[Chronic fatigue: What investigations? And what for?] / Fatigue chronique : quelles investigations ? Dans quels objectifs ?

Chronic fatigue is a frequent complaint, expressed at all levels of the healthcare system. It is perceived as disabling in a high proportion of cases, and internists are frequently called upon to find "the" cause. The etiological diagnostic approach of an unexplained state of fatigue relies on the careful search for more specific clues by questioning and clinical examination. It is necessary to recognize the limited place of complementary examinations apart from the basic biological parameters. Simple rating scales can be useful in the etiological and differential diagnosis of fatigue. Chronic fatigue syndrome (CFS), in the current state of knowledge, cannot be considered as a specific pathological entity distinct from idiopathic chronic fatigue states, and does not have validated biomarkers. It is important to know that a state of chronic asthenia often results from several intricated etiological factors (biological, psychological and social), to be classified as predisposing, precipitating and perpetuating. The metabolic and cardiorespiratory exercise test has a major place in the assessment and management of fatigue, as a prerequisite for personalized retraining or adapted physical activity (APA), which are the treatments of choice for chronic fatigue.

[Rhabdomyolysis with tetraparesis secondary to hepatitis E virus infection in a patient on statins]. / Rhabdomyolyse avec tétraparésie secondaire à une hépatite virale E chez un patient sous statines.

INTRODUCTION: Neurologic and muscular damage associated with acute hepatitis due to hepatitis E virus (HEV) are rare and may be underdiagnosed. CASE REPORT: We report the case of a 56-year-old man, presenting with flaccid tetraparesis secondary to an acute rhabdomyolysis induced by acute E virus hepatitis. He fully recovered after one month under supportive treatment. DISCUSSION: Rare cases of acute rhabdomyolysis induced by HEV infection have been reported in the literature. We discuss the potential adjuvant role of statin treatment in our patient. Unexplained acute neurological conditions should prompt the search for HEV infection.

Degradation of energy cost with fatigue induced by trail running: effect of distance.

PURPOSE: The effect of trail running competitions on cost of running (Cr) remains unclear and no study has directly examined the effect of distances in similar conditions on Cr. Accordingly, the aims of this study were to (i) assess the effect of trail running races of 40-170 km on Cr and (ii) to assess whether the incline at which Cr is measured influences changes in Cr. METHODS: Twenty trail runners completed races of < 100 km (SHORT) and 26 trail runners completed races of > 100 km (LONG) on similar courses and environmental conditions. Oxygen uptake, respiratory exchange ratio, ventilation, and blood lactate were measured before and after the events on a treadmill with 0% (FLAT) and 15% incline (UH) and Cr was calculated. RESULTS: Cr increased significantly after SHORT but not LONG races. There was no clear relationship between changes in Cr and changes in ventilation or blood lactate. There was a significant correlation (r = 0.75, p < 0.01) between changes in FLAT and UH Cr, and the change in Cr was not affected by the incline at which Cr was measured. CONCLUSION: The distance of the trail running race, but not the slope at which it is measured, influence the changes in Cr with fatigue. The mechanism by which Cr increases only in SHORT is not related to increased cost of breathing.

Pregnancy and myopathies: Reciprocal impacts between pregnancy, delivery, and myopathies and their treatments. A clinical review.

During pregnancy, women undergo physical and physiological changes, which can impact the neuromuscular disease course, but also delivery and fetus health. Generally, there is little impact on the disease course, but sometimes an impairment is noticed, which could be attributed to pregnancy and not to disease progression. Cardiac and respiratory functions have to be assessed at the beginning of pregnancy and a close follow-up is mandatory in case of disorder. Labour and delivery are often impacted. Labour is prolonged because of muscle weakness that is an increased risk of instrumental delivery or Cesarean sections. Patients with myotonic dystrophy are at risk of postpartum hemorrhage. Fetal loss can be associated with fetal disease in myotonic dystrophy, and is at high risk for patients with active inflammatory myopathy only.

Reduced fibre size, capillary supply and mitochondrial activity in constitutional thinness' skeletal muscle.

AIM: Constitutional thinness (CT) is a rare condition of natural low body weight, with no psychological issues, no marker of undernutrition and a resistance to weight gain. This study evaluated the skeletal muscle phenotype of CT women by comparison with a normal BMI control group. METHODS: Ten CT women (BMI < 17.5 kg/m2 ) and 10 female controls (BMI: 18.5-25 kg/m2 ) underwent metabolic and hormonal assessment along with muscle biopsies to analyse the skeletal muscular fibres pattern, capillarity, enzymes activities and transcriptomics. RESULTS: Constitutional thinness displayed similar energy balance metabolic and hormonal profile to controls. Constitutional thinness presented with lower mean area of all the skeletal muscular fibres (-24%, P = .01) and percentage of slow-twitch type I fibres (-25%, P = .02, respectively). Significant downregulation of the mRNA expression of several mitochondrial-related genes and triglycerides metabolism was found along with low cytochrome c oxidase (COX) activity and capillary network in type I fibres. Pre- and post-mitochondrial respiratory chain enzymes levels were found similar to controls. Transcriptomics also revealed downregulation of cytoskeletal-related genes. CONCLUSION: Diminished type I fibres, decreased mitochondrial and metabolic activity suggested by these results are discordant with normal resting metabolic rate of CT subjects. Downregulated genes related to cytoskeletal proteins and myocyte differentiation could account for CT's resistance to weight gain.

Assessement of quadriceps strength, endurance and fatigue in FSHD and CMT: benefits and limits of femoral nerve magnetic stimulation.

OBJECTIVES: To (i) evaluate the feasibility and the reliability of a test assessing quadriceps strength, endurance and fatigue in patients with fascioscapulohumeral dystrophy (FSHD) and Charcot-Marie-Tooth disease (CMT), (ii) compare quadriceps function between patients and healthy controls. METHODS: Controls performed the test once and patients twice on two separate visits. It involved progressive sets of 10 isometric contractions each followed by neuromuscular assessments with FNMS. RESULTS: Volitional assessment of muscle strength, endurance and fatigue appeared to be reliable in FSHD and CMT patients. Supramaximal FNMS was achieved in ∼70% of FSHD patients and in no CMT patients. In FSHD patients, Femoral nerve magnetic stimulation (FNMS) provided reliable assessment of central (typical error as a coefficient of variation (CVTE)<8% for voluntary activation) and peripheral (CVTE<10% and intraclass coefficient correlation >0.85 for evoked responses) function. Patients and controls had similar reductions in evoked quadriceps responses, voluntary activation and similar endurance. CONCLUSIONS: This test provides reliable evaluation but FNMS exhibits limitations due to insufficient stimulation intensity particularly in neurogenic conditions. It showed similar central and peripheral quadriceps fatigability in patients and controls. SIGNIFICANCE: This test may be a valuable tool for patient follow-up although further development of magnetic stimulation devices is needed to extend its applicability.

Hemolysis induced by an extreme mountain ultra-marathon is not associated with a decrease in total red blood cell volume.

Prolonged running is known to induce hemolysis. It has been suggested that hemolysis may lead to a significant loss of red blood cells; however, its actual impact on the erythrocyte pool is unknown. Here, we test the hypothesis that prolonged running with high hemolytic potential decreases total red blood cell volume (RCV). Hemolysis (n = 22) and RCV (n = 19) were quantified in ultra-marathon runners before and after a 166-km long mountain ultra-endurance marathon (RUN) with 9500 m of altitude gain/loss. Assessment of total hemoglobin mass (Hbmass) and RCV was performed using a carbon monoxide rebreathing technique. RUN induced a marked acute-phase response and promoted hemolysis, as shown by a decrease in serum haptoglobin (P < 0.05). Elevated serum erythropoietin concentration and reticulocyte count after RUN were indicative of erythropoietic stimulation. Following RUN, runners experienced hemodilution, mediated by a large plasma volume expansion and associated with a large increase in plasma aldosterone. However, neither Hbmass nor RCV were found to be altered after RUN. Our findings indicate that mechanical/physiological stress associated with RUN promotes hemolysis but this has no impact on total erythrocyte volume. We therefore suggest that exercise 'anemia' is entirely due to plasma volume expansion and not to a concomitant decrease in RCV.

Potential interests and limits of magnetic and electrical stimulation techniques to assess neuromuscular fatigue.

Neuromuscular function can change under different conditions such as ageing, training/detraining, long-term spaceflight, environmental conditions (e.g. hypoxia, hyperthermia), disease, therapy/retraining programs and also with the appearance of fatigue. Neuromuscular fatigue can be defined as any decrease in maximal voluntary strength or power. There is no standardized method to induce fatigue and various protocols involving different contraction patterns (such as sustained or intermittent submaximal isometric or dynamic contractions on isokinetic or custom chairs) have been used. Probably due to lack of motivation/cooperation, results of fatigue resistance protocols are more variable in patients than in healthy subjects. Magnetic and electrical stimulation techniques allow non-invasive assessment of central and peripheral origins of fatigue. They also allow investigation of different types of muscle fatigue when combining various types of stimulation with force/surface EMG measurements. Since maximal electrical stimuli may be uncomfortable or even sometimes painful, several alternative methods have been recently proposed: submaximal muscle stimulation, low/high-frequency paired pulses instead of tetanic stimuli and the use of magnetic stimulation at the peripheral level.

Effect of α-thalassaemia on exercise-induced oxidative stress in sickle cell trait.

AIM: Alpha-thalassaemia is known to reduce intra-erythrocyte HbS (sickle haemoglobin) concentration in sickle cell trait (SCT) subjects. Because HbS was shown to increase oxidative stress, the purpose of this study was to assess the effects of the coexistence of α-thalassaemia and SCT on oxidative stress markers and nitric oxide (NO) metabolism after an acute physical exercise. METHODS: Forty subjects (age: 23.5 ± 2.21 years), SCT carriers (HbAS) or healthy subjects (HbAA), with (-αT) or without (-NαT) an associated α-thalassaemia took part in the study. Plasma markers of oxidative stress [advanced oxidation protein products (AOPP), protein carbonyl, malondialdehyde (MDA) and nitrotyrosine], anti-oxidant defences and NO metabolism (NOx) were measured at rest (T(rest)), immediately following an incremental maximal exercise test (T(ex)) and during recovery (T(1h), T(2h) and T(24h)). RESULTS: Malondialdehyde expressed as the percentage of changes from baseline was significantly higher in the HbAS-NαT compared with HbAS-αT during recovery (+36.3 ± 14.1% vs. -1.8 ± 13.2% at T(1h), P = 0.02; +36.6 ± 13.4% vs. -11.4 ± 12.5% at T(2h), P = 0.004 and +24.1 ± 12.3% vs. -14.4 ± 11.5% at T(24h), P = 0.02 in HbAS-NαT vs. HbAS-αT). Compared with HbAS-NαT, HbAS-αT had a higher NOx change from baseline at T(ex) (-23.4 ± 20.6% vs. +57.7 ± 19.3%, respectively; P = 0.005) and lower nitrotyrosine change from baseline at T(1h) (+7.2 ± 22.2% vs. +93.5%±29.3%, respectively; P = 0.04). CONCLUSION: All these data suggest that the presence of α-thalassaemia may blunt the higher level of oxidative stress and the impaired bioavailability of NO observed in the SCT carriers.

Endurance but not resistance training increases intra-myocellular lipid content and ß-hydroxyacyl coenzyme A dehydrogenase activity in active elderly men.

AIM: Endurance and resistance training (ET and RT, respectively) in older subjects have been proven beneficial against metabolic or cardiovascular disorders and against sarcopaenia respectively. Like ET, RT may also increase muscle oxidative capacities. In addition, it could be questioned whether RT, similarly to ET, is able to increase muscle energetic stores such as intra-myocellular lipids (IMCL) and glycogen contents. To evaluate a possible ET- and RT-induced parallel increase in oxidative capacity and energetic stores, active elderly men (72 ± 2 years) were submitted to a 14-week training programme (three times week(-1) ) combining lower body endurance and upper body resistance. METHODS: Muscle samples were collected in ET vastus lateralis (VLat) and RT deltoid (Del) muscles before and after training. IMCL and glycogen contents were assessed by histochemistry (Oil Red O and periodic acid-Schiff staining, respectively) and by biochemical assay for glycogen. Citrate synthase (CS, marker of mitochondrial citric acid cycle), ß-hydroxyacyl coenzyme A dehydrogenase (ß-HAD, beta-oxidation) and phosphofructokinase (PFK, glycolytic pathway) activities were determined and so was the capillary interface index (LC/PF). RESULTS: Both training regimens significantly increased CS and LC/PF in ET-VLat and RT-Del. IMCL content and ß-HAD activity increased (P < 0.05) only in ET-VLat, whereas PFK activity increased (P < 0.05) only in RT-Del. Glycogen content was not significantly altered in response to training in both muscles. CONCLUSION: Unlike RT, which induced an increase in PFK, ET is able to increase IMCL content and ß-oxidation capacity in active elderly men, even though both training may improve CS activity and LC/PF.

Physiological and biological factors associated with a 24 h treadmill ultra-marathon performance.

The purpose of this study was to examine the physiological and biological factors associated with ultra-endurance performance. Fourteen male runners volunteered to run on a treadmill as many kilometers as possible over a 24-h period (24TR). Maximal oxygen uptake (VO(2max)), velocity associated with VO(2max)(VO(2max)) and running economy (RE) at 8 km/h were measured. A muscle biopsy was also performed in the vastus lateralis muscle. The subjects ran 149.2 ± 15.7 km in 18 h 39 ± 41 min of effective attendance on the treadmill, corresponding to 39.4 ± 4.2% of . Standard multiple-regression analysis showed that performance was significantly (R(2) = 0.82; P = 0.005) related to VO(2max) and specific endurance, i.e. the average speed sustained over the 24TR expressed in . VO(2max) was associated with a high capillary tortuosity (R(2) = 0.66; P = 0.01). Specific endurance was significantly related to RE and citrate synthase activity. It is concluded that a high VO(2max) and an associated developed capillary network are essential for ultra-endurance running performance. The ability to maintain a high %VO(2max) over a 24TR is another factor associated with performance and is mainly related to RE and high mitochondrial oxidative capacity in the vastus lateralis.

[Exercise therapy and myopathies]. / Thérapie par l'exercice et myopathies.

Since the first consensus papers published early in the 2000s, a growing number of recent publications has shown that adapted physical activity is not only safe in the context of myopathy but also potentially effective as a therapeutic tool. After a short recall of the different exercise modalities, the mechanical strain they induce and the expected muscular benefits, the present paper reviews the different studies related to exercise therapy in myopathic patients and provides a critical analysis of the topic. Myopathies are rare diseases with many different etiologies and a large number of training modalities which could be useful for the different muscular challenges have been proposed. We have chosen to focus on several specific training modalities and to discuss the results from the most recent papers. The purpose of this review is to, firstly, update physical training guidelines for patients with myopathy and, secondly, highlight some common pitfalls associated with this strategy. This is particularly important for medical and allied professionals involved in prescribing and managing exercise therapy protocols.

Regulation of ubiquitin-proteasome system, caspase enzyme activities, and extracellular proteinases in rat soleus muscle in response to unloading.

In the present study, we determined the impact of 5 and 10 days of muscle deconditioning induced by hindlimb suspension (HS) on the ubiquitin-proteasome system of protein degradation and caspase enzyme activities in rat soleus muscles. A second goal was to determine whether activities of matrix metalloproteinase-2/9 (MMP-2/9) and urokinase-type/tissue-type plasminogen activator (PAs) were responsive to HS. As expected, HS led to a pronounced atrophy of soleus muscle. Level of ubiquitinated proteins, chymotrypsin-like activity of 20S proteasome, and Bcl-2-associated gene product-1 protein level were all transitory increased in response to 5 days of HS. These changes may thus potentially account for the decrease in muscle mass observed in response to 5 days of HS. Caspase-3 activity was significantly increased throughout the experimental period, whereas activities of caspase-6, another effector caspase, and caspase-9, the mitochondrial-dependent activator of both caspase-3 and -6, were only increased in response to 10 days of HS. This suggests that caspase-3 may be regulated through mitochondrial-independent and mitochondrial-dependent mechanisms in response to HS. Finally, MMP-2/9 activities remained unchanged, whereas PAs activities were increased after 5 days of HS. Overall, these data suggest that time-dependent regulation of intracellular and extracellular proteinases are important in setting the new phenotype of rat soleus muscle in response to HS.

Fatigue and neuromuscular diseases.

PURPOSE: To identify the role of fatigue, its evaluation and its causes in the pathophysiology context of acquired or hereditary neuromuscular diseases of the spinal anterior horn cell, peripheral nerve, neuromuscular junction and muscle. MATERIAL AND METHODS: A literature review has been done on Medline with the following keywords: neuromuscular disease, peripheral neuropathy, myopathy, fatigue assessment, exercise intolerance, force assessment, fatigue scale and questionnaire, then with the terms: Fatigue Severity Scale, Chalder Fatigue Scale, Fatigue Questionnaire, Piper Fatigue Scale, electromyography and the combination of the word Fatigue with the following terms: Amyotrophic Lateral Sclerosis (ALS), Post-Polio Syndrome (PPS), Guillain-Barre Syndrome, Immune Neuropathy, Charcot-Marie-Tooth Disease, Myasthenia Gravis (MG), Metabolic Myopathy, Mitochondrial Myopathy, Muscular Dystrophy, Facioscapulohumeral Dystrophy, Myotonic Dystrophy. RESULTS: Fatigue is a symptom very frequently reported by patients. Fatigue is mainly evaluated by strength loss after an exercise, by change in electromyographic activity during a given exercise and by questionnaires that takes into account the subjective (psychological) part of fatigue. Due to the large diversity of motor disorders, there are multiple clinical expressions of fatigue that differ in their presentation, consequences and therapeutic approach. CONCLUSION: This review shows that fatigue has to be taken into account in patients with neuromuscular diseases. In this context, pathophysiology of fatigue often implies the motor component but the disease evolution and the physical obligates of daily life also induce an important psychological component.

Effect of endurance training on muscle microvascular filtration capacity and vascular bed morphometry in the elderly.

AIM: Exercise training is a strong stimulus for vascular remodelling and could restore age-induced vascular alterations. The purpose of the study was to test the hypothesis that an increase in vascular bed filtration capacity would corroborate microvascular adaptation with training. METHODS: We quantified (1) microvascularization from vastus lateralis muscle biopsy to measure the capillary to fibre interface (LC/PF) and (2) the microvascular filtration capacity (K(f)) in lower limbs through a venous congestion plethysmography procedure. Twelve healthy older subjects (74 +/- 4 years) were submitted to a 14-week training programme during which lower-limbs were trained for endurance exercise. RESULTS: The training programme induced a significant increase in the aerobic exercise capacity of lower limbs (+11% V(O2peak); P < 0.05; +28% Citrate Synthase Activity; P < 0.01). K(f) was largely increased (4.3 +/- 0.9 10(-3) mL min(-1) mmHg(-1) 100 mL(-1) post-training vs. 2.4 +/- 0.8 pre-training, mean +/- SD; P < 0.05) and microvascularization developed as shown by the rise in LC/PF (0.29 +/- 0.06 post- vs. 0.23 +/- 0.06 pre-training; P < 0.05). Furthermore, K(f) and LC/PF were correlated (r = 0.65, P < 0.05). CONCLUSION: These results demonstrated the microvascular adaptation to endurance training in the elderly. The increase in K(f) with endurance training was probably related to a greater surface of exchange with an increased microvessel/fibre interface area. We conclude that measurement of the microvascular filtration rate reflects the change in the muscle exchange area and is influenced by exercise training.

Effects of training on lactate kinetics parameters and their influence on short high-intensity exercise performance.

The purpose of the present study was to relate the training-induced alterations in lactate kinetics parameters to the concomitant changes in time to exhaustion (T(lim)) at a work rate corresponding to maximal oxygen uptake (Pa(peak)). Eight subjects performed before and after training i) an incremental exercise up to exhaustion to determine Pa(peak), ii) a 5-min 90 % Pa(peak) exercise followed by a 90-min passive recovery to determine an individual blood lactate recovery curve fitted to the bi-exponential time function: La(t) = La(0) + A1(1 - e -gamma1 x t) + A2(1 - e -gamma2 x t), and iii) a time to exhaustion at Pa peak to determine T lim. A biopsy of the vastus lateralis muscle was made before and after training. The training programme consisted in pedalling on a cycle ergometer 2 h a day, 6 days a week, for 4 weeks. Training-induced increases (p < 0.05) in Pa(peak), muscle capillary density, citrate synthase activity, gamma2 that denotes the lactate removal ability (from 0.0547 +/- 0.0038 to 0.0822 +/- 0.0071 min (-1)) and T(lim) (from 299 +/- 23 to 486 +/- 63 s), decreases (p < 0.05) in activities of lactate dehydrogenase (LDH) and muscle type of LDH, the phosphofructokinase/citrate synthase activities ratio and the estimated net amount of lactate released (NALR) during exercise recovery (from 66.5 +/- 8.6 to 47.2 +/- 11.1 mmol) were also observed. The improvement of T (lim) with training was related to the increase in gamma2 (r = 0.74, p = 0.0367) and to the decrease in NALR (r = 0.77, p = 0.0250). These results suggest that the post-training greater ability to remove lactate from the organism and reduced muscle lactate accumulation during exercise account for the concomitant improvement of the time to exhaustion during high-intensity exercise performed at the same relative work rate.

[Isokinetic assessment of muscular strength in subjects with acute inflammatory demyelinating polyradiculoneuropathy]. / Evaluation isocinétique de la force musculaire de patients atteints de polyradiculonévrite aiguë.

OBJECTIVE: To evaluate the feasibility and the interest of isokinetic measures tests in subjects with inflammatory demyelinating polyradiculoneuropathy or Guillain-Barré syndromes (GBS). METHODS: Nine patients with GBS are tested at the beginning and after 6 months of recovery stage. They benefit from (1) isokinetic assessment of muscular strength of knee, elbow, ankle: flexion/extension and shoulder abduction/adduction ranging 30 per s at 180 per s angular velocity; (2) isometric assessment of the same muscular groups; (3) manual muscle testing; (4) functional independence measure. RESULTS: Isokinetic tests were tolerated at 60 and 120 per s. Fatigability appears since the third second of isometric test. The relationships between isokinetic, manual tests and isometric tests are variables (0.29 < r < 0.97). The evaluation after 6 months of recovery showed a good sensibility of isokinetic test. CONCLUSION: The continuation of this motor isokinetic evaluation, in a large population, will permit to establish longitudinal and evolutive profile of each patient and will facilitate to chose the rehabilitation program.

Devic disease and thymoma with anti-central nervous system and antithymus antibodies.

A patient with myasthenia gravis and thymoma developed neuromyelitis optica (NMO) and necrotizing myositis 4 months after treatment of the tumor. Antibodies reacting with the CNS and thymic epithelial cells were detected in the serum during the acute phase of NMO, suggesting that the NMO was linked to the thymoma.

Enhancement of microvessel tortuosity in the vastus lateralis muscle of old men in response to endurance training.

Muscle microvascularization is usually quantified in transverse sections, in absolute terms (capillaries around fibres, CAF, or capillary-to-fibre ratio, C/F) or as CAF related to fibre area (CAF/area, CAFA). The capillary-to-fibre perimeter exchange ratio (CFPE) has been introduced in order to assess the role of the capillary-to-fibre interface in resistance to O(2) diffusion. The ratio between the length of capillaries in contact with fibres and fibre perimeter (LC/PF) has also been used as an index for capillary tortuosity. The possibility of change in capillary tortuosity with endurance training was not considered in previous studies. Consequently, this study investigated the effect of 14 weeks of endurance training on muscle microvascularization, including microvessel tortuosity, in 11 elderly men (8th decade). Microvessels were analysed using the CD31 antibody. Together with the significant increase in peak oxygen exchange and citrate synthase activity, there was a significant increase in C/F. While CFPE and CAFA remained unchanged, an important finding was the clear increase in LC/PF (56%; P < 0.001) for a same sarcomere length. We also found a strong correlation between oxidative enzyme activity and LC/PF both before and after training. These results indicate that endurance training induces significant remodelling in the microvessel network in elderly men and that an increase in the degree of microvessel tortuosity would be an important mechanism of adaptation to endurance training.