Review Fatigue: a common but poorly understood symptom in neurological and non-neurological diseases 2025 Penner et al

[Andy]

Abstract​

Fatigue is a severely disabling symptom that can substantially impair quality of life and employment prospects, and has serious socioeconomic consequences. Different individual and disease-related variables interact to generate this complex symptom, leading to clinical heterogeneity. We currently lack a common understanding and definition of fatigue and its origins, thereby impeding professional exchange among disciplines regarding diagnosis and underlying pathophysiology. To aid the development of a common language that encapsulates the heterogeneity of fatigue, we propose a taxonomy consisting of neurogenic, myogenic and systemic clusters. Each cluster comprises the same five distinct concepts and their phenotypic expression. The interplay between multifactorial pathophysiological mechanisms might vary between diseases and over time, and additional factors such as comorbidities can modulate fatigue. Understanding this complexity is essential to improve both the diagnostic process and the development of targeted therapeutic interventions.

In this Review, we compare the clinical and pathophysiological characteristics of a range of neurological and non-neurological diseases within predefined clusters of fatigue origin. We propose an integrative model for fatigue of different origin and over time based on the interplay of genetics and epigenetics, immunological changes, structural and functional brain abnormalities, and behavioural alterations. Large research consortia will be required to tackle the methodological shortcomings that currently hamper our understanding of fatigue and to initiate large longitudinal cohort studies with multidimensional readouts to further explore and address this burdensome symptom.

Key points​

• Fatigue is a major unmet medical need with serious socioeconomic implications.
• The use of a more precise taxonomy, including clusters of origin (neurogenic, myogenic and systemic) and different concepts of fatigue should foster a better understanding of the condition among researchers and clinicians and enable more precise therapeutic decisions to be made.
• Heterogeneity in pathological mechanisms and phenotypes, as well as a lack of methodological standardization, hinder progress in identifying biomarkers and therapeutic approaches for fatigue.
• Genetics and epigenetics, immunological changes, behavioural alterations, and structural and functional CNS abnormalities are the main pathogenetic drivers that govern fatigue phenotypes, and fatigue is modulated by comorbidities, personality, motivation and other factors.
• Management of fatigue requires a multidisciplinary, individualized and integrated approach.
• Larger consortia that can recruit large longitudinal cohorts and use multidimensional readouts would be best suited to tackle the conundrum of fatigue.

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[Andy]

Can't access the paper but can see the references. The ones that seem to apply to us.

Johnson, S. K., DeLuca, J. & Natelson, B. H. Personality dimensions in the chronic fatigue syndrome: a comparison with multiple sclerosis and depression. J. Psychiatr. Res. 30, 9–20 (1996).

Taillefer, S. S., Kirmayer, L. J., Robbins, J. M. & Lasry, J. C. Correlates of illness worry in chronic fatigue syndrome. J. Psychosom. Res. 54, 331–337 (2003).

National Guideline Centre. Monitoring and Reviewing People with ME/CFS: Myalgic Encephalomyelitis (or Encephalopathy)/Chronic Fatigue Syndrome: Diagnosis And Management. Evidence Review J (National Institute for Health and Care Excellence, 2021).

Paul, B. D., Lemle, M. D., Komaroff, A. L. & Snyder, S. H. Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome. Proc. Natl Acad. Sci. USA 118, e2024358118 (2021).

Vercoulen, J. H. et al. The measurement of fatigue in patients with multiple sclerosis. A multidimensional comparison with patients with chronic fatigue syndrome and healthy subjects. Arch. Neurol. 53, 642–649 (1996).

 

[arnoble]

Would it be fair to infer that there may not be much biology informing their paper?

 

[TiredMathematician]

Can't access the paper but can see the references. The ones that seem to apply to us.

These are the bits that mention ME.

Neuroticism is prevalent in various neurological disorders, including MS, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Alzheimer disease and Parkinson disease (PD), and seems to be a risk factor for fatigue in these conditions44,45,46

45. Johnson, S. K., DeLuca, J. & Natelson, B. H. Personality dimensions in the chronic fatigue syndrome: a comparison with multiple sclerosis and depression. J. Psychiatr. Res. 30, 9–20 (1996).

46. Taillefer, S. S., Kirmayer, L. J., Robbins, J. M. & Lasry, J. C. Correlates of illness worry in chronic fatigue syndrome. J. Psychosom. Res. 54, 331–337 (2003).

As defined in the 2021 NICE guideline for ME/CFS, energy management is a self-management strategy that helps patients with fatigue to manage their daily life activities within their personal energy limits151. As many people are not aware of their personal energy limits, the learning process is facilitated by specialized health-care professionals. This intervention was popularized following the emergence of post-COVID-19 syndrome, when health-care professionals were confronted with a large number of patients with fatigue. A well-designed occupational therapy-based self-management education programme was introduced152, providing behavioural adaptations to enable affected individuals to participate in daily life. As a person’s behavioural patterns are established over many years and can become over learned, behavioural changes are difficult to implement alone. Thus, experts from different disciplines, including occupational therapists and psychologists, are needed to support this change process, not only by offering alternative strategies such as energy conservation but also by explaining the importance of the change. The combination of education and the offer of concrete strategies serves as a powerful approach for patient empowerment and long-term implementation of behavioural modification.

151. National Guideline Centre. Monitoring and Reviewing People with ME/CFS: Myalgic Encephalomyelitis (or Encephalopathy)/Chronic Fatigue Syndrome: Diagnosis And Management. Evidence Review J (National Institute for Health and Care Excellence, 2021).

152. Hersche, R., Weise, A., Hummel, B. & Barbero, M. Occupational therapy-based self-management education in persons with post-COVID-19 condition related fatigue: a feasibility study with a pre-post design. Disabil. Rehabil. 46, 3060–3066 (2024).

A large network meta-analysis including 113 trials of different forms of exercise training and behavioural interventions in people with MS revealed that balance training was the most powerful approach to reduce fatigue symptoms, followed by CBT155. General exercise, including two or more of the key exercise types — balance, aerobic, strength and flexibility — also showed moderate-to-large effects on fatigue severity. These results support combined treatment regimens in which patients with fatigue are offered cognitive–behavioural approaches together with exercise training. However, in contrast to other diseases, ME/CFS and post-COVID-19 syndrome are associated with impaired exercise capacity and post-exertional malaise156. Therefore, patients with these conditions experience aggravation of fatigue with potentially long-lasting deterioration after exercise training and cognitive stimulation.

156. Appelman, B. et al. Muscle abnormalities worsen after post-exertional malaise in long COVID. Nat. Commun. 15, 17 (2024).

For rehabilitation of people with fatigue, a combination of approaches is recommended. However, individual adjustments might be necessary; for example, to avoid post-exertional malaise, people with post-COVID-19 syndrome or ME/CFS should not begin with the type of high-intensity interval training that is recommended for people with MS fatigue. Careful tailoring to individual needs is necessary, as some individuals might benefit more from CBT whereas others benefit more from exercise.

 

[MrMagoo]

Neuroticism is prevalent in ME, ME, Parkinson’s…seems is a risk factor for fatigue. Really?

Am I understanding neuroticism correctly? Is there a meaning beyond the popular one?

 

[Utsikt]

@TiredMathematician
Thank you!

That’s bad, it doesn’t look like they’ve understood the sources at all. Or maybe like they are parroting anything that’s said without considering the inevitable logical inconsistencies in their paper.

 

[SNT Gatchaman]

In reference to our thread On fatigability and rationing as improved terminology over fatigue and pacing

The clinical phenomenon of fatigue is distinct from fatigability, which describes a decline in physical or mental performance over the course of a task. Fatigue and fatigability are likely to be largely independent as associations between them are reported to be quite weak. Nevertheless, fatigability is often considered to be an objectifiable proxy for fatigue, and several assessment strategies targeting performance fatigability have been implemented.

Physical or motor performance fatigability can be measured by gait parameters, using sensor-based techniques during in-laboratory usual walking and treadmill walking. […] One sensitive gait pattern component is walking speed, which can easily be quantified by the Distance Walked Index. A 10% or greater decrease in walking speed between the first and sixth minutes of the 6-Minute Walk Test indicates motor performance fatigability. Another approach is to use neurophysiological methods such as electromyography or transcranial magnetic stimulation (TMS) to assess and quantify motor fatigability. […] Motor fatigability is often assessed during a task such as maximal muscle contractions or exercise. Central motor desynchronization, altered spinal feedback mechanisms, modifications at the neuromuscular junction, and intramuscular cellular changes due to metabolic, intracellular and muscle–tendon complex changes are all physiological parameters that can be measured to objectively assess changes during task performance, but these methods have so far received little attention in research into fatigue assessment in neurological and non-neurological conditions.

Cognitive performance fatigability describes a decrement in cognitive performance over the course of a task and has been shown to be a better predictor of employment status than the subjective sensation of being fatigued. Cognitive performance fatigability can be measured using computerized alertness tasks, which should ideally be executed at two or more timepoints during a comprehensive neuropsychological evaluation. […] Combining digital biomarkers — for example, cognitive processing speed assessed by a smartphone or voice recordings — with self-reported questionnaires is a promising approach to assess fatigue in real-world settings. These new technologies allow us to quantify the behavioural changes that are associated with fatigue.

On psychology —

Various predisposing factors such as personality traits (for example, neuroticism) and behaviour (for example, apathy, agitation and irritability) have been described for both the onset and persistence of fatigue. Whether a person’s personality constitution can be regarded as a predisposition for fatigue or whether a chronic disease ultimately leads to accentuation of a basic disposition remains unclear. Furthermore, the concept of motivational fatigue, a change in behaviour due to fatigue, has been introduced, emphasizing an additional interplay that contributes to the complex interaction between personality and behaviour.

Neuroticism describes an individual’s tendency to experience negative emotions and an increased vulnerability to stress, leading to low resilience and an increased risk of poor health outcomes. Neuroticism is prevalent in various neurological disorders, including MS, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Alzheimer disease and Parkinson disease (PD), and seems to be a risk factor for fatigue in these conditions. A strong correlation between neuroticism and fatigue has already been reported in people with MS, and neuroticism has been identified as a concrete risk factor for cancer-related fatigue.

Apathy is a clinical syndrome that is characterized by reductions in self-initiation and goal-directed behaviour. The assessment of apathy requires a multidomain approach that encompasses cognition, emotion, social interaction and behaviour. The Apathy Motivation Index has been developed for this purpose and has a clear three-factor structure (behavioural activation, emotional sensitivity and social motivation) […] Interestingly, fatigue was shown to be associated positively with the behavioural and social motivation components […] whereas the emotional sensitivity component showed a negative association. Thus, some but not all subtypes of apathy overlap with fatigue.

Note they classify ME/CFS as a neurological disorder. Although they don't further define it in their sections on Central Neurogenic Fatigue, Peripheral Neurogenic Fatigue, Myogenic Fatigue or Systemic Fatigue. I.e.

Central neurogenic: MS, PD, AD, stroke
Peripheral neurogenic: neuropathy, ALS
Myogenic: myasthaenia gravis
Systemic: RA and Sjögren

 

[Utsikt]

One of the worst concepts in medical and psychological research is «risk factor».

It’s usually used do describe correlating factors, but it heavily implies a one-directional causal relationship.

It is borderline doublespeak and is frequently used as a not so subtle dogwhistle for psychopathology.

 

[rvallee]

One of the worst concepts in medical and psychological research is «risk factor».

It’s usually used do describe correlating factors, but it heavily implies a one-directional causal relationship.

It is borderline doublespeak and is frequently used as a not so subtle dogwhistle for psychopathology.

Especially when they are so generic they are of absolutely no use in any context. Such as literally all Long Covid research assessing those things.

Looking for a woman of a certain age, probably between 5 and 75 or so, who had life events who may or may not have a respiratory system and also probably had some unknown infection at some point, uh? Well that sure narrows things down. Let's have everyone be on the lookout for that 'risk factor'!