Clinical and Laboratory Characteristics of Fatigue-dominant Long-COVID subjects: A Cross-Sectional Study

Abstract:

Background: Long-COVID is defined by persistent symptoms following COVID-19 infection. Approximately 71% of individuals with long-COVID experience ongoing fatigue, post-exertional malaise, and cognitive impairments, which share pathological similarities with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This similarity has prompted studies to explore the characteristics of long-COVID to gain a better understanding of ME/CFS. To gain insights, we investigated the clinical and laboratory characteristics of individuals with fatigue-dominant long-COVID.

Methods: We enrolled 100 subjects (36 males, 64 females) with long-COVID who had a higher score than 60 in modified Korean version of the Chalder Fatigue Scale (mKCFQ11) and higher than 5 in fatigue-focused Visual Analogue Scale (VAS). To investigate fatigue symptoms, the mKCFQ11, the Multidimensional Fatigue Inventory (MFI-20), and VAS for fatigue and brain-fog, along with the Short Form Survey (SF-12) were employed. We also measured three cytokines and cortisol levels for immunological and endocrinological indicators. As a cross-sectional observational study, the data were collected at a single point in time.

Results: The mean scores on the measurements showed severe fatigue, and these scores were significantly correlated, with no differences based on sex, the post-COVID period, or age. Among the laboratory tests, plasma cortisol levels had a significant negative correlation with fatigue scores and a positive correlation with living quality. The negative correlation between cortisol levels and mKCFQ11 scores appeared to be more specific to mental fatigue than physical, which conflicted with other measurements.

Conclusion: Our findings provide the first insights into the characteristics of fatigue in individuals with long-COVID, particularly in terms of fatigue severity and cortisol levels. These results serve as valuable reference data for clinicians dealing with fatigue symptoms in long-COVID patients and for researchers exploring post-viral fatigue symptoms, including ME/CFS, in the future.

Source: Lee JS, Choi Y, Joung JY, Son CG. Clinical and Laboratory Characteristics of Fatigue-dominant Long-COVID subjects: A Cross-Sectional Study. Am J Med. 2024 Feb 6:S0002-9343(24)00057-3. doi: 10.1016/j.amjmed.2024.01.025. Epub ahead of print. PMID: 38331137. https://pubmed.ncbi.nlm.nih.gov/38331137/

Post-Exertional Malaise May Be Related to Central Blood Pressure, Sympathetic Activity and Mental Fatigue in Chronic Fatigue Syndrome Patients

Abstract:

Post-exertional malaise (PEM) is regarded as the hallmark symptom in chronic fatigue syndrome (CFS). The aim of the current study is to explore differences in CFS patients with and without PEM in indicators of aortic stiffness, autonomic nervous system function, and severity of fatigue. One-hundred and one patients met the Fukuda criteria.

A Chronic Fatigue Questionnaire (CFQ) and Fatigue Impact Scale (FIS) were used to assess the level of mental and physical fatigue. Aortic systolic blood pressure (sBPaortic) and the autonomic nervous system were measured with the arteriograph and Task Force Monitor, respectively. Eighty-two patients suffered prolonged PEM according to the Fukuda criteria, while 19 did not.

Patients with PEM had higher FIS scores (p = 0.02), lower central systolic blood pressure (p = 0.02) and higher mental fatigue (p = 0.03). For a one-point increase in the mental fatigue component of the CFQ scale, the risk of PEM increases by 34%. For an sBPaortic increase of 1 mmHg, the risk of PEM decreases by 5%. For a one unit increase in sympathovagal balance, the risk of PEM increases by 330%.

Higher mental fatigue and sympathetic activity in rest are related to an increased risk of PEM, while higher central systolic blood pressure is related to a reduced risk of PEM. However, none of the between group differences were significant after FDR correction, and therefore conclusions should be treated with caution and replicated in further studies.

Source: Kujawski S, Słomko J, Hodges L, Pheby DFH, Murovska M, Newton JL, Zalewski P. Post-Exertional Malaise May Be Related to Central Blood Pressure, Sympathetic Activity and Mental Fatigue in Chronic Fatigue Syndrome Patients. J Clin Med. 2021 May 26;10(11):2327. doi: 10.3390/jcm10112327. PMID: 34073494. https://pubmed.ncbi.nlm.nih.gov/34073494/

Less efficient and costly processes of frontal cortex in childhood chronic fatigue syndrome

Abstract:

The ability to divide one’s attention deteriorates in patients with childhood chronic fatigue syndrome (CCFS). We conducted a study using a dual verbal task to assess allocation of attentional resources to two simultaneous activities (picking out vowels and reading for story comprehension) and functional magnetic resonance imaging.

Patients exhibited a much larger area of activation, recruiting additional frontal areas. The right middle frontal gyrus (MFG), which is included in the dorsolateral prefrontal cortex, of CCFS patients was specifically activated in both the single and dual tasks; this activation level was positively correlated with motivation scores for the tasks and accuracy of story comprehension.

In addition, in patients, the dorsal anterior cingulate gyrus (dACC) and left MFG were activated only in the dual task, and activation levels of the dACC and left MFG were positively associated with the motivation and fatigue scores, respectively.

Patients with CCFS exhibited a wider area of activated frontal regions related to attentional resources in order to increase their poorer task performance with massive mental effort. This is likely to be less efficient and costly in terms of energy requirements. It seems to be related to the pathophysiology of patients with CCFS and to cause a vicious cycle of further increases in fatigue.

 

Source: Mizuno K, Tanaka M, Tanabe HC, Joudoi T, Kawatani J, Shigihara Y, Tomoda A, Miike T, Imai-Matsumura K, Sadato N, Watanabe Y. Less efficient and costly processes of frontal cortex in childhood chronic fatigue syndrome. Neuroimage Clin. 2015 Sep 10;9:355-68. doi: 10.1016/j.nicl.2015.09.001. ECollection 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589845/ (Full article)

 

Cognitive dysfunction and mental fatigue in childhood chronic fatigue syndrome–a 6-month follow-up study

Abstract:

OBJECTIVES: Cognitive function was investigated in patients with childhood type chronic fatigue syndrome (CCFS) using the modified advanced trail making test (mATMT).

METHODS: mATMT was performed on 19 patients with CCFS and 25 healthy controls of comparable age and sex. The effectiveness of combined treatment with cognitive behavioral therapy (CBT) and pharmacotherapy and its relationship to cognitive function was investigated by evaluation of Chalder’s fatigue scale and behavior state before and after treatment for 6 consecutive months.

RESULTS: All three tasks (motor skill, selective and alternative attention, and spatial working memory) of the mATMT, especially the difference in reaction time of the alternative attention task, could discriminate CCFS patients from control subjects with 70.5% accuracy (P=0.007). CCFS patients showed significantly lower alternative attention and Chalder’s fatigue score before treatment (P=0.037 and 0.002, respectively). A significant improvement in performance status scores was found during the 6 months follow-up period with combined treatment with CBT and medication (P<0.001). Improvement of their cognitive symptoms was significantly correlated with improvement of alternative attention (r=0.653, P=0.002).

CONCLUSIONS: Higher-order level cognitive dysfunction affects CCFS pathogenesis. Alternative attention performance evaluated by the mATMT may be used to monitor improvement in patients with CCFS. Combined treatment with CBT and medication may be effective to improve poor attention characteristics associated with CCFS.

Copyright © 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

 

Source: Kawatani J, Mizuno K, Shiraishi S, Takao M, Joudoi T, Fukuda S, Watanabe Y, Tomoda A. Cognitive dysfunction and mental fatigue in childhood chronic fatigue syndrome–a 6-month follow-up study. Brain Dev. 2011 Nov;33(10):832-41. doi: 10.1016/j.braindev.2010.12.009. Epub 2011 May 6. https://www.ncbi.nlm.nih.gov/pubmed/21530119

 

Cognitive dysfunction relates to subjective report of mental fatigue in patients with chronic fatigue syndrome

Abstract:

Patients with chronic fatigue syndrome (CFS) frequently complain of cognitive dysfunction. However, evidence of cognitive impairment in CFS patients has been found in some, but not other, studies. This heterogeneity in findings may stem from the relative presence of mental fatigue in the patient populations examined. The present study assessed this possibility in a population-based sample of CFS patients.

In all, 43 patients with CFS defined by the criteria of the 1994 research case definition using measurements recommended by the 2003 International CFS Study Group, and 53 age-, sex-, and race/ethnicity-matched nonfatigued subjects were included in the study. Mental fatigue was assessed using the mental fatigue subscale of the multidimensional fatigue inventory. Cognitive function was evaluated using an automated battery of computerized tests (Cambridge neuropsychological test automated battery (CANTAB)) that assessed psychomotor function, planning and problem-solving abilities, and memory and attentional performance.

CFS patients with significant complaints of mental fatigue (score of mental fatigue 2 standard deviations above the mean of nonfatigued subjects) exhibited significant impairment in the spatial working memory and sustained attention (rapid visual information processing) tasks when compared to CFS patients with low complaints of mental fatigue and nonfatigued subjects. In CFS patients with significant mental fatigue, sustained attention performance was impaired only in the final stages of the test, indicating greater cognitive fatigability in these patients. CFS patients with low mental fatigue displayed performance comparable to nonfatigued subjects on all tests of the CANTAB battery. These findings show strong concordance between subjective complaints of mental fatigue and objective measurement of cognitive impairment in CFS patients and suggest that mental fatigue is an important component of CFS-related cognitive dysfunction.

 

Source: Capuron L, Welberg L, Heim C, Wagner D, Solomon L, Papanicolaou DA, Craddock RC, Miller AH, Reeves WC. Cognitive dysfunction relates to subjective report of mental fatigue in patients with chronic fatigue syndrome. Neuropsychopharmacology. 2006 Aug;31(8):1777-84. Epub 2006 Jan 4. http://www.nature.com/npp/journal/v31/n8/full/1301005a.html (Full article)

 

Reliability of physiological, psychological and cognitive variables in chronic fatigue syndrome and the role of graded exercise

Abstract:

The objective of this study was to assess variability in symptoms and physical capabilities in chronic fatigue syndrome (CFS) participants both before and after a graded exercise intervention. Sixty-one CFS subjects participated in a 12-week randomized controlled trial of either graded exercise (n =32) or relaxation/stretching therapy (n = 29). Specific physiological, psychological and cognitive variables were assessed once weekly over a four-week period both prior to and after the intervention period. All scores were assessed for reliability using an intraclass correlation coefficient (ICC).

Apart from mental and physical fatigue, baseline ICC scores for all variables assessed were moderately to highly reliable, indicating minimal variability. Baseline scores for mental and physical fatigue were of questionable reliability, indicating a fluctuating nature to these symptoms (R1 = 0.64 and 0.60, respectively). Variability in scores for mental fatigue was reduced after graded exercise to an acceptable classification (R1 = 0.76). Results from this study support a variable nature to the symptoms of mental and physical fatigue only.

Consequently, in order to more accurately report the nature of mental and physical fatigue in CFS, future studies should consider using repeated-measures analysis when assessing these symptoms. Graded exercise resulted in the reclassification of scores for mental fatigue from questionable to acceptable reliability.

Key Points: Chronic fatigue syndrome sufferers often report a fluctuating nature to their symptoms and physical capabilities.Weekly assessment over a four-week period of psychological, physiological and cognitive variables demonstrated that only mental and physical fatigues were of questionable reliability.A 12-week graded exercise intervention resulted in the improvement of ICC scores for mental fatigue to that of acceptable reliability.

 

Source: Wallman KE, Morton AR, Goodman C, Grove R. Reliability of physiological, psychological and cognitive variables in chronic fatigue syndrome and the role of graded exercise. J Sports Sci Med. 2005 Dec 1;4(4):463-71. eCollection 2005. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3899663/ (Full article)

 

The importance of mental fatigue

Comment onRelation between neuropsychological impairment and functional disability in patients with chronic fatigue syndrome. [J Neurol Neurosurg Psychiatry. 1998]

 

The paper by Christodoulou et al in this issue of the Journal (pp 431–4) draws attention to memory deficits in some patients with operationally defined chronic fatigue syndrome, and days of (enforced) physical inactivity. Many studies have assessed cognitive dysfunction in patients with chronic fatigue. The earliest reported superior abilities in such patients against controls or age matched normal subjects, probably reflecting a biased selection of cases from higher socioeconomic groups. Later studies have been the subject of at least two major reviews.1 2

You can read the rest of this article here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2170046/pdf/v064p00430.pdf

 

Source: Lambert MV, David A. The importance of mental fatigue. J Neurol Neurosurg Psychiatry. 1998 Apr;64(4):430. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2170046/pdf/v064p00430.pdf (Full article)

 

A brief mental fatigue questionnaire

Abstract:

A brief mental fatigue questionnaire was administered to normal subjects and muscle-diseased, Chronic Fatigue Syndrome (CFS), recovered CFS and depressed patients. The questionnaire was found to have excellent internal consistency and discriminated effectively between CFS and depressed patients on the one hand and recovered CFS, normal and muscle-diseased patients on the other. However, the scale failed to discriminate between CFS and depressed subjects, who were found to experience qualitatively and quantitatively similar mental fatigue symptoms.

 

Source: Bentall RP, Wood GC, Marrinan T, Deans C, Edwards RH. A brief mental fatigue questionnaire. Br J Clin Psychol. 1993 Sep;32 ( Pt 3):375-9. http://www.ncbi.nlm.nih.gov/pubmed/7902751

 

Cognitive impairment in patients with chronic fatigue: a preliminary study

Erratum in: J Neurol Neurosurg Psychiatry 1993 Oct;56(10):1142

Abstract:

Subjective impairment of memory and concentration is a frequent complaint in sufferers from chronic fatigue. To study this, 65 general practice attenders identified as having chronic fatigue were administered a structured psychiatric interview and a brief screening battery of cognitive tests.

Subjective cognitive impairment was strongly related to psychiatric disorder, especially depressed mood, but not fatigue, anxiety, or objective performance. Simple tests of attention and concentration showed some impairment but this was influenced by both fatigue and depression.

Subjects with high levels of fatigue performed less well on a memory task requiring cognitive effort, even in the absence of depression. There was no evidence for mental fatiguability. The relationship between depression, fatigue, and cognitive function requires further research.

 

Source: McDonald E, Cope H, David A. Cognitive impairment in patients with chronic fatigue: a preliminary study. J Neurol Neurosurg Psychiatry. 1993 Jul;56(7):812-5. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1015065/ (Full article)