Nicol C. Voermans

Pain in Ehlers-Danlos Syndrome Is Common, Severe, and Associated with Functional Impairment

CONTEXT The Ehlers-Danlos Syndrome (EDS) is a clinically and genetically heterogeneous group of heritable connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Musculoskeletal pain is mentioned in the diagnostic criteria and described as early in onset, chronic, and debilitating. However, systematic research on pain in EDS is scarce. OBJECTIVES We investigated prevalence and impact of pain and associated features in a large group of EDS patients. METHODS We performed a study among members of the Dutch EDS patient organization (n=273) and included the McGill Pain Questionnaire to investigate various aspects of pain, the Sickness Impact Profile to study functional impairment, the Symptom Checklist subscale sleep to evaluate sleep disturbances, and the Checklist Individual Strength subscale fatigue to determine fatigue severity. RESULTS The results of this study show that 1) chronic pain in EDS is highly prevalent and associated with regular use of analgesics; 2) pain is more prevalent and more severe in the hypermobility type than in the classic type; 3) pain severity is correlated with hypermobility, dislocations, and previous surgery; 4) pain is correlated with low nocturnal sleep quality; and 5) pain contributes to functional impairment in daily life, independent of the level of fatigue. CONCLUSION From this large cohort of EDS patients, we conclude that pain is common and severe in EDS. Pain is related to hypermobility, dislocations, and previous surgery and associated with moderate to severe impairment in daily functioning. Therefore, treatment of pain should be a prominent aspect of symptomatic management of EDS.

Neuromuscular involvement in various types of Ehlers-Danlos syndrome.

Ehlers–Danlos syndrome (EDS) is a clinically and genetically heterogeneous group of heritable connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Muscle involvement is plausible based on recently discovered interactions between muscle cells and extracellular matrix molecules; however, muscle symptoms are only sporadically reported. We designed a cross‐sectional study to find out whether neuromuscular features are part of EDS.

The 2017 international classification of the Ehlers-Danlos syndromes.

The Ehlers–Danlos syndromes (EDS) are a clinically and genetically heterogeneous group of heritable connective tissue disorders (HCTDs) characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Over the past two decades, the Villefranche Nosology, which delineated six subtypes, has been widely used as the standard for clinical diagnosis of EDS. For most of these subtypes, mutations had been identified in collagen‐encoding genes, or in genes encoding collagen‐modifying enzymes. Since its publication in 1998, a whole spectrum of novel EDS subtypes has been described, and mutations have been identified in an array of novel genes. The International EDS Consortium proposes a revised EDS classification, which recognizes 13 subtypes. For each of the subtypes, we propose a set of clinical criteria that are suggestive for the diagnosis. However, in view of the vast genetic heterogeneity and phenotypic variability of the EDS subtypes, and the clinical overlap between EDS subtypes, but also with other HCTDs, the definite diagnosis of all EDS subtypes, except for the hypermobile type, relies on molecular confirmation with identification of (a) causative genetic variant(s). We also revised the clinical criteria for hypermobile EDS in order to allow for a better distinction from other joint hypermobility disorders. To satisfy research needs, we also propose a pathogenetic scheme, that regroups EDS subtypes for which the causative proteins function within the same pathway. We hope that the revised International EDS Classification will serve as a new standard for the diagnosis of EDS and will provide a framework for future research purposes.

Fatigue Is a Frequent and Clinically Relevant Problem in Ehlers-Danlos Syndrome

OBJECTIVES Ehlers-Danlos Syndrome (EDS) is a clinically and genetically heterogeneous group of inherited connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Fatigue and musculoskeletal pain are associated features but have never been studied systematically. We used a multidimensional assessment method to measure fatigue, its clinical relevance, and possible determinants. METHODS A questionnaire study was performed among 273 EDS patients. The following dimensions were assessed: fatigue severity, functional impairment in daily life, physical activity, psychological distress, sleep disturbances, concentration problems, social functioning, self-efficacy concerning fatigue, causal attribution of fatigue, pain, and disease-related factors. RESULTS More than three-quarters of EDS patients suffer from severe fatigue. Patients who are severely fatigued are more impaired than nonseverely fatigued patients and report a higher level of psychological distress. The 5 possible determinants involved in fatigue are sleep disturbances, concentration problems, social functioning, self-efficacy concerning fatigue, and pain severity. CONCLUSIONS This is the first study of fatigue and its possible determinants in EDS and shows that fatigue is a frequent and clinically significant problem in EDS. The 5 possible determinants of fatigue could form a starting point for the development of an effective cognitive behavioral intervention for fatigue in EDS.

Mutations in RYR1 are a common cause of exertional myalgia and rhabdomyolysis

Mutations in the skeletal muscle ryanodine receptor (RYR1) gene are a common cause of neuromuscular disease, ranging from various congenital myopathies to the malignant hyperthermia (MH) susceptibility trait without associated weakness. We sequenced RYR1 in 39 unrelated families with rhabdomyolysis and/or exertional myalgia, frequent presentations in the neuromuscular clinic that often remain unexplained despite extensive investigations. We identified 9 heterozygous RYR1 mutations/variants in 14 families, 5 of them (p.Lys1393Arg; p.Gly2434Arg; p.Thr4288_Ala4290dup; p.Ala4295Val; and p.Arg4737Gln) previously associated with MH. Index cases presented from 3 to 45 years with rhabdomyolysis, with or without exertional myalgia (n=12), or isolated exertional myalgia (n=2). Rhabdomyolysis was commonly triggered by exercise and heat and, less frequently, viral infections, alcohol and drugs. Most cases were normally strong and had no personal MH history. Inconsistent additional features included heat intolerance, and cold-induced muscle stiffness. Muscle biopsies showed mainly subtle changes. Familial RYR1 mutations were confirmed in relatives with similar or no symptoms. These findings suggest that RYR1 mutations may account for a substantial proportion of patients presenting with unexplained rhabdomyolysis and/or exertional myalgia. Associated clinico-pathological features may be subtle and require a high degree of suspicion. Additional family studies are paramount in order to identify potentially MH susceptible relatives.

Clinical and molecular overlap between myopathies and inherited connective tissue diseases

This review presents an overview of myopathies and inherited connective tissue disorders that are caused by defects in or deficiencies of molecules within the extracellular matrix (ECM). We will cover the myopathies caused by defects in transmembrane protein complexes (dystroglycan, sarcoglycan, and integrins), laminin, and collagens (collagens VI, XIII, and XV). Clinical characteristics of several of these myopathies imply skin and joint features. We subsequently describe the inherited connective tissue disorders that are characterized by mild to moderate muscle involvement in addition to the dermal, vascular, or articular symptoms. These disorders are caused by defects of matrix-embedded ECM molecules that are also present within muscle (collagens I, III, V, IX, lysylhydroxylase, tenascin, fibrillin, fibulin, elastin, and perlecan). By focussing on the structure and function of these ECM molecules, we aim to point out the clinical and molecular overlap between the groups of disorders. We argue that clinicians and researchers dealing with myopathies and inherited connective tissue disorders should be aware of this overlap. Only a multi-disciplinary approach will allow full recognition of the wide variety of symptoms present in the spectrum of ECM defects, which has important implications for scientific research, diagnosis, and for the treatment of these disorders.

Statin-Induced Myopathy Is Associated with Mitochondrial Complex III Inhibition

Cholesterol-lowering statins effectively reduce the risk of major cardiovascular events. Myopathy is the most important adverse effect, but its underlying mechanism remains enigmatic. In C2C12 myoblasts, several statin lactones reduced respiratory capacity and appeared to be strong inhibitors of mitochondrial complex III (CIII) activity, up to 84% inhibition. The lactones were in general three times more potent inducers of cytotoxicity than their corresponding acid forms. The Qo binding site of CIII was identified as off-target of the statin lactones. These findings could be confirmed in muscle tissue of patients suffering from statin-induced myopathies, in which CIII enzyme activity was reduced by 18%. Respiratory inhibition in C2C12 myoblasts could be attenuated by convergent electron flow into CIII, restoring respiration up to 89% of control. In conclusion, CIII inhibition was identified as a potential off-target mechanism associated with statin-induced myopathies.

Why old people fall (and how to stop them)

![Graphic][1] Falls in older people are a common, dangerous and frequently incapacitating problem. They are often perceived as being untreatable—but this is an overly negative perspective. In any event, in the next few decades we will increasingly be confronted with elderly fallers as life expectancy continues to rise. This applies particularly to general practitioners, emergency department staff, geriatricians and neurologists. In this review, we will underscore the clinical significance of falls in the elderly and then outline a practical approach for their management. Core elements of this approach include: Falls in the elderly are a major health problem, first and foremost for the affected individuals whose quality of life is markedly reduced, and also for the public health system because of the immense costs associated with falls and the resultant injuries. The risk of falls increases with age: about one third of those over 65 years of age fall at least once a year, and about half of them even more often.1 Apart from age, prominent risk factors include previous falls, female gender, concomitant neurological disease, living in a nursing home, fear of recurrent falling, and regular alcohol intake.2,3 
 About one third of those over 65 years of age fall at least once a year Falling is serious, for several reasons: [1]: /embed/graphic-1.gif

Rituximab treatment in patients with refractory inflammatory myopathies

OBJECTIVE To assess the efficacy of rituximab on disease activity and muscle strength in patients with inflammatory myopathies refractory to conventional therapy. METHODS; Thirteen patients were treated with rituximab 1000 mg i.v., twice, with a 2-week interval and followed for a median of 27 months. Primary outcomes were disease activity measured by creatine phosphokinase (CPK), lactate dehydrogenase (LDH) levels and muscle strength measured by hand-held dynamometry and manual muscle testing (MMT). Secondary outcomes were improvement in secondary laboratory measures, global assessment of general health, disease activity and pain, CS dose, functional ability, health-related quality of life and safety. Retreatment with rituximab was conducted if disease activity relapsed. RESULTS; The median levels of CPK and LDH were significantly reduced by 93.2 and 39.8%, respectively, compared with baseline after 34.6 months. The median muscle strength measured by hand-held dynamometry was significantly improved by 21.5% after 24 months. The median increase in muscle strength measured with MMT was 7.0% after 24 months of follow-up, although this did not reach statistical significance. Secondary outcomes improved as well. CONCLUSION; Rituximab is an effective treatment in refractory inflammatory myopathies, showing a decrease in CPK and LDH, an increase in muscle strength and improvement in scores of disease activity, general health, functional ability and health related quality of life with sustained effect during a median of 27.1 months of follow-up.

Both pain and fatigue are important possible determinants of disability in patients with the Ehlers-Danlos syndrome hypermobility type

Patients with Ehlers-Danlos Syndrome (EDS), a group of inherited connective tissue disorders, often complain about pain. Until recently, almost no research was done on this symptom and its consequences in patients with EDS. In their interesting study, Rombaut et al. [1] showed that for patients with EDS of the hypermobility type (HT) ‘moderate to severe pain is an everyday occurrence’. They also found a reduced quality of life and high level of disability in patients with EDS. The authors state that the HT probably is the most debilitating form of EDS with respect to musculoskeletal function, but as they only included HT patients a direct comparison with other subtypes with respect to the prevalence and severity of pain was not possible. Our recently published study on pain in EDS [2] replicated the findings of Rombaut et al. and also provided some new insights in the role of pain in the different subtypes of EDS. We also found a high prevalence of pain in a group of 162 patients with HT. Further analysis showed that pain severity was a possible determinant of the level of disability. A comparison of different subtypes of EDS showed, as suggested by Rombaut et al., that both the prevalence and severity of pain is higher in patients with HT than in patients with the classic and vascular type EDS. Next, chronic pain is in EDS is associated with regular use of analgesics sleep disturbances, and pain severity is related to hypermobility, dislocations and previous operations [2]. A remarkable discrepancy with the study of Rombaut et al. is the high frequency of severe fatigue in the group of 273 patients with EDS in our study on fatigue in EDS [3]. More than threequarters of the total group of patients with EDS and 84% of the patients with HT suffered from severe fatigue. Severely fatigued patients were more impaired than non-severely fatigued patients and reported a higher level of psychological distress. Our findings are in accordance with the results of another recent study on the natural history and manifestations in the hypermobility type EDS by Castori et al. [4], in which chronic asthenia and/or fatigue was reported by 86% of the patients. In the sample of 27 patients in the study of Rombaut et al., only about 25% complained about fatigue. A