Hand grip strength and fatigability: correlation with clinical parameters and diagnostic suitability in ME/CFS

Chronic Fatigue Syndrome (also known as Myalgic Encephalomyelitis, ME/CFS), is a complex disease with persistent mental and physical fatigue causing severe impairment of quality of life. The cardinal symptom is exertional intolerance with post-exertional malaise (PEM), which describes a disproportionate intensification of symptoms and a prolonged regeneration phase after physical or mental effort [1‐3]. Muscle fatigability is another important hallmark in which muscles become weaker after exertion and it can last for days before full muscle strength is restored.

To date, the etiology and pathophysiology of ME/CFS is still unresolved, but there is ample evidence for a disturbed vascular regulation [4]. Diagnosing of ME/CFS is challenging for patients and physicians due to many unspecific symptoms, the broad differential diagnosis of chronic fatigue and the lack of an established biomarker. Currently, ME/CFS is a clinical diagnosis using comprehensive clinical evaluation and diagnostic criteria with the international Canadian Consensus Criteria (CCC) formulated by Carruthers et al. in 2003 as the most accepted [5]. However, to date ME/CFS patients are often un- or misdiagnosed as depression or burn-out, leading probably to a marked underestimation of prevalence [1, 6].

As objective measure to assess exertion intolerance in ME/CFS a repeat cardiopulmonary exercise test (CPET) is recommended by the National Institute of Health (NIH). Studies showed the maximum oxygen uptake and workload is significantly reduced at the day two of CPET [7]. However, the repeated exercise tests frequently lead to severe PEM and cannot be recommended for most patients [8].

Assessment of disease severity is mostly relied on questionnaires. Fatigue is a complex symptom and can be both mental and physical related to impaired muscle performance. Physical fatigue can be assessed objectively. Assessment of hand grip strength (HGS) is an established and highly reproducible tool to assess muscular strength and provides information about the person's physical function and state of health [9]. First studies showed that HGS is impaired in ME/CFS [10‐12]. A recent study showed that maximal handgrip strength was significantly correlated with peak oxygen uptake and can predict maximal physical performance in CPET [13]. In the study by Meeus et al. also the HGS recovery after 45 min was analyzed and found to be impaired, while it was normal in HC [10]. Another approach to assess muscular force is the measurement of the quadriceps strength (QS). In an earlier study, ME/CFS patients showed lower QS and a prolonged recovery compared to the control group when performing consecutive contractions [14], another study reported normal quadriceps muscle force in ME/CFS [15].

Chronic fatigue occurs in many other diseases including cancer. About 30% of cancer survivors suffer from cancer-related fatigue (CRF) years after treatment severely impairing patients’ quality of life [16]. In order to assess specificity of HGS assessment for ME/CFS we included a cohort of CRF patients in our study.

In this study we evaluate repeat HGS measurement for assessing muscle fatigue in ME/CFS. By performing repeat hand grip testing fatigability and recovery of muscle strength could be assessed as diagnostic test.

In our study we show that patients with ME/CFS have reduced Fmax and Fmean HGS compared to HC. Our finding of impaired Fmax is in line with previous studies [10‐13]. In addition, the greater decrease of HGS during ten repeated measurements compared to HC resulted in a higher Fatigue Ratio as was shown already in the study by Neu et al. [12]. Further, upon repeat measurement after an hour HGS was significantly lower in ME/CFS while it was fully recovered in HC indicating an impaired recovery rate in patients with ME/CFS as a parameter for fatigability. This finding is in accordance with the study by Meeus et al. describing an impaired recovery 45 min after 18 repeat maximal contractions [10].

Our study provides further evidence that repeat measurement of muscle strength via a hand dynamometer is a simple and useful method to objectively detect muscular fatigue and fatigability. ROC analyses revealed a high diagnostic sensitivity and specificity to distinguish between HC and ME/CFS with Fmean2 yielding best discrimination in women and men in both age groups. For assessing HGS as diagnostic marker in ME/CFS, we think it is important to use the Canadian Consensus Criteria requiring PEM. In contrast Ickmans et al. using the “Fukuda criteria” for diagnosis, which do not require PEM, observed significant differences in strength and recovery only for ME/CFS patients with comorbid fibromyalgia [27, 28].

Our findings are, however, not specific for ME/CFS as CRF patients showed significantly lower HGS parameters compared to HC, too. We found fatigability and impaired recovery also in female CRF patients. For HGS in patients with multiple sclerosis (MS) two studies delivered inconsistent findings. Nacul et al. showed diminished Fmax in MS patients in contrast to normal Fmax and recovery of HGS in the study by Meeus et al. [10, 11].

The quadriceps force measurement provides evidence that diminished muscular strength is found in leg muscles, too, showing in a similar pattern as the HGS that ME/CFS patients have a stronger drop in force upon repeated exertion. Thus, our study confirms the findings by Paul et al. [14] and is in contrast to the report by Gibson et al. of normal quadriceps muscle function in ME/CFS [15].

The correlations between HGS and clinical parameters underline the clinical relevance of HGS assessment in ME/CFS. 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. A potential explanation is that more severe PEM is associated with more muscular fatigability and muscle pain. This might explain why pacing as a strategy to avoid PEM results in improvement of physical fatigue [29]. In the studies by Nacul et al. and Neu et al. fatigue assessed by a fatigue questionnaire correlated with Fmax HGS. In the male cohort we found correlations between the SF-36 physical functioning, and Fmax2 and Fmean2. 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).

Serum LDH and CK are both marker of muscle metabolism and damage and known to rise after exertion. 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. LDH is an enzyme catalyzing the conversion of pyruvate to lactate and may indicate a preferential energy production via glycolysis rather than the more efficient oxidative phosphorylation. Diminished pyruvate dehydrogenase function is described in ME/CFS resulting in increased conversion of pyruvate to lactate [30]. Thus enhanced LDH may indicate diminished capacity of oxidative phosphorylation, which may well explain lower muscle strength during repeat exercise. Further we found that higher CK levels are associated with poorer Recovery Ratio and higher Fatigue Ratio2 in women. CK plays a central role in the energy supply of the muscle and muscular strain can increase the serum concentration of CK, although there are inter-individual differences [31]. A previous study found that CK concentrations are lower in patients with severe ME/CFS [32, 33]. This is not in contrast to our study as CK was analyzed after exertion in our study.

The pathomechanism of muscular fatigue and fatigability in ME/CFS is not fully elucidated yet. Histologic alterations with an increase in the more fatigue-prone, energetically expensive fast fibre type was described in muscle biopsies from ME/CFS patients, while contractile properties of muscle fibres were preserved [34]. Further metabolic alterations with altered expression of genes for mitochondrial and energy function were described [35]. Another study reported impaired glucose uptake and adenosine monophosphate activated protein kinase (AMPK) activity in cultured muscle cells from ME/CFS patients [36]. Fluge et al. showed that myoblasts grown in presence of serum from patients with severe ME/CFS showed increased mitochondrial respiration and excessive lactate secretion indicating impaired pyruvate dehydrogenase function [30]. Impaired oxygen supply to muscles upon exertion in ME/CFS was described, too. ME/CFS patients showed evidence of reduced hyperemic flow and reduced oxygen delivery [37]. In line with this hypoperfusion in cerebral vessels was recently shown [38]. A MRI study revealed that patients with ME/CFS have abnormalities in recovery of intramuscular pH following exercise which is related to autonomic dysfunction [39]. Paradox vasoconstriction due to ß2 adrenergic dysfunction resulting in muscle hypoperfusion is considered as an important pathomechanism in ME/CFS [4]. In an own study we observed disease severity to correlate with endothelial dysfunction in ME/CFS [40]. In line with this concept, we observed here a strong correlation between vasomotor dysregulation assessed by COMPASS questionnaire with Fmax and Fmean of repeat testing.

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.

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. Advantages of HGS measurement are easy handling, low cost and the low risk of causing PEM. Thus, it can be implemented easily in both primary care and research as an objective outcome parameter in clinical studies and drug development.