Tag: post-exertional malaise

Post-exertional Malaise in People With Chronic Cancer-Related Fatigue

Abstract:

CONTEXT: Cancer-related fatigue (CRF) is a distressing and persistent sense of tiredness or exhaustion that interferes with usual functioning. Chronic CRF continues for months after curative cancer treatment is complete. Post-exertional malaise (PEM) is a worsening of symptoms after physical or mental activity, with limited investigations in people with chronic CRF.

OBJECTIVES: The purpose of this study was to identify and describe self-reported incidences of PEM in people with chronic CRF.

METHODS: Participants (n = 18) were eligible if they scored ≤34 on the Functional Assessment of Chronic Illness Therapy-Fatigue scale and had a cancer-related onset of fatigue. Participants completed a brief questionnaire to assess PEM during a six-month time frame (the DePaul Symptom Questionnaire-PEM). In addition, a maximal exercise test was used to investigate self-reported symptom exacerbation (via an open-ended questionnaire) after strenuous physical exertion.

RESULTS: On the DePaul Symptom Questionnaire-PEM, three participants met previously defined scoring criteria, which included experiencing moderate to very severe symptoms at least half of the time, worsening of fatigue after minimal effort, plus a recovery duration of >24 hours. Content analysis of responses to open-ended questionnaires identified five people who experienced a delayed recovery and symptoms of PEM after maximal exercise.

CONCLUSION: A subset of people with chronic CRF (up to 33% in this sample) may experience PEM. Exercise specialists and health care professionals working with people with chronic CRF must be aware that PEM may be an issue. Symptom exacerbation after exercise should be monitored, and exercise should be tailored and adapted to limit the potential for harm.

Copyright © 2020 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

Source: Twomey R, Yeung ST, Wrightson JG, Millet GY, Culos-Reed SN. Post-exertional Malaise in People With Chronic Cancer-Related Fatigue. J Pain Symptom Manage. 2020 Feb 24. pii: S0885-3924(20)30098-1. doi: 10.1016/j.jpainsymman.2020.02.012. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/32105793

Connectivity differences between Gulf War Illness (GWI) phenotypes during a test of attention

Abstract:

One quarter of veterans returning from the 1990–1991 Persian Gulf War have developed Gulf War Illness (GWI) with chronic pain, fatigue, cognitive and gastrointestinal dysfunction. Exertion leads to characteristic, delayed onset exacerbations that are not relieved by sleep. We have modeled exertional exhaustion by comparing magnetic resonance images from before and after submaximal exercise.

One third of the 27 GWI participants had brain stem atrophy and developed postural tachycardia after exercise (START: Stress Test Activated Reversible Tachycardia). The remainder activated basal ganglia and anterior insulae during a cognitive task (STOPP: Stress Test Originated Phantom Perception). Here, the role of attention in cognitive dysfunction was assessed by seed region correlations during a simple 0-back stimulus matching task (“see a letter, push a button”) performed before exercise. Analysis was analogous to resting state, but different from psychophysiological interactions (PPI).

The patterns of correlations between nodes in task and default networks were significantly different for START (n = 9), STOPP (n = 18) and control (n = 8) subjects. Edges shared by the 3 groups may represent co-activation caused by the 0-back task. Controls had a task network of right dorsolateral and left ventrolateral prefrontal cortex, dorsal anterior cingulate cortex, posterior insulae and frontal eye fields (dorsal attention network). START had a large task module centered on the dorsal anterior cingulate cortex with direct links to basal ganglia, anterior insulae, and right dorsolateral prefrontal cortex nodes, and through dorsal attention network (intraparietal sulci and frontal eye fields) nodes to a default module. STOPP had 2 task submodules of basal ganglia–anterior insulae, and dorsolateral prefrontal executive control regions. Dorsal attention and posterior insulae nodes were embedded in the default module and were distant from the task networks.

These three unique connectivity patterns during an attention task support the concept of Gulf War Disease with recognizable, objective patterns of cognitive dysfunction.

Source: Clarke T, Jamieson JD, Malone P, Rayhan RU, Washington S, VanMeter JW, et al. (2019) Connectivity differences between Gulf War Illness (GWI) phenotypes during a test of attention. PLoS ONE 14(12): e0226481. https://doi.org/10.1371/journal.pone.0226481 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226481 (Full text)

An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an enigmatic condition characterized by exacerbation of symptoms after exertion (post-exertional malaise or “PEM”), and by fatigue whose severity and associated requirement for rest are excessive and disproportionate to the fatigue-inducing activity. There is no definitive molecular marker or known underlying pathological mechanism for the condition.

Increasing evidence for aberrant energy metabolism suggests a role for mitochondrial dysfunction in ME/CFS. Our objective was therefore to measure mitochondrial function and cellular stress sensing in actively metabolizing patient blood cells.

We immortalized lymphoblasts isolated from 51 ME/CFS patients diagnosed according to the Canadian Consensus Criteria and an age- and gender-matched control group. Parameters of mitochondrial function and energy stress sensing were assessed by Seahorse extracellular flux analysis, proteomics, and an array of additional biochemical assays.

As a proportion of the basal oxygen consumption rate (OCR), the rate of ATP synthesis by Complex V was significantly reduced in ME/CFS lymphoblasts, while significant elevations were observed in Complex I OCR, maximum OCR, spare respiratory capacity, nonmitochondrial OCR and “proton leak” as a proportion of the basal OCR. This was accompanied by a reduction of mitochondrial membrane potential, chronically hyperactivated TOR Complex I stress signaling and upregulated expression of mitochondrial respiratory complexes, fatty acid transporters, and enzymes of the β-oxidation and TCA cycles. By contrast, mitochondrial mass and genome copy number, as well as glycolytic rates and steady state ATP levels were unchanged.

Our results suggest a model in which ME/CFS lymphoblasts have a Complex V defect accompanied by compensatory upregulation of their respiratory capacity that includes the mitochondrial respiratory complexes, membrane transporters and enzymes involved in fatty acid β-oxidation. This homeostatically returns ATP synthesis and steady state levels to “normal” in the resting cells, but may leave them unable to adequately respond to acute increases in energy demand as the relevant homeostatic pathways are already activated.

Source: Missailidis D, Annesley SJ, Allan CY, Sanislav O, Lidbury BA, Lewis DP, Fisher PR. An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients.Int J Mol Sci. 2020 Feb 6;21(3). pii: E1074. doi: 10.3390/ijms21031074.  https://www.mdpi.com/1422-0067/21/3/1074 (Full text)

Post-exertional malaise is associated with greater symptom burden and psychological distress in patients diagnosed with Chronic Fatigue Syndrome

Abstract:

OBJECTIVE: Post-exertional malaise (PEM) is often considered a cardinal symptom of Chronic Fatigue Syndrome (CFS). There is no gold standard diagnostic method for CFS, however, and the Centers for Disease Control (CDC) Fukuda case definition does not require PEM. Research has identified differences in symptom burden between patients according to PEM, but whether it is associated with psychological distress has not been investigated.

METHODS: The CDC CFS Inventory, Fatigue Symptom Inventory, Profile of Mood States, Center for Epidemiologic Studies Depression Scale, Perceived Stress Scale, and subscales of the Sickness Impact Profile were administered to 261 patients diagnosed with the Fukuda criteria. PEM status (loPEM/hiPEM) was determined via self-reported post-exertional fatigue severity. Analyses of covariance (ANCOVA), controlling for age and gender, assessed cross-sectional group differences, and cross-sectional linear regressions using the continuous PEM severity predictor paralleled these analyses.

RESULTS: hiPEM patients reported greater symptom intensity, frequency, and interference than loPEM counterparts (p’s < .001). hiPEM patients also reported greater social disruption, depressive symptoms, and mood disturbance (p’s ≤ .011). Groups did not differ in recent negative life experiences, perceived stress, or demographic variables. The results of regression analyses mirrored those of ANCOVAs.

CONCLUSION: This study replicates the association between PEM and symptom burden and additionally associates PEM with psychological distress; psychological distress could, however, be a consequence of symptom burden. Differences between hiPEM and loPEM CFS patients highlight the heterogeneity of diagnoses resulting from the Fukuda criteria. It is also possible that PEM identifies particularly distressed patients for whom psychological intervention would be most beneficial.

Copyright © 2019 Elsevier Inc. All rights reserved

Source: May M, Milrad SF, Perdomo DM, Czaja SJ, Fletcher MA, Jutagir DR, Hall DL, Klimas N, Antoni MH. Post-exertional malaise is associated with greater symptom burden and psychological distress in patients diagnosed with Chronic Fatigue Syndrome. J Psychosom Res. 2019 Dec 16;129:109893. doi: 10.1016/j.jpsychores.2019.109893. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31884303

Scientific Advances in and Clinical Approaches to Small-Fiber Polyneuropathy: A Review

Abstract:

IMPORTANCE: Small-fiber polyneuropathy involves preferential damage to the thinly myelinated A-delta fibers, unmyelinated C sensory fibers, or autonomic or trophic fibers. Although this condition is common, most patients still remain undiagnosed and untreated because of lagging medical and public awareness of research advances. Chronic bilateral neuropathic pain, fatigue, and nausea are cardinal symptoms that can cause disability and dependence, including pain medication dependence.

OBSERVATIONS: Biomarker confirmation is recommended, given the nonspecificity of symptoms. The standard test involves measuring epidermal neurite density within a 3-mm protein gene product 9.5 (PGP9.5)-immunolabeled lower-leg skin biopsy. Biopsies and autonomic function testing confirm that small-fiber neuropathy not uncommonly affects otherwise healthy children and young adults, in whom it is often associated with inflammation or dysimmunity. A recent meta-analysis concluded that small-fiber neuropathy underlies 49% of illnesses labeled as fibromyalgia. Initially, patients with idiopathic small-fiber disorders should be screened by medical history and blood tests for potentially treatable causes, which are identifiable in one-third to one-half of patients. Then, secondary genetic testing is particularly important for familial and childhood cases. Treatable genetic causes include Fabry disease, transthyretin and primary systemic amyloidosis, hereditary sensory autonomic neuropathy-1, and ion-channel mutations. Immunohistopathologic evidence suggests that small-fiber dysfunction and denervation, especially of blood vessels, contributes to diverse symptoms, including postexertional malaise, postural orthostatic tachycardia, and functional gastrointestinal distress. Preliminary evidence implicates acute or chronic autoreactivity in some cases, particularly in female patients and otherwise healthy children and young adults. Different temporal patterns akin to Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy have been described; here, corticosteroids and immunoglobulins, which are often efficacious for inflammatory neuropathic conditions, are increasingly considered.

CONCLUSIONS AND RELEVANCE: Because small fibers normally grow throughout life, improving contributory conditions may permit regrowth, slow progression, and prevent permanent damage. The prognosis is often hopeful for improving quality of life and sometimes for abatement or resolution, particularly in the young and otherwise healthy individuals. Examples include diabetic, infectious, toxic, genetic, and inflammatory causes. The current standard of care requires prompt diagnosis and treatment, particularly in children and young adults, to restore life trajectory. Consensus diagnostic and tracking metrics should be established to facilitate treatment trials.

Source: Oaklander AL, Nolano M. Scientific Advances in and Clinical Approaches to Small-Fiber Polyneuropathy: A Review. JAMA Neurol. 2019 Sep 9. doi: 10.1001/jamaneurol.2019.2917. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31498378

Post-Exertional Malaise Is Associated with Hypermetabolism, Hypoacetylation and Purine Metabolism Deregulation in ME/CFS Cases

Abstract:

Post-exertional malaise (PEM) is a cardinal predictive symptom in the definition of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). If the cases overexert themselves they have what is termed “payback” resulting in a worsening of symptoms or relapse which can last for days, weeks or even months. The aim was to assess the changes in biochemistry associated with the cases self-reported PEM scores over a 7-day period and the frequency of reporting over a 12-month period.

Forty-seven ME/CFS cases and age/sex-matched controls had a clinical examination, completed questionnaires; were subjected to standard serum biochemistry; had their serum and urine metabolomes analyzed in an observational study. Thirty-five of the 46 ME/CFS cases reported PEM in the last 7-days and these were allocated to the PEM group.

The principal biochemical change related to the 7-day severity of PEM was the fall in the purine metabolite, hypoxanthine. This decrease correlated with alterations in the glucose:lactate ratio highly suggestive of a glycolytic anomaly. Increased excretion of urine metabolites within the 7-day response period indicated a hypermetabolic event was occurring. Increases in urine excretion of methylhistidine (muscle protein degradation), mannitol (intestinal barrier deregulation) and acetate were noted with the hypermetabolic event.

These data indicate hypoacetylation was occurring, which may also be related to deregulation of multiple cytoplasmic enzymes and DNA histone regulation. These findings suggest the primary events associated with PEM were due to hypoacetylation and metabolite loss during the acute PEM response.

Source: Neil R. McGregor, Christopher W. Armstrong , Donald P. Lewis and Paul R. Gooley. Post-Exertional Malaise Is Associated with Hypermetabolism, Hypoacetylation and Purine Metabolism Deregulation in ME/CFS Cases. Diagnostics 2019, 9(3), 70; https://doi.org/10.3390/diagnostics9030070 https://www.mdpi.com/2075-4418/9/3/70/htm (Full article)

Abnormal blood lactate accumulation during repeated exercise testing in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Post-exertional malaise and delayed recovery are hallmark symptoms of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Studies on repeated cardiopulmonary exercise testing (CPET) show that previous exercise negatively affects oxygen uptake (VO2 ) and power output (PO) in ME/CFS. Whether this affects arterial lactate concentrations ([Laa ]) is unknown.

We studied 18 female patients (18-50 years) fulfilling the Canadian Consensus Criteria for ME/CFS and 15 healthy females (18-50 years) who underwent repeated CPETs 24 h apart (CPET1 and CPET2 ) with [Laa ] measured every 30th second. VO2 at peak exercise (VO2 peak) was lower in patients than in controls on CPET1 (P < 0.001) and decreased in patients on CPET2 (P < 0.001).

However, the difference in VO2peak between CPETs did not differ significantly between groups. [Laa ] per PO was higher in patients during both CPETs (Pinteraction < 0.001), but increased in patients and decreased in controls from CPET1 to CPET2 (Pinteraction < 0.001). Patients had lower VO2 (P = 0.02) and PO (P = 0.002) at the gas exchange threshold (GET, the point where CO2 production increases relative to VO2 ), but relative intensity (%VO2peak ) and [Laa ] at GET did not differ significantly from controls on CPET1 .

Patients had a reduction in VO2 (P = 0.02) and PO (P = 0.01) at GET on CPET2 , but no significant differences in %VO2peak and [Laa ] at GET between CPETs. Controls had no significant differences in VO2 , PO or %VO2peak at GET between CPETs, but [Laa ] at GET was reduced on CPET2 (P = 0.008).

In conclusion, previous exercise deteriorates physical performance and increases [Laa ] during exercise in patients with ME/CFS while it lowers [Laa ] in healthy subjects.

© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Source: Lien K, Johansen B, Veierød MB, Haslestad AS, Bøhn SK, Melsom MN, Kardel KR, Iversen PO. Abnormal blood lactate accumulation during repeated exercise testing in myalgic encephalomyelitis/chronic fatigue syndrome. Physiol Rep. 2019 Jun;7(11):e14138. doi: 10.14814/phy2.14138. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546966/ (Full article)

Myalgic Encephalomyelitis or What? The International Consensus Criteria

Abstract:

Myalgic encephalomyelitis (ME) is a neuromuscular disease with two distinctive types of symptoms (muscle fatigability or prolonged muscle weakness after minor exertion and symptoms related to neurological disturbance, especially of sensory, cognitive, and autonomic functions) and variable involvement of other bodily systems. Chronic fatigue syndrome (CFS), introduced in 1988 and re-specified in 1994, is defined as (unexplained) chronic fatigue accompanied by at least four out of eight listed (ill-defined) symptoms. Although ME and CFS are two distinct clinical entities (with partial overlap), CFS overshadowed ME for decades.

In 2011, a panel of experts recommended abandoning the label CFS and its definition and proposed a new definition of ME: the International Consensus Criteria for ME (ME-ICC). In addition to post-exertional neuroimmune exhaustion (PENE), a mandatory feature, a patient must experience at least three symptoms related to neurological impairments; at least three symptoms related to immune, gastro-intestinal, and genitourinary impairments; and at least one symptom related to energy production or transportation impairments to meet the diagnosis of ME-ICC.

A comparison between the original definition of ME and the ME-ICC shows that there are some crucial differences between ME and ME-ICC. Muscle fatigability, or long-lasting post-exertional muscle weakness, is the hallmark feature of ME, while this symptom is facultative for the diagnosis under the ME-ICC. PENE, an abstract notion that is very different from post-exertional muscle weakness, is the hallmark feature of the ME-ICC but is not required for the diagnosis of ME. The diagnosis of ME requires only two type of symptoms (post-exertional muscle weakness and neurological dysfunction), but a patient has to experience at least eight symptoms to meet the diagnosis according to the ME-ICC. Autonomic, sensory, and cognitive dysfunction, mandatory for the diagnosis of ME, are not compulsory to meet the ME-ICC subcriteria for ‘neurological impairments’.

In conclusion, the diagnostic criteria for ME and of the ME-ICC define two different patient groups. Thus, the definitions of ME and ME-ICC are not interchangeable.

Source: Twisk, F. Myalgic Encephalomyelitis or What? The International Consensus Criteria. Diagnostics 2019, 9, 1. https://www.mdpi.com/2075-4418/9/1/1/htm (Full article)

Meta-analysis investigating post-exertional malaise between patients and controls

Abstract:

Post-exertional malaise is either required or included in many previously proposed case definitions of myalgic encephalomyelitis/chronic fatigue syndrome. A meta-analysis of odds ratios (ORs; association between patient status and post-exertional malaise status) and a number of potential moderators (i.e. study-level characteristics) of effect size were conducted.

Post-exertional malaise was found to be 10.4 times more likely to be associated with a myalgic encephalomyelitis/chronic fatigue syndrome diagnosis than with control status. Significant moderators of effect size included patient recruitment strategy and control selection. These findings suggest that post-exertional malaise should be considered a cardinal symptom of myalgic encephalomyelitis/chronic fatigue syndrome.

Source: Brown A, Jason LA. Meta-analysis investigating post-exertional malaise between patients and controls. J Health Psychol. 2018 Jul 1:1359105318784161. doi: 10.1177/1359105318784161. [Epub ahead of print]  https://www.ncbi.nlm.nih.gov/pubmed/29974812

Deconstructing post-exertional malaise in myalgic encephalomyelitis/ chronic fatigue syndrome: A patient-centered, cross-sectional survey

Abstract:

BACKGROUND: Post-exertional malaise (PEM) is considered to be the hallmark characteristic of myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS). Yet, patients have rarely been asked in formal studies to describe their experience of PEM.

OBJECTIVES: To describe symptoms associated with and the time course of PEM.

METHODS: One hundred and fifty subjects, diagnosed via the 1994 Fukuda CFS criteria, completed a survey concerning 11 symptoms they could experience after exposure to two different types of triggers. We also inquired about onset and duration of PEM and included space for subjects to write in any additional symptoms. Results were summarized with descriptive statistics; McNemar’s, paired t-, Fisher’s exact and chi-square goodness-of-fit tests were used to assess for statistical significance.

RESULTS: One hundred and twenty-nine subjects (90%) experienced PEM with both physical and cognitive exertion and emotional distress. Almost all were affected by exertion but 14 (10%) reported no effect with emotion. Fatigue was the most commonly exacerbated symptom but cognitive difficulties, sleep disturbances, headaches, muscle pain, and flu-like feelings were cited by over 30% of subjects. Sixty percent of subjects experienced at least one inflammatory/ immune-related symptom. Subjects also cited gastrointestinal, orthostatic, mood-related, neurologic and other symptoms. Exertion precipitated significantly more symptoms than emotional distress (7±2.8 vs. 5±3.3 symptoms (median, standard deviation), p<0.001). Onset and duration of PEM varied for most subjects. However, 11% reported a consistent post-trigger delay of at least 24 hours before onset and 84% endure PEM for 24 hours or more.

CONCLUSIONS: This study provides exact symptom and time patterns for PEM that is generated in the course of patients’ lives. PEM involves exacerbation of multiple, atypical symptoms, is occasionally delayed, and persists for extended periods. Highlighting these characteristics may improve diagnosis of ME/CFS. Incorporating them into the design of future research will accelerate our understanding of ME/CFS.

Source:  Chu L, Valencia IJ, Garvert DW, Montoya JG. Deconstructing post-exertional malaise in myalgic encephalomyelitis/ chronic fatigue syndrome: A patient-centered, cross-sectional survey. PLoS One. 2018 Jun 1;13(6):e0197811. doi: 10.1371/journal.pone.0197811. eCollection 2018. (Full study)