Objective assessment of diverse types of MS related fatigue and fatiguability

[Mithriel]

I read an article in the MS association magazine which was reprinted from one in the RA magazine - got it? That said that a lot of the fatigue in MS and RA was caused by the sheer extra effort it takes to do anything with a body that doesn't function properly. My friend with cerebral palsy could climb stairs but it took all her strength to pull herself up each step.

So a central mechanism may be important but the difficulty of opening a tin of beans with clumsy fingers or climbing into bed when your legs don't work shouldn't be underestimated.

 

[rvallee]

I read an article in the MS association magazine which was reprinted from one in the RA magazine - got it? That said that a lot of the fatigue in MS and RA was caused by the sheer extra effort it takes to do anything with a body that doesn't function properly. My friend with cerebral palsy could climb stairs but it took all her strength to pull herself up each step.

So a central mechanism may be important but the difficulty of opening a tin of beans with clumsy fingers or climbing into bed when your legs don't work shouldn't be underestimated.

You can see that clearly in people rehabilitating nerve damage. They strain through the effort like they are doing high-intensity training, sweating and breathing hard, even when all they're doing is raising a leg or an arm. This aspect is seriously underestimated and with the rising FND crap it's unlikely to get any better soon.

 

[MSEsperanza]

@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?

I seem to have misrepresented the listed studies by only quoting the abstracts of the studies that used fMRI.

Actually I find the earlier papers examining gait more relevant, see the papers I posted (again) here https://www.s4me.info/threads/objec...lity-lurija-institute.4241/page-2#post-184072 (kinematic gait analysis).

I thought the devices they used could be applied and adapted for studying pwME, e.g. in addition to the device for the ankle a similar device for the wrist or several small devices for fingers (I'm imagining e.g. rings for the thumb, pointer and annulary could document motor/ muscle fatiguability in those parts of the body most pwME still regularly use).

see:

Old link: https://www.hasomed.de/fileadmin/us...k/RehaGait_Faltblatt_Englisch_2016-11_Web.pdf

Valid link:
https://hasomed.de/en/products/rehagait/

Edited to add: I forgot about the thread where Jonathan Edwards already suggested to use accelometers: https://www.s4me.info/threads/measu...ernatives-to-questionnaires.7325/#post-130804

To begin with, some videos documeting pwME's abnormal movement patterns might be helpful?

 

[NelliePledge]

I seem to have misrepresented the listed studies by only quoting the abstracts of the studies that used fMRI.

Actually I find the earlier papers examining gait more relevant, see the papers I posted (again) here https://www.s4me.info/threads/objec...lity-lurija-institute.4241/page-2#post-184072 (kinematic gait analysis).

I thought the devices they used could be applied and adapted for studying pwME, e.g. in addition to the device for the ankle a similar device for the wrist or several small devices for fingers (I'm imagining e.g. rings for the thumb, pointer and annulary could document motor/ muscle fatiguability in those parts of the body most pwME still regularly use).

see: https://www.hasomed.de/fileadmin/us...k/RehaGait_Faltblatt_Englisch_2016-11_Web.pdf

To begin with, some videos documeting pwME's abnormal movement patterns might be helpful?

At my basic patient level I’ve wondered about gait and ME since it is looked at in MS Parkinson’s there must be a case for investigating. I can walk normally on a good day when I’m just starting to use up my energy. When my energy is low I am noticeably more wobbly, the weakness seems around hips/pelvis. Couple of times I’ve been out and had to use public transport to get home. By the time I was doing the normal person 2 minute walk from the bus stop to my house it took me around 10 minutes and I was going so slowly I was almost going backwards. Bent over forwards old lady walking I call it. Wouldn’t this be something neuro physios would be interested in looking at @PhysiosforME

 

[Amw66]

At my basic patient level I’ve wondered about gait and ME since it is looked at in MS Parkinson’s there must be a case for investigating. I can walk normally on a good day when I’m just starting to use up my energy. When my energy is low I am noticeably more wobbly, the weakness seems around hips/pelvis. Couple of times I’ve been out and had to use public transport to get home. By the time I was doing the normal person 2 minute walk from the bus stop to my house it took me around 10 minutes and I was going so slowly I was almost going backwards. Bent over forwards old lady walking I call it. Wouldn’t this be something neuro physios would be interested in looking at @PhysiosforME

Yes. When energy is low your body adapts to try and enable you to continue functioning. My daughter's s posture and gait changes when exhausted or in PEM.

 

[PhysiosforME]

At my basic patient level I’ve wondered about gait and ME since it is looked at in MS Parkinson’s there must be a case for investigating. I can walk normally on a good day when I’m just starting to use up my energy. When my energy is low I am noticeably more wobbly, the weakness seems around hips/pelvis. Couple of times I’ve been out and had to use public transport to get home. By the time I was doing the normal person 2 minute walk from the bus stop to my house it took me around 10 minutes and I was going so slowly I was almost going backwards. Bent over forwards old lady walking I call it. Wouldn’t this be something neuro physios would be interested in looking at @PhysiosforME

thank you for tagging us @NelliePledge this is really interesting. I will share with the other physios in the group and we will add it to the list of things we are trying to work through - there is so much for us to do!

 

[Michelle]

I too have bad walking days and good walking days. Was even once passed on the street by an old lady with a cane while walking from the streetcar. One of my bad walking days actually happened on a day I had pelvic floor physical therapy. My PT was appalled at my apparent walking difficulties while I simply shrugged and said it was one of my bad walking days. It's feels something like becoming hemiplegic. My right leg just seems to drag. The more I crash, the more noticeable the limp of my right leg. If I'm really bad, I walk like a drunk Frankenstein with both legs dragging.

I use a pedometer to measure steps to get a rough approximation of functional capacity. Initially I couldn't figure out why I would have such a jump in step count on better days despite trying very hard to conserve energy. As I paid more attention to the pedometer over a period of time, it became apparent that the problem was that I walk differently on better days. On bad days, I shuffle, and the steps don't get picked up by the pedometer. On better days, I actually walk with a half-decent stride. Which is why pedometers can present challenges when used to measure functional capacity (to say nothing of recording as steps my leg jiggling when I've gotta pee or my wanderings around the apartment on bad cognitive days). Better than questionnaires, to be sure. But not perfect.

 

[Sean]

My right leg just seems to drag. The more I crash, the more noticeable the limp of my right leg.

Same here.

Are you right sided? I am.

I have sometimes wondered if there is any degree of lateral (left-right) asymmetry in the effects of ME on biomechanics, with the dominant or preferred side being more affected.

It is certainly something that could be measured objectively and relatively easily, and if present then it could be a biomarker (at least at the patient population level, if not uniquely diagnostic).

It could be just that it just exaggerates the normal asymmetry of biomechanical function in humans.

Just a thought.

 

[lansbergen]

Are you right sided? I am.

I have sometimes wondered if there is any degree of lateral (left-right) asymmetry in the effects of ME on biomechanics, with the dominant or preferred side being more affected.

I am right handed and my right side is still worse.

 

[Michelle]

Are you right sided?

Yes. Though it's a bit more complicated in my case as I'm extremely right-handed as I've had four fractures among my fingers and my arm [EDIT: on my left side!] on four separate occasions -- three of them when I was 12 and younger. Moreover, when it comes to my right leg, I've had multiple fractures and soft tissue injuries and even major surgery on my right leg starting at age ten. The musculature of my right hip is substantially smaller than my left. Even on my good walking days, I still walk with half a stride on my right side. Though, again, to complicate it further, my ME symptoms started about 10-12 months or so after the ankle fracture that started it all when I was 10. So who knows what sort of connection between the two there might be -- if there is one.

I wouldn't be surprised if there was some sort of signalling issue with regard to gait and muscle use with this disease. Gait is definitely a woefully under-studied issue in this disease -- among so so so many others.

 

[rvallee]

I wouldn't be surprised if there was some sort of signalling issue with regard to gait and muscle use with this disease. Gait is definitely a woefully under-studied issue in this disease -- among so so so many others.

My gait also changes a lot along with PEM and I wouldn't be surprised if it were an adaptation to use less energy. Huge change compared to how I used to walk, or on the rare occasions where I have a tiny energy surplus and walk normally (because damn it feels good).

 

[MSEsperanza]

Not read yet, not from the Lurija Instiute either, but as they discuss objective measures of fatigue and fatiguability, I just leave it here:

Linnhoff, S., Fiene, M., Heinze, H. J., & Zaehle, T. (2019). Cognitive Fatigue in Multiple Sclerosis: An Objective Approach to Diagnosis and Treatment by Transcranial Electrical Stimulation. Brain sciences, 9(5), 100. doi:10.3390/brainsci9050100,
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562441/

Abstract

Cognitive fatigue is one of the most frequent symptoms in multiple sclerosis (MS), associated with significant impairment in daily functioning and quality of life. Despite its clinical significance, progress in understanding and treating fatigue is still limited. This limitation is already caused by an inconsistent and heterogeneous terminology and assessment of fatigue. In this review, we integrate previous literature on fatigue and propose a unified schema aiming to clarify the fatigue taxonomy.

With special focus on cognitive fatigue, we survey the significance of objective behavioral and electrophysiological fatigue parameters and discuss the controversial literature on the relationship between subjective and objective fatigue assessment. As MS-related cognitive fatigue drastically affects quality of life, the development of efficient therapeutic approaches for overcoming cognitive fatigue is of high clinical relevance. In this regard, the reliable and valid assessment of the individual fatigue level by objective parameters is essential for systematic treatment evaluation and optimization. Transcranial electrical stimulation (tES) may offer a unique opportunity to manipulate maladaptive neural activity underlying MS fatigue. Therefore, we discuss evidence for the therapeutic potential of tES on cognitive fatigue in people with MS.

 

[Woolie]

Thanks for posting, @MSEsperanza. I had a look a this one, mainly because the names were familiar:

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

Its kind of the whole problem with what happens when psychology meets medicine in a nutshell.

They mention in their paper that a drug called natalizumab has been found to significantly improve self-reported fatigue in MS. I was interested, because the drug's main mechanism is an anti-inflammatory one, so I wondered if people with ME might enjoy a similar effect. But then they said:

Some studies demonstrated that natalizumab may decrease fatigue in patients with MS, although this might result from a primary effect of natalizumab on depression.

Hmm, sounded to me a lot like an attempt to psychologise fatigue in MS, so I looked up the reference they cited, which was a paper by Penner et al from 2015 in Frontiers in Neurology.

I found that Penner and colleagues assessed "depression" used the CES-D, which asks the person 20 questions about their experience, seven of which seemed to me could be directly influenced by fatigue levels:
"I could not 'get going'"
"I talked less than usual"
"I enjoyed life"
"my sleep was restless"
"I feel like everything I did was an effort"
"I was bothered by things that usually don't bother me"
"I did not feel like eating; my appetite was poor".

In other words, they seem to have got it all arse about face. They seem to think the drug worked somehow psychologically on the fatigue, by "relieving depression", but it was the other way around - it worked on the fatigue, which improved responses on the self-report scale for depression.

I'm hugely annoyed by this. Honestly, depression can't "explain" anything because it isn't an explanatory concept at all - its just a bunch of features. So you can't say this happened "because of their depression", that just makes no sense. People so easily slide from "bunch of features" to "underlying mechanism" without any real awareness of what they're doing. And this was authors who do otherwise good work.

I despair.

 

[Jonathan Edwards]

I'm hugely annoyed by this. Honestly, depression can't "explain" anything because it isn't an explanatory concept at all - its just a bunch of features. So you can't say this happened "because of their depression", that just makes no sense. People so easily slide from "bunch of features" to "underlying mechanism" without any real awareness of what they're doing.

Couldn't agree more.

 

[MSEsperanza]

Thank you @Woolie for digging into one of the most recent papers.

I don't know whether I will be able to write a bit more why I updated the list but I'm afraid that there are more reasons to be annoyed.

As mentioned above, I only skimmed the papers, so not able to word clearly or to substantiate what preoccupies me with this regard.

So some unsubstantiated and maybe unjustified thoughts.

It seems to me that fatigue is being conceived as basically one feature, a perception consisting of different subtypes. Those subtypes appear to be conceived in two main etiological categories: either having a pathophysiological basis or being somehow merely imagined. In that perspective, there would be basically two types of fatigue -- an adequately perceived fatigue and an inadequately perceived fatigue. (Perhaps similar to the conecption of pain .)

At the same time, most researchers I think admit that all their ideas how the physiology of 'fatigue' in chronic illness works are still only hypotheses. Fatigue still mostly seems "medically unexplained".

Yet there were some attempts to specify and differentiate manifestations of MS related fatigue which at a first glance, I thought made sense, because they weren't based on premature ideas about the etiology, but on precise observations, and objective measurement derived from those observations.

I'm afraid though that those attempts to differentiate (e.g. Kluger er al/ 4.1 in the opening post) also apply the underlying concept of adequate and inadequate perceptions. Which maybe doesn't matter so much for the specific features they study if they are seen as 'adequately perceived' fatigue -- like it seems to be the case with motor fatigability and cognitive fatigability in MS.

It just matters if it implies that similar symptoms in the same illness or in a comorbidity (or in another illness that is framed as 'medically unexplained' per se) are not worthy to be differentiated and assessed in a similarly elaborated manner, because they are seen as a distortion. They then are being denied the possibility of objectively measurable 'real' alterations or any other relevant objective measures.

Don't know if this post makes sense, but in the light of Covid-19 and the potential rise of chronic post-viral syndromes implying 'fatigue', I think it would be extremely helpful if someone could write a critique on the concept(s) of fatigue in chronic illnesses, validating the idea of differentiating and speaking of fatigue only with a specifier. Also perhaps, validating the importance of both improving the quality of subjective reports and approaching objective measures of specific symptoms associated with 'fatigue'.

(Edited for clarity.)

 

[MSEsperanza]

Anyhow, this might be part of the problem:

(from Manjaly Z et al, Pathophysiological and cognitive mechanisms of fatigue in multiple sclerosis -- the paper @Woolie looked at ).

 

[Snow Leopard]

Anyhow, this might be part of the problem:

(from Manjaly Z et al, Pathophysiological and cognitive mechanisms of fatigue in multiple sclerosis -- the paper @Woolie looked at ).

The "metacongition" stuff is merely speculation. The authors don't seem to understand, nor care about how peripheral efferents are directly coupled with central drive through the spinal column. No magical (meta) brain interaction is necessary (or likely).

The authors are probably confused by assuming (like many investigators) that questionnaire answers are symptoms and experiences themselves. They don't realise that it is merely the reporting of these symptoms and experiences that is affected by metacognition.

And as usual, they have no idea what perception of effort is, or how effort and peripheral feedback is incorporated to produce a sense of fatigue (unexpected low performance while performing a task and the compensatory increase in central drive to compensate - a sense of fatigue is due to a prediction error, but this is not in anyway metacognitive).
Other sensations associated with fatigue is not fatigue itself. They are simply warnings of fatiguability. I know many people make this mistake - patients are not "fatigued" at rest!

 

[MSEsperanza]

Park this here for adding it to the OP later.

Harrison, A. M., das Nair, R., & Moss-Morris, R. (2016). Operationalising cognitive fatigability in multiple sclerosis: A Gordian knot that can be cut? Multiple Sclerosis Journal, 23(13), 1682–1696. doi:10.1177/1352458516681862

sci-hub.se/10.1177/1352458516681862

Contains a potentially useful "Summary of measures of cognitive fatigability operationalised in existing research" on MS (table 1, p.2-11).

Thread: https://www.s4me.info/threads/opera...multiple-sclerosis-2016-harrison-et-al.21852/

From skimming it seems that for my rather pragmatic question I won't find an answer there:

What defines abnormal/ pathological cognitive fatigability in general (not illness-specific), especially if there is no (other) cognitive impairment per se?

I assume, in general, just everything you think and do gets slower over a defined period of time? (Which also shows in altered concentration, so that you'll get more confused and make more errors.)

How is the period of time defined (in time units) that is needed to assess abnormal cognitive fatigability?

I realize that this might depend on which kind of cognitive performance is assessed, but I still hope there is a pragmatic definition at least in the context of assessing fitness for work? (And that people wanting to develop better measures or 'guiding theories' could learn from those more pragmatic assessments?)

(Edited for clarity.)

 

[MSEsperanza]

Parking another title on cognitive fatigability:

Fatigue and fatigability in patients with multiple sclerosis before and after cognitive load versus relaxation – a pilot study (2021)
S. E. Stoll, M. S. Gölz, D. Watolla, I. Bauer, V. Lunz, M. Metsch, P. Kath, A. Löser, S. Schwarz, A. Ruchay-Plößl, D. Klaasen van Husen, M. Jöbges,
C. Dettmers, J. Randerath

https://www.hippocampus.de/abstract-3-Fatigue.65610.html

Abstract
Fatigue is a subjective feeling of extreme exhaustion. It is commonly
described as one of the most burdening symptoms in multiple sclerosis
(MS). However, the concept of fatigue is not fully understood. One reason
may be the ambiguous differentiation between a subjective feeling of
exhaustion (fatigue) and an objective load-induced decline in performance
(fatigability).

The current study examines the relationship between
subjective exhaustion and objective performance decline after cognitive
load.

Twenty-four persons with MS participated in two experimental
sessions. In one session, the subjects performed a 3-hour cognitive test
intervention, and in the other session, they took part in a 30-minute
relaxation intervention. The participants’ subjective well-being, as well as
their current reaction time performance, were assessed before and after each
session. Reaction time performance was measured using a standardized
alertness test (“Testbatterie zur Aufmerksamkeitsprüfung”[TAP] 2.3.1).
Subjective well-being was assessed using a questionnaire.

Reaction time performance was significantly prolonged after the cognitive
load-based intervention. Furthermore, the participants indicated a
significantly reduction in well-being afterward. There were no significant
changes in reaction time performance or well-being due to the relaxation
intervention. There was no significant correlation between the reduction
in well-being and the reaction time performance decline, although
performance and well-being were similarly affected by load.

The results of the current study indicate that subjectively experienced
fatigue and objectively measured fatigability might reflect distinct aspects.
We discuss a working model that proposes using separate fatigue and
fatigability constructs. Additionally, options for the operationalization of
both constructs considering state- and trait-components are discussed.

Article paywalled & in German, unfortunately.

Neurol Rehabil 2021; 27(1): 23–30, DOI 10.14624/NR2101003

Does anyone have access to the paper?

 

[MSEsperanza]

And a submission to the RIMS (Rehabilitation in MS) Annual Conference 2019 on motor fatigability

Visual evaluation of gait pattern compared to Fatigue Index Kliniken Schmieder in terms of motor fatigability (Identification of fatigability by gait observation) 2019

1Kim-Charline Broscheid, 2Simon Sailer, 3Odin Hoogerbeets 4Manfred Vieten, 2,3Christian Dettmers

https://journals.sagepub.com/doi/full/10.1177/1352458519844447#_i194


Motor Fatigability is a common disabling symptom in people with Multiple Sclerosis (pwMS). There are few approaches to quantify fatigability. In clinical everyday life, it is evaluated by medical professionals based on gait observations. There are no consistent guidelines so that the intention of our study was to develop a short standardized test procedure to identify motor fatigability.

35 pwMS (9 male/26 female) aged 48.1±9.2 years with an averaged Expanded Disability Status Scale of 3.3±1.0 (all types of MS) were included. The pwMS walked on a treadmill in their comfort velocity plus 15 % over 20 min or until exhaustion (Borg-scale 17). The first and the last minute of the trials were recorded by acceleration sensors to calculate the Fatigue Index Kliniken Schmieder (FKS) [1] and were filmed to evaluate visually the gait pattern afterwards. One neurologist (N) and two experienced physiotherapists (PT1 & PT2) categorized the pwMS as having no (0), mild (1), moderate (2) or strong (3) fatigability. The FKS, normally performed over 60 min, was adapted to the shorter protocol and distinguishes between no fatigability (FKS<1.9) and fatigability (FKS⩾1.9) [1].

In 27 cases (16 fatigability/11 no fatigability) the experts were in accordance with the FKS. In 8 cases the experts agreed with each other but not with the FKS. The Kendall’s Tau-b correlation analysis has shown moderate to strong Correlation Coefficients (CC) between the three medical experts (N_PT1: n=29/CC=0.63/p<0.000; N_PT2: n=36/CC=0.81/p<0.000; PT1_PT2: n=29/CC=0.75/p<0.000). Combining the video ratings with the FKS the contingency coefficients (cc) revealed weak to moderate correlations (N_FKS: n=36/cc=0.40/p=0.009; PT1_FKS: n=29/cc=0.51/p=0.001; PT2_FKS: n=36/cc=0.40/p=0.009).

There is a high concordance in between the experts in evaluating visually fatigability while walking in pwMS. If the experts rated the gait pattern with moderate (2) to strong (3) fatigability, the FKS matched. Rating mild (1) fatigability was inconsistent among the raters.