Review The role of clinical neurophysiology in the definition and assessment of fatigue and fatigability, 2024, Tankisi et al

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.

Open access, https://www.sciencedirect.com/science/article/pii/S2467981X23000367

 

"3.1. Myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS)

ME/CFS is a serious, long-term, multi-system disorder characterised by a wide range of symptoms including extreme fatigue, autonomic and cognitive dysfunction, sleep disturbances and pain. ME/CFS affects motor, sensory and cognitive processing networks, which may be assessed through differing neurophysiological methods.

Various measures of EEG have been used in ME/CFS, with varying results. A resting state quantitative EEG study showed lower beta 2 current density in a variety of cortical and subcortical regions including the somatomotor cortex, superior parietal lobe and precuneus and posterior cingulate in those with ME/CFS (Zinn et al., 2018). EEG Low-resolution electromagnetic tomography (LORETA) analysis in cohorts of those with ME/CFS found hypoconnectivity in delta, alpha and alpha-2 bands in patients compared with controls (Zinn et al., 2016). With brain EEG mapping (BEAM), significantly elevated levels of delta, theta and alpha 1 waves were found in the right frontal and occipital regions of those with ME/CFS (Wu et al., 2016). Sleep and awake EEG studies recording beyond the conventional EEG bands have shown lower ultra-slow delta waves (0.5–0.8 Hz) in ME/CFS groups than controls while the other frequency bands did not differ between the groups (Le Bon et al., 2012). Interesting though these studies are, they have not been compared with other chronic conditions, so whether they are specific to ME/CFS remains unclear. Similarly, their mechanisms and significance remain unclear. The hope of such research, to find neural correlates of fatigue states, remains distant. To explore such ideas, other studies have used EEG during cognitive tasks (word finding and dot localisation). Significant differences were found in left frontal-temporal- parietal regions in those with ME/CFS compared with controls (Flor-Henry et al., 2010), though of course causal correlation is difficult to show and its possible significance again can only be speculated upon.

Autonomic nervous system dysfunction has been proposed as one of the primary mechanisms of ME/CFS (Wirth and Scheibenbogen, 2021). For instance, the prevalence of postural orthostatic tachycardia syndrome is increased in ME/CFS (between 13 % and 29 %) based on the heart rate dynamic responses during the head-up tilt test, though Valsalva tests could not distinguish ME/CFS patients from controls (Wirth and Scheibenbogen, 2021). Autonomic dysfunction in ME/CFS requires further research. Zinn and Jason explored the role of the cortical autonomic network (CAN) involved in higher-order control of autonomic nervous system functioning in those with ME/CFS, using resting-state qEEG, and source analysis (eLORETA) (Zinn and Jason, 2021). They found evidence of reduced higher-order homeostatic regulation and adaptability in ME/CFS which may suggest involvement of the cortical autonomic network, which may in turn be a potential therapeutic target for managing ME/CFS symptoms.

Surprisingly few studies have used needle EMG and/or sfEMG in ME/CFS and those that have do not show unanimity. Connolly et al. found increased fibre density in 11 of 35 participants with ME/CFS, with normal jitter (Connolly et al., 1993), while others have found increased jitter and blocking, (in all 10 participants (Jamal and Hansen, 1989), in 30 out of 40 participants (Jamal and Hansen, 1985), and in 16 out of 30 participants (Roberts and Byrne, 1994)). In all studies, participants had pronounced long term supraspinal and peripheral fatigability. One prominent feature of ME/CFS is pain which is often worse the day after the exertion. This feature may distinguish ME/CFS from myasthenia gravis. Studies are needed to correlate EMG and sfEMG findings with peripherally originating fatigability. This is not of course to exclude central involvement in these conditions as well; rather the balance between supraspinal and peripheral originating fatigability may be important both in its pathophysiology and its treatment."

This "One prominent feature of ME/CFS is pain which is often worse the day after the exertion." seems to be how they cover PEM.