included in the clinic visit.

Conclusion: The challenges of a clinic visit (including cognitive testing) can lead to further cognitive deficits. A single short session of intense exercise does not further reduce speed of performance on any CBSB tasks.

Source: Lange G, Lin JS, Chen Y, Fall EA, Peterson DL, Bateman L, Lapp C, Podell RN, Natelson BH, Kogelnik AM, Klimas NG, Unger ER. Cognitive assessment in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a cognitive substudy of the multi-site clinical assessment of ME/CFS (MCAM). Front Neurosci. 2024 Nov 1;18:1460157. doi: 10.3389/fnins.2024.1460157. PMID: 39554847; PMCID: PMC11565701. https://pmc.ncbi.nlm.nih.gov/articles/PMC11565701/ (Full text)

Maximal oxidative capacity during exercise is associated with muscle power output in patients with long coronavirus disease 2019 (COVID-19) syndrome. A moderation analysis

Abstract:

Background & aims: Long COVID syndrome (LCS) involves persistent symptoms experienced by many patients after recovering from coronavirus disease 2019 (COVID-19). We aimed to assess skeletal muscle energy metabolism, which is closely related to substrate oxidation rates during exercise, in patients with LCS compared with healthy controls. We also examined whether muscle power output mediates the relationship between COVID-19 and skeletal muscle energy metabolism.

Methods: In this cross-sectional study, we enrolled 71 patients with LCS and 63 healthy controls. We assessed clinical characteristics such as body composition, physical activity, and muscle strength. We used cardiopulmonary exercise testing to evaluate substrate oxidation rates during graded exercise. We performed statistical analyses to compare group characteristics and peak fat oxidation differences based on power output.

Results: The two-way analysis of covariance (ANCOVA) results, adjusted for covariates, showed that the patients with LCS had lower absolute maximal fatty acid oxidation (MFO), relative MFO/fat free mass (FFM), absolute carbohydrates oxidation (CHox), relative CHox/FFM, and oxygen uptake (V˙˙O2) at maximum fat oxidation (g min-1) than the healthy controls (P < 0.05). Moderation analysis indicated that muscle power output significantly influenced the relationship between LCS and reduced peak fat oxidation (interaction β = -0.105 [95% confidence interval -0.174; -0.036]; P = 0.026). Therefore, when muscle power output was below 388 W, the effect of the LCS on MFO was significant (62% in our study sample P = 0.010). These findings suggest compromised mitochondrial bioenergetics and muscle function, represented by lower peak fat oxidation rates, in the patients with LCS compared with the healthy controls.

Conclusion: The patients with LCS had lower peak fat oxidation during exercise compared with the healthy controls, potentially indicating impairment in skeletal muscle function. The relationship between peak fat oxidation and LCS appears to be mediated predominantly by muscle power output. Additional research should continue investigating LCS pathogenesis and the functional role of mitochondria.

Source: Ramírez-Vélez R, Oscoz-Ochandorena S, García-Alonso Y, García-Alonso N, Legarra-Gorgoñon G, Oteiza J, Lorea AE, Izquierdo M, Correa-Rodríguez M. Maximal oxidative capacity during exercise is associated with muscle power output in patients with long coronavirus disease 2019 (COVID-19) syndrome. A moderation analysis. Clin Nutr ESPEN. 2023 Dec;58:253-262. doi: 10.1016/j.clnesp.2023.10.009. Epub 2023 Oct 14. PMID: 38057014. https://clinicalnutritionespen.com/article/S2405-4577(23)02166-6/fulltext (Full text)

Adrenergic dysfunction in patients with myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia: A systematic review and meta-analysis

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are comorbid disorders with overlapping symptoms. Research highlights autonomic dysfunction compared to healthy individuals, particularly involving the sympathetic branch. While past reviews focused on neurophysiological assessments, this systematic review summarises biological adrenergic markers, offering deeper insights into the observed sympathetic dysfunction in ME/CFS and FM aiming to identify targetable pathophysiological mechanisms.

Methods: A systematic search was performed on PubMed, Web of Science, Embase and Scopus. Studies investigating peripheral biological markers of adrenergic function in patients with ME/CFS or FM compared to healthy controls at baseline were included. Meta-analyses were performed using R statistical software.

Results: This meta-analysis of 37 studies, encompassing 543 ME/CFS patients and 651 FM patients, compared with 747 and 447 healthy controls, respectively, revealed elevated adrenaline (SMD = .49 [.31-.67]; Z = 5.29, p < .01) and β1 adrenergic receptor expression (SMD = .79 [.06-1.52]; Z = 2.13; p = .03) in blood of ME/CFS patients at rest. Additionally, patients with ME/CFS had a greater increase in the expression of α2A adrenergic receptor (AR, SMD = .57 [.18-.97]; Z = 2.85, p < .01), β2 AR (SMD = .41 [.02-.81]; Z = 2.04; p = .04) and COMT (SMD = .42 [.03-.81]; Z = 2.11; p = .03) after exercise and an increased response of noradrenaline to an orthostatic test (SMD = .11 [-.47 to -.70]; Z = 2.10; p = .04), both found in blood. FM patients showed no significant differences at baseline but exhibited a diminished adrenaline response to exercise (SMD = -.79 [-1.27 to -.30]; Z = -3.14; p < .01).

Conclusion: This systematic review and meta-analysis revealed adrenergic dysfunction mainly in patients with ME/CFS. Higher baseline adrenaline levels and atypical responses to exercise in ME/CFS indicate that sympathetic dysfunction, underscored by adrenergic abnormalities, is more involved in the pathophysiology of ME/CFS rather than FM.

Source: Hendrix J, Fanning L, Wyns A, Ahmed I, Patil MS, Richter E, Van Campenhout J, Ickmans K, Mertens R, Nijs J, Godderis L, Polli A. Adrenergic dysfunction in patients with myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia: A systematic review and meta-analysis. Eur J Clin Invest. 2024 Sep 25:e14318. doi: 10.1111/eci.14318. Epub ahead of print. PMID: 39319943. https://pubmed.ncbi.nlm.nih.gov/39319943/

Post-Exertional Malaise in Veterans with Gulf War Illness

Abstract:

Post-exertional malaise (PEM) is a potentially debilitating aspect of Gulf War Illness (GWI) that has received limited research attention. The purpose of the present investigation was to determine symptom severity changes following exercise in Veterans with GWI compared to control Veterans without GWI (CO).

Sixty-seven Veterans (n=39 GWI; n=28 CO) underwent a 30-minute submaximal exercise challenge at 70% of heart rate reserve. Symptom measurements (e.g. fatigue, pain) occurred pre-, immediately post-, and 24-hours post-exercise. Self-reported physical and mental health, and physiological and perceptual responses to exercise were compared between groups using descriptive statistics, independent samples t-tests and repeated measures Analysis of Variance (RM-ANOVA).

Post-exertional malaise was modeled using Group by Time (2 × 3) doubly-multivariate, RM-MANOVAs for (1) mood, (2) pain and (3) GWI-related symptoms, respectively (α=0.05). Data were analyzed for the full sample of Veterans with GWI (n=39) compared to CO (n=28) and a subsample of Veterans (n=18) who endorsed “feeling unwell after physical exercise or exertion” (“PEM endorsers”) during screening.

Veterans with GWI reported significantly lower physical and mental health. Groups exercised at similar relative exercise intensities, but GWI perceived exercise as more painful and fatiguing. Group-by-Time interactions were not significant for the entire sample for the three PEM models, however limiting the GWI sample to “PEM endorsers” resulted in significant interactions for Pain- and GWI-related PEM models.

These results indicate that not all GVs with GWI experience PEM 24 hr after exercise, and that more research is needed to determine the extent that exercise worsens symptoms in GWI.

Source: Lindheimer JB, Stegner AJ, Wylie GR, Klein-Adams JC, Almassi NE, Ninneman JV, Van Riper SM, Dougherty RJ, Falvo MJ, Cook DB. Post-exertional malaise in veterans with gulf war illness. Int J Psychophysiol. 2020 Jan;147:202-212. doi: 10.1016/j.ijpsycho.2019.11.008. Epub 2019 Nov 28. PMID: 31786249; PMCID: PMC6957714. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957714/ (Full text)

‘You don’t want to get better’: the outdated treatment of ME/CFS patients is a national scandal

By George Monbiot

It’s the greatest medical scandal of the 21st century. For decades, patients with ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) have been told they can make themselves better by changing their attitudes. This devastating condition, which afflicts about 250,000 people in the UK, was psychologised by many doctors and scientists, adding to the burden of a terrible physiological illness.

Long after this approach was debunked in scientific literature, clinicians who championed it have refused to let go. They continue to influence healthcare systems, governments and health insurers. And patients still suffer as a result.

Read the full article in The Guardian HERE.

Cardiorespiratory abnormalities in ICU survivors of COVID-19 with Post-acute Sequelae of SARS-CoV-2 infection are unrelated to invasive mechanical ventilation

Abstract:

Post-acute Sequelae of SARS-CoV-2 infection (PASC) often leads to exertional intolerance and reduced exercise capacity, particularly in individuals previously admitted to an intensive care unit (ICU). However, the impact of invasive mechanical ventilation (IMV) on PASC-associated cardiorespiratory abnormalities during exercise remains poorly understood.

This single-center, cross-sectional study aimed to gather knowledge on this topic. Fifty-two patients with PASC recruited ~6 months after ICU discharge were clustered based on their need for IMV (PASC+IMV, n=27) or non-invasive support therapy (PASC+NIS, n=25). Patients underwent pulmonary function and cardiopulmonary exercise testing (CPX), and were compared to a reference group (CONTROL, n=19) comprising individuals of both sexes with similar age, comorbidities, and physical activity levels, but without a history of COVID-19 illness.

Individuals with PASC, irrespective of support therapy, presented with higher rates of cardiorespiratory abnormalities than CONTROL, especially dysfunctional breathing patterns, dynamic hyperinflation, reduced oxygen uptake and oxygen pulse, and blunted heart rate recovery (all P<0.05). Only the rate of abnormal oxygen pulse was greater among PASC+IMV than PASC+NIS (P=0.05). Mean estimates for all CPX variables were comparable between PASC-IMV and PASC-NIS (all P>0.05).

These findings indicate significant involvement of both central and peripheral factors, leading to exertional intolerance in individuals with PASC previously admitted to the ICU, regardless of their need for IMV.

Source: Longobardi I, Prado DMLD, de Andrade DCO, Goessler KF, de Oliveira Júnior GN, Azevedo RA, Leitão AE, Santos JVP, de Sá Pinto AL, Gualano B, Roschel H. Cardiorespiratory abnormalities in ICU survivors of COVID-19 with Post-acute Sequelae of SARS-CoV-2 infection are unrelated to invasive mechanical ventilation. Am J Physiol Heart Circ Physiol. 2024 Feb 9. doi: 10.1152/ajpheart.00073.2024. Epub ahead of print. PMID: 38334972. https://pubmed.ncbi.nlm.nih.gov/38334972/ (Full study available as PDF file)

Exploring the neurocognitive consequences of post-exertional malaise in myalgic encephalomyelitis

Background and aims:

Myalgic encephalomyelitis (ME) is a complex, debilitating and heterogeneous disorder. It affects over 500,000 people in Canada but remains poorly understood. People are affected with multi-systemic symptoms such as fatigue that is not alleviated by rest, pain, cognitive impairment and post-exertional malaise (PEM), which is considered as the hallmark symptom of ME. PEM is triggered by minimal mental or physical effort and exacerbates other symptoms. Our aim was to measure how individuals’ cognition can be impacted by the induction of PEM, and investigate the difference in cognitive response.

Section snippets:

Methods
A prospective cohort of people with ME (n = 42) and matched healthy controls (n = 15) was recruited and subjected to PEM induction through a 90-minutes mechanical arm stimulation. BrainCheck test (BrainCheck, Inc., TX, USA) was used at baseline (T0) and after 90 minutes of stimulation to evaluate six cognitive domains for which each participant received a score and a population percentile based on their performance.

Results
Comparison between both groups was significant (p < 0.05) at T90, but not at T0, in four out of six cognitive domains. We then classified our ME cohort in three clusters by k-means method based on the Δ percentile (T90-T0) for each cognitive task. This stratification allowed us to notice how some cognitive domains seem more affected depending on the cluster, namely memory and attention.

Conclusions
These results showed the impact of PEM on the disturbance of cognition in the context of ME as well as the variability of cognitive domains affected in people with ME.

Source: Corinne Leveau, Iurie Caraus, Anita Franco, Alain Moreau. Exploring the neurocognitive consequences of post-exertional malaise in myalgic encephalomyelitis. Journal of the Neurological Sciences, Volume 455, Supplement, December 2023, 122590. https://www.sciencedirect.com/science/article/abs/pii/S0022510X23020518

 

Post-exertional malaise in daily life and experimental exercise models in patients with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Post-exertional malaise (PEM) is commonly recognized as a hallmark of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and is often used as one of several criteria for diagnosing ME/CFS.

In this perspective paper we want to reflect on how PEM is understood, assessed, and evaluated in scientific literature, and to identify topics to be addressed in future research.

Studies show that patients use a wide variety of words and concepts to label their experience of PEM in everyday life, and they report physical or mental exertions as triggers of PEM. They also report that PEM may have an immediate or delayed onset and may last from a few days to several months.

When standardized exercise tests are used to trigger PEM experimentally, the exacerbation of symptoms has a more immediate onset but still shows a wide variability in duration.

There are indications of altered muscular metabolism and autonomic nervous responses if exercise is repeated on successive days in patients with ME/CFS. The decreased muscular capacity appears to be maintained over several days following such controlled exercise bouts. These responses may correspond to patients’ experiences of increased exertion.

Based on this background we argue that there is a need to look more closely into the processes occurring in the restitution period following exercise, as PEM reaches the peak in this phase.

Source: Nina K. Vøllestad, Anne Marit Mengshoel. Post-exertional malaise in daily life and experimental exercise models in patients with myalgic encephalomyelitis/chronic fatigue syndrome. Frontiers in Physiology, Volume 14- 2023. https://www.frontiersin.org/articles/10.3389/fphys.2023.1257557/abstract

Maximal Oxidative Capacity During Exercise is Associated with Muscle Power Output in Patients with Long coronavirus disease 2019 (COVID-19) Syndrome. A Moderation Analysis

Abstract:

Background & Aims: Long COVID syndrome (LCS) involves persistent symptoms experienced by many patients after recovering from coronavirus disease 2019 (COVID-19). We aimed to assess skeletal muscle energy metabolism, which is closely related to peak fat oxidation rates during exercise, in patients with LCS compared with healthy controls. We also examined whether muscle power output mediates the relationship between COVID-19 and skeletal muscle energy metabolism.

Methods: In this cross-sectional study, we enrolled 71 patients with LCS and 63 healthy controls. We assessed clinical characteristics such as body composition, physical activity, and muscle strength. We used cardiopulmonary exercise testing to evaluate substrate oxidation rates during graded exercise. We performed statistical analyses to compare group characteristics and peak fat oxidation differences based on power output.

Results: The two-way analysis of covariance (ANCOVA) results, adjusted for covariates, showed that the patients with LCS had lower absolute maximal fatty acid oxidation (MFO), relative MFO/fat-free mass (FFM), absolute carbohydrates oxidation (CHox), relative CHox/FFM, and oxygen uptake (VO2) at maximum fat oxidation (mL∙min−1) than the healthy controls (P < 0.05). Moderation analysis indicated that muscle power output significantly influenced the relationship between LCS and reduced peak fat oxidation (interaction β = −0.105 [95% confidence interval −0.174; −0.036]; P = 0.026). Therefore, when muscle power output was below 388 W, the effect of the LCS on MFO was significant (62% in our study sample P = 0.010). These findings suggest compromised mitochondrial bioenergetics and muscle function, represented by lower peak fat oxidation rates, in the patients with LCS compared with the healthy controls.

Conclusion: The patients with LCS had lower peak fat oxidation during exercise compared with the healthy controls, potentially indicating impairment in skeletal muscle function. The relationship between peak fat oxidation and LCS appears to be mediated predominantly by muscle power output. Additional research should continue investigating LCS pathogenesis and the functional role of mitochondria.

Source: Robinson Ramírez-Vélez, Sergio Oscoz-Ochandorena, Yesenia García-Alonso, Nora García-Alonso, Gaizka Legarra-Gorgoñon, Julio Oteiza, Ander Ernaga Lorea, Mikel Izquierdo, María Correa-Rodríguez. Maximal Oxidative Capacity During Exercise is Associated with Muscle Power Output in Patients with Long coronavirus disease 2019 (COVID-19) Syndrome. A Moderation Analysis. Clinical Nutrition ESPEN, 2023, ISSN 2405-4577, https://doi.org/10.1016/j.clnesp.2023.10.009. https://www.sciencedirect.com/science/article/pii/S2405457723021666 (Full text)

Decreased physical performance despite objective and subjective maximal exhaustion in post-COVID-19 individuals with fatigue

Abstract:

Introduction: Fatigue is a common symptom in post-COVID-19 patients. Individuals with fatigue often perform less well compared to healthy peers or without fatigue. It is not yet clear to what extent fatigue is related to the inability to reach maximum exhaustion during physical exercise.

Methods: A symptom-based questionnaire based on the Carruthers guidelines (2003) was used for reporting the presence of fatigue and further symptoms related to COVID-19 from 85 participants (60.0% male, 33.5 ± 11.9 years). Cardiopulmonary exercise testing (CPET) and lactate measurement at the end of the test were conducted. Objective and subjective exhaustion criteria according to Wasserman of physically active individuals with fatigue (FS) were compared to those without fatigue (NFS).

Results: Differences between FS and NFS were found in Peak V̇O2/BM (p < 0.001) and Max Power/BM (p < 0.001). FS were more likely to suffer from further persistent symptoms (p < 0.05). The exhaustion criterion Max. lactate was reached significantly more often by NFS individuals.

Conclusion: Although the aerobic performance (Max Power/BM) and the metabolic rate (Peak V̇O2/BM and Max. lactate) of FS were lower compared to NFS, they were equally able to reach objective exhaustion criteria. The decreased number of FS who reached the lactate criteria and the decreased V̇O2 peak indicates a change in metabolism. Other persistent post-COVID-19 symptoms besides fatigue may also impair performance, trainability and the ability to reach objective exhaustion.

Trial registration: Trial registration: DRKS00023717; date of registration: 15.06.2021 (retrospectively registered).

Source: Vollrath S, Matits L, Schellenberg J, Kirsten J, Steinacker JM, Bizjak DA. Decreased physical performance despite objective and subjective maximal exhaustion in post-COVID-19 individuals with fatigue. Eur J Med Res. 2023 Aug 26;28(1):298. doi: 10.1186/s40001-023-01274-5. PMID: 37633931; PMCID: PMC10464445. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10464445/ (Full text)