Objective assessment of diverse types of MS related fatigue and fatiguability

[MSEsperanza]

The following list of studies and other papers could be helpful with regard to the claim that symptoms classified as 'fatigue' can't be measured objectively, or that potential objective measures are too unspecific.

In the field of MS research, some people looked for objective measures correlating with diverse types of fatigue and fatiguability. Others compared fatigue in different neurological illnesses. I can't judge the quality of their papers, neither do I know whether any of these measures can be adapted in a sensible way to ME specific symptoms. But perhaps other forum members are interested?

There was a short discussion on this topic a while ago here:
The Dopamine Imbalance Hypothesis of Fatigue in Multiple Sclerosis by @Marco

Note that this is not a systematically composed list.

Research on objective measures for diverse types of MS related fatigability

1. Motor fatigue/ fatigubility in MS: The Fatigue Index Kliniken Schmieder (FKS)

1.1 Objective assessment of motor fatigue in multiple sclerosis: the Fatigue index Kliniken Schmieder
Sehle, A., Vieten, M., Sailer, S. et al. J Neurol (2014) 261: 1752. https://doi.org/10.1007/s00415-014-7415-7,
(used kinematic gait analysis)

1.2 Fatigability Assessment Using the Fatigue Index Kliniken Schmieder (FKS) Is Not Compromised by Depression.
Dettmers, C. , Riegger, M. , Müller, O. and Vieten, M. (2016), Health, 8, 1485-1494. doi: 10.4236/health.2016.814147.

1.3 Difference in Motor Fatigue between Patients with Stroke and Patients with Multiple Sclerosis: A Pilot Study. Sehle A, Vieten M, Mundermann A, Dettmers C. (2014), Frontiers in Neurology 2014, 5: 279, https://doi.org/10.3389/fneur.2014.00279

1.4 Disability and Fatigue Can Be Objectively Measured in Multiple Sclerosis. Motta, C., Palermo, E., Studer, V., Germanotta, M., Germani, G., Centonze, D., Cappa, P., Rossi, S., & Rossi, S. (2016), PloS one, 11(2), e0148997. https://doi.org/10.1371/journal.pone.0148997

Related research:

1.5 Vieten MM, Sehle A, Jensen RL. A novel approach to quantify time series differences of gait data using attractor attributes.(2013) PloS one. 2013, 8 (8): e71824, http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0071824

1.6 Role of body-worn movement monitor technology for balance and gait rehabilitation. Horak, F., King, L., & Mancini, M. (2015), Physical therapy, 95(3), 461–470. https://doi.org/10.2522/ptj.20140253

1.6 cited by recent papers:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4348720/citedby/


2. Cognitive fatigue/ fatigability

2.1 Claros-Salinas D, Dittmer N, Neumann M, Sehle A, Spiteri S, Willmes K et al. Induction of cognitive fatigue in MS patients through cognitive and physical load. Neuropsychol Rehabil. 2013, 23 (2): 182-201, https://www.ncbi.nlm.nih.gov/pubmed/23153337
(paywalled)

Abstract

The objective of the study was to investigate whether cognitive fatigue in patients with multiple sclerosis (MS) is a spontaneous phenomenon or whether it can be provoked or exacerbated through cognitive effort and motor exercise.

Thirty two patients with definite MS and cognitive fatigue according to the Fatigue Scale for Motor and Cognitive Functions (FSMC ≥ 22) performed attention tests (alertness, selective, and divided attention subtests from the TAP test battery for attention performance) twice during rest (baseline), and before and after treadmill training and cognitive load (a standardised battery of neuropsychological tests lasting 2.5 hours). Subjective exhaustion was assessed with a 10-point rating scale.

Tonic alertness turned out to be the most sensitive test and showed significantly increased reaction times after treadmill training and after cognitive load. Patients' subjective assessment of exhaustion (10-point rating scale) and the objective test results were discrepant. In contrast, healthy control subjects (N = 20) did not show any decline of performance in the subtest alertness after cognitive or physical load. Data favour the concept that fatigue is induced by physical and mental load. Discrepancies between subjective and objective assessment offer therapeutic options. The common notion of a purely "subjective" lack of physical and/or mental energy should be reconsidered.

2.2 Neumann M, Sterr A, Claros-Salinas D, Gutler R, Ulrich R, Dettmers C. Modulation of alertness by sustained cognitive demand in MS as surrogate measure of fatigue and fatigability, Journal of the neurological sciences. 2014, 340 (1-2): 178-82, https://www.jns-journal.com/article/S0022-510X(14)00168-3/fulltext

Abstract

OBJECTIVE:
This study used reaction time (RT) as an objective marker of cognitive fatigue and fatigability in patients with multiple sclerosis (MS).

METHOD:
RT was measured in fifteen healthy controls and in thirty MS patients with cognitive fatigue identified with the Fatigue Scale for Motor and Cognitive Function (FSMC). Secondary fatigue was excluded through the Epworth Sleepiness Scale and the Beck Depression Inventory. RT was measured at rest (t1), following a 2.5 hour test session inducing high cognitive load (t2), and a one hour recovery period (t3).

RESULTS:
At rest mean RT was longer in patients than in controls (391 ms vs 205 ms). After exerting cognitive load (t2), RT in patients increased dramatically but remained unchanged in controls. After the recovery period (t3), RT returned to baseline levels in most patients. Patients further showed a significant correlation between RT and FMSC scores at t1, t2 and t3.

CONCLUSION:
RT performance is a suitable surrogate marker for assessing fatigue. RT is sensitive to cognitive load and the recovery from cognitive demand. It hence represents an objective index for fatigability which can inform the management and treatment of MS.

3. Neural correlates of fatigue and fatigability

Spiteri S, Hassa T, Claros-Salinas D, Dettmers C, Schoenfeld MA. Neural correlates of task-dependent and independent fatigue components in patients with Multiple Sclerosis. Neurobiol Aging. 2017, http://journals.sagepub.com/doi/10.1177/1352458517743090 (paywalled)

Abstract

Background:
Among patients with multiple sclerosis (MS), fatigue is the most commonly reported symptom. It can be subdivided into an effort-dependent (fatigability) and an effort-independent component (trait-fatigue).

Objective:
The objective was to disentangle activity changes associated with effort-independent “trait-fatigue” from those associated with effort-dependent fatigability in MS patients.

Methods:
This study employed behavioral measures and functional magnetic imaging to investigate neural changes in MS patients associated with fatigue. A total of 40 MS patients and 22 age-matched healthy controls performed in a fatigue-inducing N-back task. Effort-independent fatigue was assessed using the Fatigue Scale of Motor and Cognition (FSMC) questionnaire.

Results:
Effort-independent fatigue was observed to be reflected by activity increases in fronto-striatal-subcortical networks primarily involved in the maintenance of homeostatic processes and in motor and cognitive control. Effort-dependent fatigue (fatigability) leads to activity decreases in attention-related cortical and subcortical networks.

Conclusion:
These results indicate that effort-independent (fatigue) and effort-dependent fatigue (fatigability) in MS patients have functionally related but fundamentally different neural correlates. Fatigue in MS as a general phenomenon is reflected by complex interactions of activity increases in control networks (effort-independent component) and activity reductions in executive networks (effort-dependent component) of brain areas.

4. Potentially relevant papers reviewing the concepts of fatigue and fatigability in MS / neurological illnesses in general

4.1 Kluger BM, Krupp LB, Enoka RM. Fatigue and fatigability in neurologic illnesses: proposal for a unified taxonomy. Neurology. 2013, 80 (4): 409-16, https://n.neurology.org/content/80/4/409 (paywalled)
free PMC article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3589241/

4.2 Rudroff, Thorsten, Kindred, John H, Ketelhut, Nathaniel B.; Fatigue in Multiple Sclerosis: Misconceptions and Future Research Directions, Frontiers in Neurology 2016 Aug 2;7:122. doi: 10.3389/fneur.2016.00122, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4969300/

4.3 Manjaly Z, Harrison NA, Critchley HD, et al, Pathophysiological and cognitive mechanisms of fatigue in multiple sclerosis, Journal of Neurology, Neurosurgery & Psychiatry 2019;90:642-651, https://jnnp.bmj.com/content/jnnp/early/2019/01/25/jnnp-2018-320050.full.pdf

(Only skimmed these papers. They seem to me to make some useful points even though they might still be criticizable in particular with regard to how they conceive the two domains of 'performance fatiguability' vs 'perception of fatigue'.)

(Updated 2020-05-29)

 

[adambeyoncelowe]

Nice. Thanks.

 

[MSEsperanza]

I did some homework and added the URLs to the articles as well as some abstracts.

I have to admit that I haven't read one of these papers. Why I think they could be relevant for ME, I tried to outline here: https://www.s4me.info/threads/membe...e-cfs-guidelines-draft-scope.4816/#post-86894

 

[Jonathan Edwards]

@MSEsperanza,
I think this sort of line of thinking is very relevant and worth exploring.

One caveat I can think of is that the reason why we look for 'objective' markers is that we want reliability of evidence. If the subjective symptom is of key importance to the patient then objective measures are there to confirm the reliability of subjective reports as indicating a relevant underlying biological change. There is a lot to be said for requiring both a subjective score and an objective measure that confirms that.

The measures given here are objective in the sense of being direct measures of biological events that correlate with types of fatigue. However, do they increase the reliability of the fatigue reports? If the objective findings just correlate reasonably well then in cases where they disagree what do you believe? Is the person fatigued if they say they are but the scan does not show it?

I think to be of use these objective measures actually need to be based on good reasons for thinking that they are a more reliable indicator of a key underlying process than the subjective report. It is reasonable to think that a serum CRP is a more reliable indicator of cytokine based inflammation than a report of tenderness. Or at least it is a reliable indicator that the tenderness is likely to be due to cytokines. I am not sure that fMRI is at a stage where it provides that sort of clear indication of an underlying process. What if the fMRI just reflects different conscious thoughts that arise from the persons subjective feelings about things at the time rather than the underlying mechanisms that give rise to those feelings?

 

[Graham]

Subjective assessment can be more "reliable" if the trial is truly double-blinded. An easy one would be in homeopathy, where the homeopathist could prescribe a certain mixture, but the patient could easily be presented with plain water (that is, as opposed to water that had been shaken and diluted with water).

It could be difficult to agree upon measures that correlate with fatigue, but surely it would be easier to agree upon measures that correlate with the consequences of fatigue? If I claim that my fatigue is greatly reduced, but, even over a period of time, the distance that I can walk remains severely restricted, it would sensibly throw doubt on my claim (assuming that I do not have another restricting condition).

 

[Jonathan Edwards]

it would be easier to agree upon measures that correlate with the consequences of fatigue?

Yes, that would be an objective indicator of a relevant underlying physical process - the ability to do exercise. I guess it does not matter whether the indicator indicates something upstream or downstream of the subjective reported symptom, as long as it suggests that the symptom reflects something worth trying to modify. I had not really thought of it but for tender joints rheumatoid factor antibodies would be upstream in a relevant process and CRP would be downstream but both are good indicators that the symptom reflects something you want to treat.

 

[Barry]

I'm intrigued by the idea of reaction time being used as an indicator of cognitive fatigue - just feels like a valid correlation. Certainly it's recognised that driving when mentally fatigued impairs reaction times. Have any such studies been done for PwME? And it's easy to measure, with a bit of care.

 

[Jonathan Edwards]

I'm intrigued by the idea of reaction time being used as an indicator of cognitive fatigue - just feels like a valid correlation. Certainly it's recognised that driving when mentally fatigued impairs reaction times. Have any such studies been done for PwME? And it's easy to measure, with a bit of care.

I would be interested to know if anyone has looked at something simple like a blink reflex or a tensor tympani reflex where the brain responds to sound by adjusting the tension of the ear drum unconsciously.

 

[Graham]

Well you live and learn. There's me thinking that I'm not remotely musical, and it appears I've got a tensor timpani reflex.

 

[Sean]

but the patient could easily be presented with plain water (that is, as opposed to water that had been shaken and diluted with water).

A question both tongue-in-cheek, and serious:

How does the researcher tell the difference between the 'active' water and the 'inactive' control water?

All water has been in contact with some other substance at some point, and subsequently diluted to the nth degree (thus rendering it mightily potent, according to homeopathy). Even distilled water has been in contact with the distilling apparatus, which is never 100% inert.

 

[Graham]

The explanation that I heard was that the shaking and diluting process enables the water to retain a memory of the shape of the molecules of the added substance.

Give me credit, I kept a straight face, which was necessary in the cirumstances.

 

[Sean]

Give me credit, I kept a straight face, which was necessary in the cirumstances.

Admirable restraint, sir.

 

[Sasha]

I would be interested to know if anyone has looked at something simple like a blink reflex or a tensor tympani reflex where the brain responds to sound by adjusting the tension of the ear drum unconsciously.

A quick google shows that various aspects of blinking have been examined in relation to fatigue (and sleepiness) but I didn't find an up-to-date review (which doesn't mean there isn't one, because I didn't do a thorough search).

The tensor tympani reflex has also been looked at, but on another shallow and incompetent google, I didn't see a review. I did find, for example, a study in which the reflex helped distinguish patients with myasthenia gravis from healthy controls:

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ana.410090604

 

[Marco]

I would be interested to know if anyone has looked at something simple like a blink reflex or a tensor tympani reflex where the brain responds to sound by adjusting the tension of the ear drum unconsciously.

There have been a (very) few studies on pre-pulse inhibition (PPI) of the startle reflex and event related potential (ERP) responses to sensory stimuli which are a similar thing and at the early procssing stage are pre attention/pre-conscious.

 

[MSEsperanza]

Thanks to all who have contributed to this thread so far. I hope I will be able to come back to some questions soon.

In the meantime, just to get a more complete picture, I added the following paper to the OP:

The Fatigue Scale for Motor and Cognitive Functions (FSMC): validation of a new instrument to assess multiple sclerosis-related fatigue
https://www.ncbi.nlm.nih.gov/pubmed/19995840

edit: I have not read this yet - might be a bad example. i.e rather subjective measure?

 

[Woolie]

I just saw this. Having only read the summary so far (the one in the OP), my first worry is that these neural correlates they've found - which are just that, correlates - could easily morph into causes, and ultimately, feed the view that fatigue is a construct created entirely in the mind.

Yes, fatigue is a construct created in the mind, just as is perceiving a fast approaching train. But the best way to deal with both is not to modify the perception, but rather the external conditions giving rise to it. Like, get off the damn train tracks!

Maybe I worry too much?

 

[Hutan]

I'm intrigued by the idea of reaction time being used as an indicator of cognitive fatigue - just feels like a valid correlation. Certainly it's recognised that driving when mentally fatigued impairs reaction times. Have any such studies been done for PwME? And it's easy to measure, with a bit of care.

I agree @Barry. I used some software ( http://www.sleepdisordersflorida.com/pvt1.html#responseOut ) to measure my reaction time, tracking it daily for quite a while. Reaction time was longer on the days when I felt worse and found it harder to focus and concentrate.

For example, on a day of slow reaction time (459), there was a difference of 41 beats per minute in the orthostatic intolerance standing test (i.e. positive for POTS), my pulse pressure was bad (low - 23), shock index high (1.1). As well as all the usual symptoms, there were extra symptoms of muscle twitches, a warm feeling on my foot, and cramps. That day, deep fatigue didn't hit until the evening, but the following day fatigue was particularly bad from the morning.

On a day of faster reaction time (307), the OI standing test had a difference of 19 beats per minute (negative for POTS), my pulse pressure was fine (36), my shock index was fine (0.7). Fatigue was moderate that day and the next day.

I would really like to see a study done correlating reaction time (and those other suggested measures of blink and ear drum reflex) with subjective measures of fatigue.

 

[MSEsperanza]

Unfortunately some of the listed papers do not seem to reflect the premise I found so promising: to differentiate clearly between specific types of fatigue when writing about fatigue. Have to read them yet.

The abstract and first paragraphs of one of the now added papers however sound quite good to me.

Could be helpful to relate to this paper when arguing with NICE re: objective measurements?

from: Rudroff, Thorsten, Kindred, John H, Ketelhut, Nathaniel B.; Fatigue in Multiple Sclerosis: Misconceptions and Future Research Directions, Frontiers in Neurology 2016 Aug 2;7:122. doi: 10.3389/fneur.2016.00122, (fulll text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4969300/ )]

Abstract:

Fatigue is one of the most disabling side effects in people with multiple sclerosis. While this fact is well known, there has been a remarkable lack of progress in determining the pathophysiological mechanisms behind fatigue and the establishment of effective treatments. The main barrier has been the lack of a unified definition of fatigue that can be objectively tested with validated experimental models. In this “perspective article” we propose the use of the following model and definition of fatigue: the decrease in physical and/or mental performance that results from changes in central, psychological, and/or peripheral factors. These changes depend on the task being performed, the environmental conditions it is performed in, and the physical and mental capacity of the individual. Our definition and model of fatigue outlines specific causes of fatigue and how it affects task performance. We also outline the strengths and weaknesses of commonly used measures of fatigue and suggest, based on our model and definition, new research strategies, which should include multiple measures. These studies should be mechanistic with validated experimental models to determine changes in central, psychological, and/or peripheral factors that explain fatigue. The proposed new research strategies may lead to the identification of the origins of MS related fatigue and the development of new, more effective treatments.

Intro:

Fatigue is the most common and disabling symptom experience by people with multiple sclerosis (PwMS). Up to 92% of PwMS are affected by fatigue, which strongly influences quality of life (1). However, fatigue remains poorly understood and PwMS continue to suffer from a lack of effective fatigue treatments. Despite significant effort to elucidate the pathogenic mechanisms of fatigue, current knowledge is limited. Several factors contribute to the lack of progress in fatigue research, but the most important factor is that “fatigue” is often not clearly defined or is used without meaningful measurements in clinical and research settings (2). Kluger et al. (3) states: “Current treatments are non-specifically targeted to a vaguely defined symptom with unsatisfactory outcomes.”

re: exercise therapy:

a recent Cochrane Review (4) on exercise therapy for fatigue in MS concluded there are important methodological issues to overcome. Heine et al. (4) reported most studies did not: explicitly include PwMS who experienced fatigue, use a validated measure of fatigue as the primary outcome, or target fatigue specifically.

re: objective measures and need to specify fatigue:

Berger 5) questions whether MS related fatigue can be treated and improved with current disease-modifying drugs, e.g., amantadine, methylphenidate, and modafinil, without having a precise definition of fatigue.

Many studies investigating fatigue have failed to objectively define fatigue, and those that did, have used varying definitions. Furthermore, the origins of fatigue vary between conditions and research in some diseases, such as MS, has failed to fully understand the difference between fatigue and related phenomena, such as depressed mood or sleep disorders

 

[MSEsperanza]

The only reservation I had about the article is that they seem to continue to assume that all types of fatigue in MS must have a central nervous system origin. What if some types have a peripheral origin, and are primarily a function of levels of circulating peripheral cytokines or the like? That would sound more plausible to me, and it would help explain why some fatigue is effort-sensitive (if its going on in the periphery, its going to be influenced by all sort of things going on there).

@Woolie, I thought this article might be of interest for your question posted in an related thread re: MS related fatigue:

from: Rudroff, Thorsten, Kindred, John H, Ketelhut, Nathaniel B.; Fatigue in Multiple Sclerosis: Misconceptions and Future Research Directions, Frontiers in Neurology 2016 Aug 2;7:122. doi: 10.3389/fneur.2016.00122, (fulll text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4969300/ )]

re: Peripheral Factors

Peripheral Factors
Fatigue in PwMS can also arise from one or several of the peripheral factors that were described above. Slowing of muscle contractile properties (48–51), decreased muscle oxidative capacity (48, 52), impaired excitation–contraction coupling (50, 53), and altered muscle metabolic response to exercise (50, 53, 54) may contribute to fatigue in MS. Sharma et al. (50) showed that intramuscular components contribute to fatigue in MS by demonstrating that greater decreases in phosphocreatine and intracellular pH was associated with greater force reduction (performance fatigability). In this context, it is important to mention muscle afferent feedback, which includes the possibility that metabolites can alter CNS motor output (55).

An example for the objective measurement of fatigue in PwMS with defined outcome variables is a study by Sharma et al. (50). Fatigability of the anterior tibialis muscle was quantified in PwMS and controls during intermittent electrical stimulation. During stimulation, the decline in tetanic force, phosphocreatine, and intracellular pH was greater in PwMS than in controls, indicating an abnormal intramuscular component of fatigue in MS. Importantly, this study eliminated the influence of perceptions of fatigue since it did not involve voluntary muscle activity.

While the study design described above was ideal to identify several peripheral factors of performance fatigability, future studies must include voluntary muscle activity, which incorporates central and psychological factors, to fully understand fatigue. This can be accomplished by measuring changes in peripheral factors (muscle strength and activity, pH, glycogen, etc.), as well as measures of central and psychological factors (dopamine, motivation, perceived effort, etc.). For example, the design used by Sharma et al. (50) could be expanded to include voluntary muscle activity, and neuroimaging techniques (fMRI and PET) could be applied to measure changes in central and psychological factors. Perceptions of fatigue should be monitored in this example using the techniques, such as the Borg scale of perceived exertion. The associations of these measures then may provide insights to the origins and mechanisms of MS related fatigue.

 

[Woolie]

Nice find, @MSEsperanza!