Hand grip strength and fatigability: correlation with clinical parameters and diagnostic suitability in ME/CFS, 2021, Jakel,Scheibenbogen et al

Abstract
Background

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex and debilitating disease accompanied by muscular fatigue and pain. A functional measure to assess muscle fatigability of ME/CFS patients is, however, not established in clinical routine. The aim of this study is to evaluate by assessing repeat maximum handgrip strength (HGS), muscle fatigability as a diagnostic tool and its correlation with clinical parameters.

Methods
We assessed the HGS of 105 patients with ME/CFS, 18 patients with Cancer related fatigue (CRF) and 66 healthy controls (HC) using an electric dynamometer assessing maximal (Fmax) and mean force (Fmean) of ten repetitive measurements. Results were correlated with clinical parameters, creatinine kinase (CK) and lactate dehydrogenase (LDH). Further, maximum isometric quadriceps strength measurement was conducted in eight ME/CFS patients and eight HC.

Results
ME/CFS patients have a significantly lower Fmax and Fmean HGS compared to HC (p < 0.0001). Further, Fatigue Ratio assessing decline in strength during repeat maximal HGS measurement (Fmax/Fmean) was higher (p ≤ 0.0012). The Recovery Ratio after an identical second testing 60 min later was significantly lower in ME/CFS compared to HC (Fmean2/Fmean1; p ≤ 0.0020). Lower HGS parameters correlated with severity of disease, post-exertional malaise and muscle pain and with higher CK and LDH levels after exertion.

Conclusion
Repeat HGS assessment is a sensitive diagnostic test to assess muscular fatigue and fatigability and an objective measure to assess disease severity in ME/CFS.


https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-021-02774-w

 

The study has a number of strengths:

- the "recovery ratio" compares the mean forces of the initial and repeat tests, 60 mins apart
- ME/CFS participants were well characterized (Canadian criteria), most had an infectious onset
- sensible questionnaires like the Bell scale and the short form of the DePaul PEM questionnaire
- measures of blood markers of exertion, creatine kinase and lactate

and weaknesses:

- ME/CFS participants were on average older than healthy and cancer-fatigue controls (female ME/CFS vs HC: +9 years, vs CF: +4.5 years, male ME/CFS vs HC: +6.5 years)
- controls were not selected based on their activity levels, i.e. not particularly sedentary
- the authors didn't adjust for multiple comparisons so their results might not be meaningful

An interesting point:

Lower Bell scores (higher severity of disability) correlated with lower Fmax1 in women and lower Fmax and Fmean and higher Fatigue Ratio1 in men indicating a causal relation of muscular strength to severity of the disease. Remarkably, PEM correlated in women with lower Fmean2 and in women and men with higher Fatigue Ratio2, providing evidence that HGS is an objective marker to assess the severity of PEM. In line with this, severity of muscle pain correlated with lower Fmean2 and impaired recovery in the female cohort.

(...) In our study we could not find an association of HGS parameters with the Chalder Fatigue Scale, which is, however, a questionnaire focusing mostly on mental fatigue (Additional file 6: Table S3).
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About lactate, which has been found to be problematic in other studies, and creatine kinase:

Interestingly LDH and CK, which we determined after repeat HGS measurements also correlated with HGS parameters. Higher LDH concentrations correlated with higher Fatigue Ratio1/2 (Fmax/Fmean) and thus fatigability in both sexes. (...) Further we found that higher CK levels are associated with poorer Recovery Ratio and higher Fatigue Ratio2 in women.
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Limitations of the study are acknowledged:

A limitation of our study is that HGS may be influenced by inactivity although much less than leg muscle strength [41]. Further HGS is associated with age. Thus, a control group of physically inactive HC closely matched by age would be best for defining normal values of HGS parameters.
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That multiple research groups have now looked at hand grip strength as a diagnostic assay that could replace the 2-day CPET is a positive development. But as with the 2-day CPET, to avoid attributing the lower hand grip strength of ME/CFS patients to deconditioning, studies with sedentary controls are much needed and medical providers must come to understand the necessity of repeating the test.

 

I didn't read it properly but I saw this as well:

"Our fndings are, however, not specific for ME/CFS as CRF patients showed significantly lower HGS parameters compared to HC, too."

 

Oh, the authors provided their raw data. https://static-content.springer.com.../MediaObjects/12967_2021_2774_MOESM6_ESM.xlsx

 

I find that my hand-grip strength, like all other symptoms, varies considerably, notably with the time of day.

 

I noticed that my hand-grip strength diminished dramatically and quickly after having a hysterectomy, and I've read similar comments from other women in the same circumstances. Not only that, if I try and maintain my strongest grip (which isn't very strong at all any more) on something, e.g. when opening a jar, I can't do it for more than a second or two and can't do it repeatedly because my hand almost stops working after the strain.

I haven't always been weak. When I was about 12 I worked on a farm occasionally at weekend. I could pick up 56lb sacks of potatoes from the ground and put them on a trailer. I hadn't done any strength training, it was just my natural levels of strength at that age.

The fact that doctors think they can cure all female ills with a hysterectomy still shocks me. Or at least they tell women that, when they must know it's a lie.

 

My strength also used to be...strong! I tried arm wrestling with a male friend, who was considerably heavier than me, and he said that I would have won if he hadn't used his extra weight. And I'm under 5 ft tall!

 

i have had dwp assessors do this handgrip strength test but only using their hands and strangely judge that i am fit from a two second handshake . since the assessment companies do everything in the name of profit i doubt if any actually have a proper measuring device but the handgrip test is still abused to deny benefits .

 

Even if it's not specific to ME I wonder if repeated HGS testing could be developed to be sufficiently sensitive to function as an objective outcome measure in treatment studies?

For the same reason the quadriceps testing they did is interesting. I'd never heard of it but looking at the references there were a couple of studies done in the 1990s. I've only skimmed the two referenced studies. Both were very small. One didn't find a difference (used Oxford), the other one did find a difference (Fukuda), links below.

In the present study, I wonder why they only assessed 8 patients and 8 controls? Looking at the methods it sure looks like a lot more fluffing about than the hand grip test but it doesn't seem that difficult or expensive?

Also, they didn't really do much with the results, they only state that their results confirm the findings of the previous Fukuda criteria study and that quadricep and hand grip results follow a similar pattern. But they didn't correlate quad results to symptoms or show individual results (e.g. did each individual pwME's performance drop or just the average, or were the individuals with the weakest hands also the ones with the weakest quads?)

Links to the older quadriceps studies:

This one didn't find a difference:
Gibson H, Carroll N, Clague JE, et al. Exercise performance and fatiguability in patients with chronic fatigue syndrome. Journal of Neurology, Neurosurgery & Psychiatry 1993;56:993-998.
Full text: https://jnnp.bmj.com/content/jnnp/56/9/993.full.pdf

This one did find a difference:
Paul, L., Wood, L., Behan, W.M. and Maclaren, W.M. (1999), Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome. European Journal of Neurology, 6: 63-69. https://doi.org/10.1046/j.1468-1331.1999.610063.x
Full text: https://sci-hub.se/https://doi.org/10.1046/j.1468-1331.1999.610063.x

 

Commentary: strong on objective measurement of fatigability, other claims are weak

What I like about this is that it builds on previous work and the proven, reproducible Handgrip Strength test (HGS) to develop a broad measure of muscle fatigability. As opposed to the subjective experience of fatigu). Plus, as it uses muscles of the forearm that operate the hand, this test is unlikely to be harmful to patients.

Handgrip Strength testing
It helps to understand how the protocol works. People are asked to put as much force as they can on the handle of a machine for three seconds followed by a five second relaxation phase, and do 10 repeats of this in succession (over 80 seconds). The machine measures the maximum force applied in any of the 10 repeats (FMax) and the average force applied across the 10 repeats (Fmean).

The fatigue ratio is a measure of how much people struggle to continuously apply maximum force. It is the maximum force applied during any of the 10 repeats divided by the average force.

In this study, the authors got people to repeat the session after a 60 minute rest.

The recovery ratio measures how much average force decreases (or increases) in that second session.

The fatigue ratio and recovery ratio are the two measures used of fatigability, how much an individual's performance fades over time. You might recognise this phenomenon.

RESULTS
For everyone, male or female, sick or healthy, performance fades slightly between the first three-second session and the tenth one. Unsurprisingly, sick people can apply less force, even from the beginning (note controls were not selected to be sedentary).

Results for men below. Top black line is healthy controls, first session. Lower black line is peopel with ME/CFS. Note the steeper slope for mecfs patients - there is a notable decline in force over the 10 repetitions.

The grey line is the results for the second session - note that healthy men do a little better second time around (no difference for healthy women).

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Fatigue ratio
It starts to get more interesting with the fatigue ratio, which shows how much people struggle to maintain maximum force. For healthy folk is about 1.1, which means the average force is about 90% of the maximum force.

People with ME/CFS do significantly worse, their average force is around 20% less than peak forece (p <0.001 for both men and women vs healthy types)People with cancer -related fatiguealso do worse (they were only female subjects). I saw no p value given and I suspect there was no statistical difference between ME/CFS patients and those with cance -related fatigue.

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Recovery ratio
And things are even more interesting with the recovery ratio, which compares the average force in the second session with first session. For healthy women, the ratio was one i.e. there is no difference at all on the repeat performance. For men it is over one (ie they perform better an hour later, as shown in hte graph above).

But there is a significant dip for people with ME/CFS. And a similar pattern seen in cancer -related fatigue

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So, compared with healthy folk, people with ME/CFS show more fatigue within a session of ten repeats, with even lower performance 60 minutes later, while helath folk recover fully within that time.
Kudos to the authors for including a fatigue with control group, people with cancer -related fatigue. The results show that there is a similar pattern for people with cancer -related fatigue, so what we see with ME/CFS is not unique to the illness.

Even so, these are interesting results.

End of part one

 

part 2, some issues

So far so good. However, given that the finding isn't specific to ME/CFS, there is a question as to its significance and I think there has been a little overreach here.

The title says "hand grip strength and fatigability: correlation with clinical parameters and diagnostic suitability in ME/CFS" . And the abstract concludes that HGS assessment is "an objective measure to assess disease severity in ME/CFS". Let's take a look at those two factors.

1. Correlation with symptoms, and with biological markers (creatine kinase and lactate dehydrogenase)

The first problem is that in this part of the study alone they are using eight different measures (Bell disability score, PEM, SF 36 physical function et cetera) and looks for correlation between those eight and five different HGS measures. That's a total of 40 comparisons, with no correction. As the authors say, P values should be considered purely descriptive.

If there were any corection for multiple comparisons, just about everything – perhaps everything – would fall away.

But there's actually a bigger problem – the correlations are all fairly weak. Almost all are 0.3 or smaller. Here is what a correlation of 0.3 looks like. (For a correlation of 1.0, the line would be much steeper (at 45 degrees) and all points would fall exactly on the line.)

​

It's barely worth reporting. And certainly does not justify the claim in the discussion section that correlations with between lower Bell scores and several HGS measures (not even identical ones for men and women) indicated "a causal relation of muscular strength to severity of the disease". Apart from the small effect sizes, correlation does not mean causation.

2. Diagnostic tool

The paper discussion claims that the analysis "revealed a high diagnostic sensitivity and specificity to distinguish between healthy controls and ME/CFS". There are some problems here:

— the healthy controls were younger and not matched as sedentary compared with the ME/CFS cases
— The researchers fine tuned the cut-offs for this particular dataset, even setting different cut-offs for different age groups. So, diagnostic accuracy would only have validity in a separate sample using the cut-offs they chose here.
— Most importantly, cancer-related fatigue patients show a similar pattern to ME/CFS patients. A diagnostic test that would help identify ME/CFS patients from other fatiguing illnesses would be useful. Merely separating from the healthy isn't really going to advance health care.

Maybe the authors were just looking to fill out the paper.

In the conclusion, they confine themselves to the good stuff. "HGS measurement is a simple diagnostic tool to assess the severity of muscle fatigue in ME/CFS. Repeat HGS assessment further allows to objectively assess fatigability and impaired recovery."

ps one oddity: the ME/CFS sample was 42% male (typically we see around 20%). With this selection bias, were men more likely to volunteer for a Test Your Strength study? ;-)

one of my finest! Should say "put as much force as they can on the handle of the machine"
not "on a phone sign the granite machine".

 

Yes, it will never be a specific measure.

The effect (reduced repeatability) is due to reduced cortical excitability (central fatigue) and is common to all fatiguing disorders, because it is mediated by peripheral afferent feedback - it doesn't matter if the illness is cancer related fatigue, ME, a muscular dystrophy or a peripheral neuropathy, the effect will be the same.

 

The Cure ME team at LSHTM also did a study on this.

https://pubmed.ncbi.nlm.nih.gov/30538664/

 

Discussed here, Hand grip strength as a clinical biomarker for ME/CFS, 2018, Nacul et al

 

That's very interesting. How do we know this, and does this apply a common pathology to fatiguing disorders?

 

The "common pathology" is that all fatiguing disorders are associated with central fatigue. We know this because the TMS, EMG studies regardless of pathology all have very similar results when fatigue is deliberately induced - central fatigue (EMG), reduced cortical excitability (TMS). (interestingly some patients suffering from some conditions such as certain muscular dystrophies actually start with increased cortical excitability, presumably a central compensation mechanism - https://pubmed.ncbi.nlm.nih.gov/21305574/)

The underlying stimulus itself can differ, but it is mediated by peripheral afferents:
https://pubmed.ncbi.nlm.nih.gov/30095164/

A key effect (and probably the main reason) of central fatigue is to decrease motor drive for a given ventilatory drive. Or phrased conversely, leads to more oxygen available by the cardiopulmonary system for a given level of motor drive.

Empirically, we know that central fatigue does not totally prevent peripheral fatigue, nor prevent muscle damage, nor is the cause of "task failure", nor is involved with any more exotic hypothetical nonsense like "Fatigue is a Brain-Derived Emotion that Regulates the Exercise Behavior to Ensure the Protection of Whole Body Homeostasis". Hence we must assume what we are left with is the primary purpose.

 

Thanks. @Snow Leopard

I think I'm being a bit dim here — what, exactly, is the common purpose? I suspect most of us are not is up as you are on exercise muscle/fatigue/neurological stuff.

but do we actually know that? One of the links goes to a study with just 16 fibromyalgia patients and I am not clear if there is any work at all on ME/CFS patients – seems more like an intriguing hypothesis, unless there is strong evidence?

I mean, given that we actually know almost nothing for sure about ME/CFS it would be remarkable if we did know that it shared a common pathology with other diseases. If this is the case, maybe researchers should be looking at it more closely?

 

I agree, I don't see that we can extrapolate from studies on afferent signals in fatiguing in normal people to speculation about what is the cause of abnormal fatiguing. There are a hundred and one unanswered questions about what is causing what down the line!