The role of clinical neurophysiology in the definition and assessment of fatigue and fatigability

Highlights:

  • Though a common symptom, fatigue is difficult to define and investigate, and occurs in a wide variety of disorders, with differing pathological causes.
  • This review aims to guide clinicians in how to approach fatigue and to suggest that neurophysiological tests may allow an understanding of its origin and severity.
  • The effectiveness of neurophysiological tests as cost-effective objective biomarkers for the assessment of fatigue has been summarised.

Abstract

Though a common symptom, fatigue is difficult to define and investigate, occurs in a wide variety of neurological and systemic disorders, with differing pathological causes. It is also often accompanied by a psychological component. As a symptom of long-term COVID-19 it has gained more attention.

In this review, we begin by differentiating fatigue, a perception, from fatigability, quantifiable through biomarkers. Central and peripheral nervous system and muscle disorders associated with these are summarised. We provide a comprehensive and objective framework to help identify potential causes of fatigue and fatigability in a given disease condition. It also considers the effectiveness of neurophysiological tests as objective biomarkers for its assessment. Among these, twitch interpolation, motor cortex stimulation, electroencephalography and magnetencephalography, and readiness potentials will be described for the assessment of central fatigability, and surface and needle electromyography (EMG), single fibre EMG and nerve conduction studies for the assessment of peripheral fatigability.

The purpose of this review is to guide clinicians in how to approach fatigue, and fatigability, and to suggest that neurophysiological tests may allow an understanding of their origin and interactions. In this way, their differing types and origins, and hence their possible differing treatments, may also be defined more clearly.

Source: Tankisi H, Versace V, Kuppuswamy A, Cole J. The role of clinical neurophysiology in the definition and assessment of fatigue and fatigability. Clin Neurophysiol Pract. 2023 Dec 18;9:39-50. doi: 10.1016/j.cnp.2023.12.004. PMID: 38274859; PMCID: PMC10808861. https://www.sciencedirect.com/science/article/pii/S2467981X23000367 (Full text)

Confirmation of COVID-19 infection status and reporting of Long COVID symptoms in a population-based birth cohort: No evidence of a nocebo effect

Abstract:

Some patients with COVID-19 develop symptoms after the acute infection, known as ‘Long COVID’. We examined whether or not confirmation of COVID-19 infection status could act as a nocebo, using data from questionnaires distributed to the Avon Longitudinal Study of Parents and Children cohort.
We examined associations between confirmation of COVID-19 infection status (confirmed by a positive test vs unconfirmed) and reporting of Long COVID symptoms. We explored the roles of sex and anxiety as potential moderators.
There was no clear evidence of a strong association between confirmation of COVID-19 infection status and the Long COVID composite score, physical or psychological symptoms or duration of symptoms. There was no clear evidence of moderation by sex or anxiety. We therefore found no evidence of a nocebo effect. Our data suggest that this psychological mechanism does not play a role in the medical symptomatology experienced by patients with Long COVID.
Source: 1.
Macleod-Hall CI, Munafò MR, Dyer ML. Confirmation of COVID-19 infection status and reporting of Long COVID symptoms in a population-based birth cohort: No evidence of a nocebo effect. Journal of Health Psychology. 2024;0(0). doi:10.1177/13591053241228711 https://journals.sagepub.com/doi/10.1177/13591053241228711

A suffering body, hidden away from others: The experience of being long-term bedridden with severe myalgic encephalomyelitis/chronic fatigue syndrome in childhood and adolescence

Abstract:

In this article, we present findings from a qualitative study examining how young women experience being long-term bedridden with myalgic encephalomyelitis (ME), also known as chronic fatigue syndrome (CFS), during childhood and adolescence. The aim is to explore how young women who fell ill with ME/CFS during childhood and adolescence look back on their lived experience of being long-term bedridden from the vantage point of being fully or partially recovered.

Informed by a phenomenological theoretical perspective, the researchers applied a narrative methodological approach involving the analysis of interviews with 13 women, aged 16–29 years at the time of the interview. Attention was particularly paid to how participants structured their narratives and to the events (telling moments) they identified as important.

Four major storylines were developed: Ambivalent responses to the presence of others; A body on the edge of life; An eternity in the dark; and Recasting painful memories of being bedridden and alone.

Based on our findings, we argue that the experience of being long-term bedridden with ME/CFS during childhood and adolescence can be understood and communicated as a plot in which individuals find themselves pushed to the extreme limit of suffering and loneliness.

Source: Krabbe, S. H., Bjorbækmo, W. S., Mengshoel, A. M., Sveen, U., & Groven, K. S. (2024). A suffering body, hidden away from others: The experience of being long-term bedridden with severe myalgic encephalomyelitis/chronic fatigue syndrome in childhood and adolescence. Nursing Inquiry, e12625. https://doi.org/10.1111/nin.12625 https://onlinelibrary.wiley.com/doi/10.1111/nin.12625 (Full text)

Chronic Fatigue Syndrome, Viruses and Related Conditions in Women: The Liver Link

Abstract:

Chronic Fatigue Syndrome (CFS) can be triggered by different factors and create a complex health situation. In the last decades incidence has been increasing. This situation is a clear example of how humans, viruses, and the environment are all connected.
In the 90s cases related to CFS, complaints about a feeling of chronic fatigue, inability for everyday tasks, dull pain, cephalalgia, de-pression, anxiety, poor concentration. Clinical tests for EBV, HHV, CMV, IgG, IgM, T4 and T8 subsets were tested, along with hormones and hemogram tests. Most of the cases were women. The timeline of the medical history showed also myomas, breast lumps, premenstrual syndrome previously to CFS development. The nature of these conditions promoted the idea of a possible common link among them and CFS. Some cases also suffered from allergies, food intolerances, candidiasis, intestinal impairment, thyroid implications, endometriosis.
As an initial working hypothesis, The Liver Link (TLL) was proposed in order to understand those different conditions affecting body, mind and emotional wellbeing. Considering liver implication can make a difference in treatment and recovery. Low grade inflammatory conditions are related to Th2 predominance and liver functions. Functional disharmonies are very important because they usually still do not appear in any conventional tests.
In 2002, TLL was presented as a framework to explain the concomitance of CFS and other conditions and the relationship with some viruses such as EBV, HHV, CMV, as a lecture in a congress at the University of Westminster (London). When SARS-CoV-2 outbroke, TLL helped to warn about the post-covid syndrome more likely to occur in specific individuals.
Source: Lorite-Ayán, N. Chronic Fatigue Syndrome, Viruses and Related Conditions in Women: The Liver Link. Preprints 2024, 2024011654. https://doi.org/10.20944/preprints202401.1654.v1 https://www.preprints.org/manuscript/202401.1654/v1 (Full text available as PDF file)

Systemic antibody responses against gut microbiota flagellins implicate shared and divergent immune reactivity in Crohn’s Disease and chronic fatigue syndrome

Abstract:

Background: Patients with Crohn’s disease (CD) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) exhibit elevated antibody responses against gut microbiota flagellins. However, flagellin-specific antibody repertoires and functional roles in the diseases remain incompletely understood. Bacterial flagellins can be categorized into three types depending on their interaction with toll-like receptor 5 (TLR5): (1) “stimulator” and (2) “silent” flagellins, binding TLR5 through a conserved N-terminal motif, with only stimulators activating TLR5 due to a specific C-terminal domain; (3) “evader” flagellins of pathogens, which circumvent TLR5 activation via mutated N-terminal TLR5 binding motifs. Here we studied the characteristics, epitope binding, and sequence (dis)similarity of anti-flagellin antibody responses in CD and ME/CFS.
Methods: Since conventional antibody profiling methods like enzyme-linked immunosorbent assays [ELISAs] do not allow for large-scale measurements of antibody repertoires, we leveraged phage-display immunoprecipitation sequencing (PhIP-Seq) to characterize 344,000 rationally selected peptide antigens in 256 patients with CD, 40 patients with ME/CFS and in two equally sized groups of age- and sex-matched healthy controls from population-based cohorts in the Netherlands and U.K., respectively. Different sequence alignment strategies were employed to compare flagellin peptide structures with observed antibody-bound flagellin peptide reactivity.
Results: Both patients with CD and ME/CFS exhibited elevated antibody responses against distinct regions of flagellin peptides compared to healthy individuals (P<0.001). N-terminal binding to Lachnospiraceae flagellins was comparable in both diseases, while C-terminal binding was more prevalent in CD. N-terminal antibody-bound flagellin sequences were similar across CD and ME/CFS, resembling ‘stimulator’ and ‘silent’ flagellins more than evaders. However, C-terminal antibody-bound flagellins showed higher resemblance to stimulator than to silent flagellins in CD, but not in ME/CFS. This group of antibody-bound flagellins was exclusively identified in a subset (10-20%) of patients with CD and characterized by its strong overrepresentation (exceeding 20-fold), underscoring its potential significance in distinguishing pathophysiologic subtypes of CD.
Conclusion: Antibody binding to the N-terminal domain of stimulator and silent flagellins may impact TLR5 activation in both CD and ME/CFS patients. Furthermore, elevated antibody binding to the C-terminal domain of stimulator flagellins in CD may explain pathophysiological differences between diseases. Our results highlight the diagnostic potential of these antibody responses and their impact on innate/adaptive immunity balance.

Source: A R Bourgonje, N V Hörstke, M Fehringer, G Innocenti, T Vogl, DOP27 Systemic antibody responses against gut microbiota flagellins implicate shared and divergent immune reactivity in Crohn’s Disease and chronic fatigue syndrome, Journal of Crohn’s and Colitis, Volume 18, Issue Supplement_1, January 2024, Page i122, https://doi.org/10.1093/ecco-jcc/jjad212.0067 https://academic.oup.com/ecco-jcc/article/18/Supplement_1/i122/7586226 (Full text available as PDF file)

Repeated Hand Grip Strength is an Objective Marker for Disability and Severity of Key Symptoms in Post-COVID ME/CFS

Abstract:

Post-COVID Syndrome (PCS) refers to a diverse array of symptoms that persist beyond 3 months of the acute phase of a SARS-CoV-2 infection. The most frequent symptom is fatigue, which can manifest both mentally and physically. In this study, handgrip strength (HGS) parameters were determined as an objective measure of muscle fatigue and fatigability. HGS parameters were correlated with other frequent symptoms among 144 female PCS patients suffering from fatigue, exertional intolerance, and cognitive impairment.

Seventy-eight patients met the Canadian Consensus Criteria (CCC) for post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The severity of disability and key symptoms were evaluated utilizing self-reported questionnaires.

Notably, patients diagnosed with ME/CFS exhibited a higher overall severity of symptoms, including lower physical function (p < 0.001), a greater degree of disability (p < 0.001), more severe fatigue (p < 0.001), post-exertional malaise (p < 0.001), and autonomic dysfunction (p = 0.004). While HGS was similarly impaired in both PCS and ME/CFS patients, the associations between HGS and the severity of symptoms and disability revealed striking differences.

We observed significant correlations of HGS parameters with physical function across all patients, but with the key symptoms PEM, fatigue, cognitive impairment, and autonomic dysfunction in ME/CFS patients only. This points to a common mechanism for these symptoms in the ME/CFS subtype, distinct from that in other types of PCS. Further HGS provides an objective marker of disease severity in ME/CFS.

Source: Anna Paffrath, Laura Kim, Claudia Kedor, Elisa Stein, Rebekka Rust, Helma Freitag, Uta Hoppmann, Leif G Hanitsch, Judith Bellmann-Strobl, Kirsten Wittke, Carmen Scheibenbogen, Franziska Sotzny. Repeated Hand Grip Strength is an Objective Marker for Disability and Severity of Key Symptoms in Post-COVID ME/CFS.
medRxiv 2024.01.25.24301776;  https://www.medrxiv.org/content/10.1101/2024.01.25.24301776v1 (Full text available as PDF file)

Low-Dose Naltrexone Improves post-COVID-19 condition Symptoms

Abstract:

Purpose: Treatments for myalgic encephalomyelitis and chronic fatigue syndrome can be adapted for post-COVID-19 condition. Our aim was to compare treatments in patients from our post-COVID-19 clinic.

Methods: We conducted a retrospective cohort study and included consecutive patients enrolled in our post-COVID-19 clinic. We included patients who received low-dose naltrexone, amitriptyline, duloxetine, and physical therapy, and evaluated improvements in fatigue, pain, dyspnea, and brain fog recorded in the electronic health record. We calculated the adjusted relative hazard of improvement using Cox proportional models. We adjusted for demographic characteristics, comorbidities, and prior COVID-19 hospitalization.

Findings: We included the first 108 patients with post-COVID-19 enrolled in the clinic. Most of the patients received amitriptyline. The relative hazard of improvement for those taking low-dose naltrexone was 5.04 (95% CI, 1.22-20.77; P = 0.02) compared with physical therapy alone. Both fatigue and pain were improved in patients taking low-dose naltrexone; only fatigue was improved in patients taking amitriptyline.

Implications: Post-COVID-19 condition symptoms may improve in patients taking medications adapted from myalgic encephalomyelitis and chronic fatigue syndrome. Randomized controlled trials should evaluate these medications and translational studies should further evaluate their mechanisms of action.

Source: Tamariz L, Bast E, Klimas N, Palacio A. Low-Dose Naltrexone Improves post-COVID-19 condition Symptoms. Clin Ther. 2024 Jan 23:S0149-2918(24)00003-1. doi: 10.1016/j.clinthera.2023.12.009. Epub ahead of print. PMID: 38267326. https://pubmed.ncbi.nlm.nih.gov/38267326/

Herpesvirus Infection as a Systemic Pathological Axis in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Understanding the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is critical for advancing treatment options. This review explores the novel hypothesis that herpesviruses’ infection of endothelial cells (ECs) may underlie ME/CFS symptomatology.
We review evidence linking herpesviruses to persistent EC infection and the implications for endothelial dysfunction, encompassing blood flow regulation, coagulation, and cognitive impairment – symptoms consistent with ME/CFS and Long COVID. The paper provides a synthesis of current research on herpesvirus latency and reactivation, detailing the impact on ECs and subsequent systemic complications, including latent modulation and long-term maladaptation.
We suggest that the chronicity of ME/CFS symptoms and the multisystemic nature of the disease may be partly attributable to herpesvirus-induced endothelial maladaptation. Our conclusions underscore the necessity for further investigation into the prevalence and load of herpesvirus infection within ECs of ME/CFS patients.
This review offers a conceptual advance by proposing an endothelial infection model as a systemic mechanism contributing to ME/CFS, steering future research towards potentially unexplored avenues in understanding and treating this complex syndrome.
Source: Nunes, J.M.; Kell, D.B.; Pretorius, E. Herpesvirus Infection as a Systemic Pathological Axis in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Preprints 2024, 2024011486. https://doi.org/10.20944/preprints202401.1486.v1 https://www.preprints.org/manuscript/202401.1486/v1 (Full text available as PDF file)

Vaccine Effectiveness Against Long COVID in Children

Abstract:

Objective: Vaccination reduces the risk of acute COVID-19 in children, but it is less clear whether it protects against long COVID. We estimated vaccine effectiveness (VE) against long COVID in children aged 5-17 years.

Methods: This retrospective cohort study used data from 17 health systems in the RECOVER PCORnet electronic health record (EHR) Program for visits after vaccine availability. Conditional logistic regression was used to estimate VE against long COVID with matching on age group (5-11, 12-17) and time period and adjustment for sex, ethnicity, health system, comorbidity burden, and pre-exposure health care utilization. We examined both probable (symptom-based) and diagnosed long COVID in the year following vaccination.

Results: The vaccination rate was 56% in the cohort of 1,037,936 children. The incidence of probable long COVID was 4.5% among patients with COVID-19, while diagnosed long COVID was 0.7%. Adjusted vaccine effectiveness within 12 months was 35.4% (95 CI 24.5 – 44.5) against probable long COVID and 41.7% (15.0 – 60.0) against diagnosed long COVID. VE was higher for adolescents 50.3% [36.3 – 61.0]) than children aged 5-11 (23.8% [4.9 – 39.0]). VE was higher at 6 months (61.4% [51.0 – 69.6]) but decreased to 10.6% (-26.8 – 37.0%) at 18-months.

Discussion: This large retrospective study shows a moderate protective effect of SARS-CoV-2 vaccination against long COVID. The effect is stronger in adolescents, who have higher risk of long COVID, and wanes over time. Understanding VE mechanism against long COVID requires more study, including EHR sources and prospective data.

Source: Razzaghi H, Forrest CB, Hirabayashi K, Wu Q, Allen A, Rao S, Chen Y, Bunnell HT, Chrischilles EA, Cowell LG, Cummins MR, Hanauer DA, Higginbotham M, Horne BD, Horowitz CR, Jhaveri R, Kim S, Mishkin A, Muszynski JA, Naggie S, Pajor NM, Paranjape A, Schwenk HT, Sills MR, Tedla YG, Williams DA, Bailey C. Vaccine Effectiveness Against Long COVID in Children. Pediatrics. 2024 Jan 16. doi: 10.1542/peds.2023-064446. Epub ahead of print. PMID: 38225804. https://publications.aap.org/pediatrics/article/doi/10.1542/peds.2023-064446/196419 (Full text available as PDF file)

Neutrophil degranulation, endothelial and metabolic dysfunction in unvaccinated long COVID patients

Abstract:

Background: Long COVID symptoms are widely diffused and have a poorly understood pathophysiology, with possible involvement of inflammatory cytokines.

Materials and methods: A prospective follow-up study involved 385 unvaccinated patients, started 1 month after SARS-CoV-2 infection and continued for up to 12 months. We compared circulating biomarkers of neutrophil degranulation, endothelial and metabolic dysfunction in subjects with long COVID symptoms and in asymptomatic post-COVID controls.

Results: The highest occurrence of symptoms (71%) was after 3 months from the infection, decreasing to 62.3% and 29.4% at 6 and 12 months, respectively. Compared to controls, long COVID patients had increased levels of the neutrophilic degranulation indices MMP-8 and MPO, of endothelial dysfunction indices L-selectin and P-selectin. Among indices of metabolic dysfunction, leptin levels were higher in long COVID patients than in controls.

Conclusion: In unvaccinated patients, symptoms may persist up to 1 year after acute COVID infection, with increased indices of neutrophil degranulation, endothelial and metabolic dysfunction. The clinical implications of specific inflammatory biomarkers require further attention, especially in individuals with fatigue and long COVID-linked cognitive dysfunctions.

Source: Di Ciaula A, Liberale L, Portincasa P, Khalil M, Galerati I, Farella I, Noto A, JohnBritto S, Moriero M, Michelauz C, Frè F, Olivero C, Bertolotto M, Montecucco F, Carbone F, Bonfrate L. Neutrophil degranulation, endothelial and metabolic dysfunction in unvaccinated long COVID patients. Eur J Clin Invest. 2024 Jan 16:e14155. doi: 10.1111/eci.14155. Epub ahead of print. PMID: 38226472. https://pubmed.ncbi.nlm.nih.gov/38226472/