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Despite the growing knowledge on the (epi)genetic background of facioscapulohumeral muscular dystrophy (FSHD), the substantial variability in disease severity that exists between FSHD patients is not fully understood. We hypothesized that smoking and alcohol consumption are disease modifiers in FSHD and contribute to the variability in disease severity, because they are both associated with higher levels of oxidative stress in muscle tissue. Oxidative stress is known to influence FSHD muscle tissue. One hundred and ninety-eight genetically confirmed FSHD patients completed a questionnaire from which the number of packyears of smoking and the lifetime cumulative alcohol units consumed were calculated. Disease severity was determined by the FSDH evaluation score. Multiple linear regression analyses showed that both the number of packyears and the amount of alcohol consumption did not influence disease severity (respectively B = 0.025, ΔR2=0.006, p = 0.231; and B = 0.000, ΔR2=0.004, p = 0.406). Although smoking and excessive alcohol consumption are unhealthy habits which should be discouraged, these results show that smoking and alcohol consumption have no clinically meaningful modifying effect on disease severity in FSHD patients. However, prospective data should show whether alcohol consumption and smoking influence disease progression rate.

Introduction: Chronic hypercapnic respiratory failure induces considerable morbidity and mortality in patients with myotonic dystrophy type 1 (DM1). This study systematically reviews the effects of noninvasive home mechanical ventilation (HMV) on gas exchange, quality of life, survival, and compliance in DM1 patients. Methods: A systematic Medline and Embase search was performed (January 1995 to January 2020). Records were screened for eligibility criteria, data were extracted from included studies, and risk of bias was assessed. We present findings mainly using a narrative synthesis. Results: Twenty-eight relevant full-text articles were screened for eligibility criteria. Nine studies were included. Randomized controlled trials were not found. Studies had either an observational (n = 8) or interventional (n = 1) design. In the pooled data analysis, HMV showed to improve mean oxygen saturation with 4.8% and decreased mean carbon dioxide values with 3 mm Hg. Compliance varied widely between studies, from no use to more than 12 h per day. Quality of life was not studied extensively, but some studies reported positive effects of HMV on symptoms of chronic respiratory failure. HMV may improve survival in DM1 patients with chronic hypercapnic respiratory failure. Conclusion: This review shows that HMV can improve gas exchange and relieve symptoms with a possible survival benefit in DM1 patients with chronic hypercapnic respiratory failure. Future studies should focus on developing strategies to optimize the timing of HMV initiation and to promote compliance.

BackgroundSELENON (SEPN1)-related myopathy (SELENON-RM) is a rare congenital myopathy characterized by slowly progressive proximal muscle weakness, early onset spine rigidity and respiratory insufficiency. A muscular dystrophy caused by mutations in theLAMA2gene (LAMA2-related muscular dystrophy, LAMA2-MD) has a similar clinical phenotype, with either a severe, early-onset due to complete Laminin subunit α2 deficiency (merosin-deficient congenital muscular dystrophy type 1A (MDC1A)), or a mild, childhood- or adult-onset due to partial Laminin subunit α2 deficiency. For both muscle diseases, no curative treatment options exist, yet promising preclinical studies are ongoing. Currently, there is a paucity on natural history data and appropriate clinical and functional outcome measures are needed to reach trial readiness.MethodsLAST STRONG is a natural history study in Dutch-speaking patients of all ages diagnosed with SELENON-RM or LAMA2-MD, starting August 2020. Patients have four visits at our hospital over a period of 1.5 year. At all visits, they undergo standardized neurological examination, hand-held dynamometry (age ≥ 5 years), functional measurements, questionnaires (patient report and/or parent proxy; age ≥ 2 years), muscle ultrasound including diaphragm, pulmonary function tests (spirometry, maximal inspiratory and expiratory pressure, sniff nasal inspiratory pressure; age ≥ 5 years), and accelerometry for 8 days (age ≥ 2 years); at visit one and three, they undergo cardiac evaluation (electrocardiogram, echocardiography; age ≥ 2 years), spine X-ray (age ≥ 2 years), dual-energy X-ray absorptiometry (DEXA-)scan (age ≥ 2 years) and full body magnetic resonance imaging (MRI) (age ≥ 10 years). All examinations are adapted to the patient’s age and functional abilities. Correlation between key parameters within and between subsequent visits will be assessed.DiscussionOur study will describe the natural history of patients diagnosed with SELENON-RM or LAMA2-MD, enabling us to select relevant clinical and functional outcome measures for reaching clinical trial-readiness. Moreover, our detailed description (deep phenotyping) of the clinical features will optimize clinical management and will establish a well-characterized baseline cohort for prospective follow-up.ConclusionOur natural history study is an essential step for reaching trial readiness in SELENON-RM and LAMA2-MD.Trial registrationThis study has been approved by medical ethical reviewing committee Region Arnhem-Nijmegen (NL64269.091.17, 2017–3911) and is registered atClinicalTrial.gov(NCT04478981).

Background and objectives Facioscapulohumeral muscular dystrophy (FHSD) is a debilitating inherited muscle disease for which various therapeutic strategies are being investigated. Thus far, little attention has been given in FSHD to the development of scientifically sound outcome measures fulfilling regulatory authority requirements. The aim of this study was to design a patient‐reported Rasch‐built interval scale on activity and participation for FSHD. Methods A pre‐phase FSHD‐Rasch‐built overall disability scale (pre‐FSHD‐RODS; consisting of 159 activity/participation items), based on the World Health Organization international classification of disease‐related functional consequences was completed by 762 FSHD patients (Netherlands: n = 171; UK: n = 287; United States: n = 221; France: n = 52; Australia: n = 32). A proportion of the patient cohort completed it twice (n = 230; interval 2–4 weeks; reliability studies). The pre‐FSHD‐RODS was subjected to Rasch analyses to create a model fulfilling its requirements. Validity studies were performed through correlation with the motor function measure. Results The pre‐FSHD‐RODS did not meet the Rasch model expectations. Based on determinants such as misfit statistics and misfit residuals, differential item functioning, and local dependency, we systematically removed items until a final 38‐inquiry (originating from 32 items; six items split) FSHD‐RODS was constructed achieving Rasch model expectations. Adequate test‐retest reliability and (cross‐cultural and external) validity scores were obtained. Conclusions The FSHD‐RODS is a disease‐specific interval measure suitable for detecting activity and participation restrictions in patients with FSHD with good item/person reliability and validity scores. The use of this scale is recommended in the near future, to determine the functional deterioration slope in FSHD per year as a preparation for the upcoming clinical intervention trials in FSHD., This paper presents the development and validation of a patient‐reported Rasch‐built interval scale on activity and participation for facioscapulohumeral muscular dystrophy (FSHD‐RODS). The final 38‐inquiry scale met Rasch model expectations and showed adequate discriminative power, test‐retest reliability and validity. The use of this scale is recommended in the near future to determine the functional deterioration slope in facioscapulohumeral muscular dystrophy (FSHD) per year as a preparation for the upcoming clinical intervention trials in FSHD.

Contains fulltext : 232905.pdf (Publisher’s version ) (Open Access) Brain involvement in myotonic dystrophy type 1 (DM1) is characterized by heterogeneous cognitive, behavioral, and affective symptoms and imaging alterations indicative of widespread grey and white matter involvement. The aim of the present study was to systematically review the literature on brain pathology in DM1. We conducted a structured search in EMBASE (index period 1974-2017) and MEDLINE (index period 1887-2017) on December 11, 2017, using free text and index search terms related to myotonic dystrophy type 1 and brain structures or regions. Eligible studies were full-text studies reporting on microscopic brain pathology of DM1 patients without potentially interfering comorbidity. We discussed the findings based on the anatomical region and the nature of the anomaly. Neuropathological findings in DM1 can be classified as follows: (1) protein and nucleotide deposits; (2) changes in neurons and glial cells; and (3) white matter alterations. Most findings are unspecific to DM1 and may occur with physiological aging, albeit to a lesser degree. There are similarities and contrasts with Alzheimer's disease; both show the appearance of neurofibrillary tangles in the limbic system without plaque occurrence. Likewise, there is myelin loss and gliosis, and there are dilated perivascular spaces in the white matter resemblant of cerebral small vessel disease. However, we did not find evidence of lacunar infarction or microbleeding. The various neuropathological findings in DM1 are reflective of the heterogeneous clinical and neuroimaging features of the disease. The strength of conclusions from this study's findings is bounded by limited numbers of participants in studies, methodological constraints, and lack of assessed associations between histopathology and clinical or neuroimaging findings.

Background: Non-invasive home mechanical ventilation (HMV) is a complex treatment in myotonic dystrophy type 1 (DM1) patients, due to a presumed poor adherence, variable symptom improvement, and uncertainty regarding survival benefits. Objectives: We aimed to investigate indications, adherence to HMV and its effects on mortality in a large cohort of DM1 patients. Methods: In this retrospective cohort study, we evaluated 224 DM1 patients. Different groups based on hypercapnia and HMV treatment were compared. Cox regression analyses were performed to compare mortality between different defined groups. Results: 224 patients were analysed of whom 111 started non-invasive HMV. Indications were daytime hypercapnia (n = 75), only nocturnal hypercapnia (n = 33), or other reasons (n = 3). Adequate adherence (≥4 h/night) was found in 84.9% of patients. Adequate ventilation was reached in 86.5% of patients. In 33 patients (29.7%), HMV was stopped prematurely due to not reaching patients’ expectations on symptom relief or treatment burden (n = 22), or intolerance (n = 8), or other reasons (n = 3). HMV did not improve survival in daytime hypercapnic patients (p = 0.61) nor in nocturnal hypercapnia patients compared to daytime hypercapnia (p = 0.21). Significant survival benefits after starting HMV were found for patients with HMV adherence ≥5 h/24 h compared to patients who used HMV less. Conclusion: In this large cohort, daytime hypercapnia is the main reason for starting HMV, which is well tolerated and used. Mortality is not associated with the reason why HMV was started, but once started, patients with ≥5 h/24 h adherence have significantly better survival compared to patients who use it less.

Contains fulltext : 241356.pdf (Publisher’s version ) (Open Access) Centronuclear myopathy (CNM) is a genetically heterogeneous congenital myopathy characterized by muscle weakness, atrophy, and variable degrees of cardiorespiratory involvement. The clinical severity is largely explained by genotype (DNM2, MTM1, RYR1, BIN1, TTN, and other rarer genetic backgrounds), specific mutation(s), and age of the patient. The histopathological hallmark of CNM is the presence of internal centralized nuclei on muscle biopsy. Information on the phenotypical spectrum, subtype prevalence, and phenotype-genotype correlations is limited. To characterize CNM more comprehensively, we retrospectively assessed a national cohort of 48 CNM patients (mean age = 32 ± 24 years, range 0-80, 54% males) from the Netherlands clinically, histologically, and genetically. All information was extracted from entries in the patient's medical records, between 2000 and 2020. Frequent clinical features in addition to muscle weakness and hypotonia were fatigue and exercise intolerance in more mildly affected cases. Genetic analysis showed variants in four genes (18 DNM2, 14 MTM1, 9 RYR1, and 7 BIN1), including 16 novel variants. In addition to central nuclei, histologic examination revealed a large variability of myopathic features in the different genotypes. The identification and characterization of these patients contribute to trial readiness.

Contains fulltext : 218857.pdf (Publisher’s version ) (Closed access)

Brody disease is a rare myopathy characterized by exercise-induced muscle stiffness caused by mutations in the ATP2A1 gene. In the largest cohort of Brody patients to date, Molenaar et al. clarify the phenotype and diagnostic possibilities to help improve understanding and recognition of this distinct myopathy., Brody disease is an autosomal recessive myopathy characterized by exercise-induced muscle stiffness due to mutations in the ATP2A1 gene. Almost 50 years after the initial case presentation, only 18 patients have been reported and many questions regarding the clinical phenotype and results of ancillary investigations remain unanswered, likely leading to incomplete recognition and consequently under-diagnosis. Additionally, little is known about the natural history of the disorder, genotype-phenotype correlations, and the effects of symptomatic treatment. We studied the largest cohort of Brody disease patients to date (n = 40), consisting of 22 new patients (19 novel mutations) and all 18 previously published patients. This observational study shows that the main feature of Brody disease is an exercise-induced muscle stiffness of the limbs, and often of the eyelids. Onset begins in childhood and there was no or only mild progression of symptoms over time. Four patients had episodes resembling malignant hyperthermia. The key finding at physical examination was delayed relaxation after repetitive contractions. Additionally, no atrophy was seen, muscle strength was generally preserved, and some patients had a remarkable athletic build. Symptomatic treatment was mostly ineffective or produced unacceptable side effects. EMG showed silent contractures in approximately half of the patients and no myotonia. Creatine kinase was normal or mildly elevated, and muscle biopsy showed mild myopathic changes with selective type II atrophy. Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) activity was reduced and western blot analysis showed decreased or absent SERCA1 protein. Based on this cohort, we conclude that Brody disease should be considered in cases of exercise-induced muscle stiffness. When physical examination shows delayed relaxation, and there are no myotonic discharges at electromyography, we recommend direct sequencing of the ATP2A1 gene or next generation sequencing with a myopathy panel. Aside from clinical features, SERCA activity measurement and SERCA1 western blot can assist in proving the pathogenicity of novel ATP2A1 mutations. Finally, patients with Brody disease may be at risk for malignant hyperthermia-like episodes, and therefore appropriate perioperative measures are recommended. This study will help improve understanding and recognition of Brody disease as a distinct myopathy in the broader field of calcium-related myopathies.

Contains fulltext : 236035.pdf (Publisher’s version ) (Open Access) Some patients with Oculopharyngeal Muscular Dystrophy (OPMD) develop frontotemporal dementia (FTD). The prevalence and clinical correlates of behavioural impairment, including FTD, is unknown in OPMD. 24 OPMD patients and their proxies completed a questionnaire concerning behavioural impairment (ALS-FTD-Q). We examined proportions with mild or severe behavioural changes, according to validated cut-off proxy scores. We examined correlations with the Hospital Anxiety and Depression Scale (HADS), the Short Form Health Survey (SF-36), motor symptoms, genotype and disease duration. In this small patient sample, behavioural impairment was present in 29%of OPMD patients; in 17%the severity of symptoms was compatible with bvFTD. Correlations were small to medium. 7 p.

Background and ObjectivesTo perform a systematic review of published N-of-1 trials (e.g., single patient crossover trials) in neurologic disorders, including an assessment of methodologic quality and reporting.MethodsWe searched PubMed, MEDLINE, and Embase from inception date to the December 1, 2019, for reports on N-of-1 trials in neurologic disorders. Basic trial information on design, disease, intervention, analysis, and treatment success was extracted. Strengths and weaknesses of the N-of-1 trials were assessed with the Consolidated Standards of Reporting Trials extension for N-of-1 trials (CENT) 2015 criteria checklist and the Jadad score as measures of quality and reporting.ResultsWe retrieved 40 reports of N-of-1 trials in neurologic disorders (19 individual N-of-1 trials, 21 series of N-of-1 trials). Most N-of-1 trials were performed in neuromuscular and neurodegenerative/movement disorders. Unlike the majority of trials that studied the main symptom(s) of a chronic stable condition, 9 N-of-1 trials studied a stable chronic symptom of a progressive or acute neurologic disorder. Besides pharmacologic interventions, electric stimulation protocols and nutritional products were studied. A mean total CENT score of 20.88 (SD 9.10, range 0–43) and mean total Jadad score of 2.90 (SD 2.15, range 0–5) were found as methodologic measures of quality and reporting across all N-of-1 trials.DiscussionN-of-1 trials have been reported in numerous neurologic disorders, not only in chronic stable disorders, but also in progressive or acute disorders with a stable symptom. This indicates the emerging therapeutic area of N-of-1 trials in neurology. Methodologic quality and reporting of N-of-1 trials were found to be suboptimal and can easily be improved in future trials by appropriately describing the methods of blinding and randomization and following CENT guidelines. Because most N-of-1 trials remain unreported in medical literature, this systematic review probably represents only the tip of the iceberg of conducted N-of-1 trials in neurologic disorders. In addition to conventional trial designs, N-of-1 trials can help to bridge the gap between research and clinical care by providing an alternative, personalized level 1 evidence base for suitable treatments.

This study focuses on the functional and psychosocial consequences of facial weakness of patients with facioscapulohumeral muscular dystrophy (FSHD) and how they manage their daily lives. We conducted a qualitative study. Sixteen FSHD patients with varying degrees of facial weakness were interviewed using a semi-structured interview guide. Data were analyzed using the constant comparison approach based on the Straussian Grounded Theory. Reduced facial expression affected different aspects of a participant’s life, which is reinforced by fatigue. Particularly the younger participants described the confrontation with reduced facial expression as upsetting. The unpredictability of the progression of facial weakness makes many participants insecure and concerned. They generally tend to avoid discussing facial weakness with loved ones as well as with strangers. Patients would like the expert teams to shed more light on effective skill training and psychosocial support, especially for the younger patient group. A multidisciplinary approach is needed in addition to programs focusing on the individual aspects of facial weakness. As the experienced psychosocial effect is not commonly equal to the objective degree of facial weakness, we recommend a tailored approach. Finally, these programs should point out the importance of the patient’s own ingenuity.Implications for RehabilitationFacial weakness affects both activities and social participation in patients with facioscapulohumeral muscular dystrophy (FSHD), which is reinforced by fatigue.Many participants try to stay down to earth and focus on their ability to self-manage their obstacles regarding facial weakness.Thus, future treatment programs should have a multidisciplinary approach and should point out the importance of the patient’s own ingenuity. Facial weakness affects both activities and social participation in patients with facioscapulohumeral muscular dystrophy (FSHD), which is reinforced by fatigue. Many participants try to stay down to earth and focus on their ability to self-manage their obstacles regarding facial weakness. Thus, future treatment programs should have a multidisciplinary approach and should point out the importance of the patient’s own ingenuity.

Background and ObjectivesOculopharyngeal muscular dystrophy (OPMD) is a late-onset, progressive muscle disease. Disease progression is known to be slow, but details on the natural history remain unknown. We aimed to examine the natural history of OPMD in a large nationwide cohort to determine clinical outcome measures that capture disease progression and can be used in future clinical trials.MethodsPatients invited by their treating physicians or identified from the national neuromuscular database and invited family members were examined twice 20 months apart with fixed dynamometry; Medical Research Council (MRC) grading; maximum bite force and isometric tongue strength; Motor Function Measure (MFM); 10-step stair test; maximum swallowing, chewing, and speech tasks; and quality of life assessments.ResultsDisease progression was captured by 8 of 18 measures over 20 months in 43 patients with genetically confirmed OPMD. The largest deterioration was seen in deltoid muscle strength (−27% [range −17% to −37%]), followed by the quadriceps (−14% [range −6 to −23%]), iliopsoas (−12.2%), tongue (−9.9%), and MRC sum score (−2.5%). The 10-step stair test (−12.5%), MFM part D1 (−7.1%), and maximum repetition rate of /pa/ (−5.3%) showed a significant decrease as well (all p < 0.05). The Physical Functioning domain of the Short Form-36 Health Survey significantly deteriorated (p = 0.044). No relationship was found between disease progression and genotype or disease duration (p > 0.05).DiscussionDespite the slow disease progression of OPMD, this study showed that several outcome measures detected progression within 20 months. Deltoid muscle strength, measured by fixed dynamometry, showed the greatest decline. These longitudinal data provide clinical outcome measures that can be used as biomarkers in future clinical trials.

ObjectivesTo describe the combination of spinocerebellar ataxia (SCA) types 3 and 6 and sporadic inclusion body myositis (IBM).MethodsA description of five patients with SCA type 3 and 6 who were diagnosed with IBM. We explore possible mechanisms explaining the coexistence of both diseases.ResultsThe patients with SCA-3 (n=4) and SCA-6 (n=1) developed asymmetric muscle weakness in a pattern suggestive of IBM in the course of their disease. Based on findings of neurological examination and additional investigations (muscle ultrasound, muscle biopsy), the diagnosis of IBM was made in all patients.ConclusionWe report on five patients with concomitant SCA and IBM. Our cases may merely illustrate coincidental co-occurrence of IBM and SCA-3/SCA-6. However, the presence of SCA mutations could predispose to the development of IBM in some SCA patients, or, the presence of toxic aggregates and malfunctioning of cellular quality control processes in both diseases could indicate a convergence of disease mechanisms.

We aimed to examine the incidence as well as the circumstances and the consequences of falling in adult patients with myotonic dystrophy type 1 and 2 (DM1/DM2). We performed a prospective cohort study in 209 subjects, of which 102 had DM1, 42 had DM2 and 65 healthy controls. An assessment of their falls was carried out during 100 consecutive days. In addition, falls during the previous year were reported. The primary outcome measure was the number of self-reported falls per participant during these 100 days. The secondary outcome measures included self-reported causes, circumstances and consequences of the falls. Mean (SD) falls per participant in 100 days was seven- to eightfold higher in patients with DM1 (0.74 (0.14)) and DM2 (0.62 (0.20)) compared to the controls (0.09 (0.04); p < 0.001)). Sixteen percent of DM1 and 17% of DM2 patients fell at least twice. Two-thirds of the falls occurred inside. Fifty percent of falls resulted in an injury, including a head trauma in four patients. Compared to non-fallers, those patients who fell were older (DM1/DM2), had a lower DM1-Activ score (DM1), had more muscle weakness (DM1), and reported less confidence in balance (DM1). This study demonstrates a high incidence and clinical relevance of falling in patients with DM1 and DM2. Fall prevention strategies in both DM1 and DM2 should focus on adaptations of the home environment and the patient's interaction in this environment.

Background Adult-onset myotonic dystrophy type 1 (DM1) is a chronic, multisystem disorder that leads to disability and premature death. Objectives The objective of our study was to conduct a systematic literature review of the health-related quality of life (HRQoL) of patients with DM1. Methods We searched Embase, Web of Science, and PubMed for English language full-text articles reporting results from studies of HRQoL in patients with adult-onset DM1 published between 1 January 2000 and 21 February 2018. We excluded reviews, editorials, and studies reporting results for a sample with fewer than five patients (to allow for meaningful inference). Results The search identified 266 unique publications. Of these, 231 were excluded following title and abstract screening and 16 after full-text review, leaving 19 articles for data synthesis. We found 15 articles measuring the HRQoL of patients with adult-onset DM1 using the 36-Item Short Form Health Survey (SF-36), six using the Individualized Neuromuscular Quality of Life Questionnaire (INQoL), and one using Cantril’s Ladder. Available evidence shows that patient HRQoL is impaired in DM1, mainly due to compromised physical health, but also reveals that substantial heterogeneity exists in estimates across studies. Conclusions HRQoL in adult-onset DM1 has been extensively studied using the SF-36 and the INQoL, but current estimates are inconclusive, and little is known of the impact of the disease as measured using other instruments. Our data synthesis should help characterize the patient burden of DM1 and inform future studies of HRQoL in this indication. Electronic supplementary material The online version of this article (10.1007/s40271-019-00357-y) contains supplementary material, which is available to authorized users.

Contains fulltext : 207092.pdf (Publisher’s version ) (Closed access) In the era of patient-centered medicine, shared decision-making (SDM) - in which healthcare professionals and patients exchange information and preferences and jointly reach a decision - has emerged as the gold standard model for the provision of formal healthcare. Indeed, in many geographical settings, patients are frequently invited to participate in choices concerning the design and delivery of their medical management. From a clinical perspective, benefits of this type of patient involvement encompass, for example, enhanced treatment satisfaction, improved medical compliance, better health outcomes, and maintained or promoted quality of life. Yet, although the theory and enactment of SDM in healthcare are well-described in the literature [1-3], comparatively less attention has been devoted to contextualizing questions relating to if, when, and how to include patients in decisions within medical research. In this context, patient involvement would be expected to be potentially relevant for and applicable to a wide range of activities and processes, from the identification of research priorities and development of grant applications, to the design of patient information and consent procedures, formulation of interventions, identification and recruitment of study sample populations, feasibility of a clinical trial, identification, selection, and specification of endpoints and outcomes in clinical trials and observational studies, data collection and analysis, and dissemination of results. To this end, 45 clinicians, healthcare professionals, researchers, patients, caregivers, and representatives from regulatory authorities and pharmaceutical companies from 15 different countries met to discuss the level of involvement of patients with neuromuscular diseases, specifically in the following settings of medical research for neuromuscular diseases: i) registries and biobanks; ii) clinical trials; and iii) regulatory processes. In this report, we present summaries of the talks that were given during the workshop, as well as discussion outcomes from the three topic areas listed above.

Contains fulltext : 205507.pdf (Publisher’s version ) (Open Access) Atrophy and fatty infiltration are important causes of muscle weakness in inclusion body myositis (IBM). Muscle weakness can also be caused by reduced specific force; i.e. the amount of force generated per unit of residual muscle tissue. This study investigates in vivo specific force of the quadriceps and ex vivo specific force of single muscle fibers in patients with IBM. We included 8 participants with IBM and 12 healthy controls, who all underwent quantitative muscle testing, quantitative MRI of the quadriceps and paired muscle biopsies of the quadriceps and tibialis anterior. Single muscle fibers were isolated to measure muscle fiber specific force and contractile properties. Both in vivo quadriceps specific force and ex vivo muscle fiber specific force were reduced. Muscle fiber dysfunction was accompanied by reduced active stiffness, which reflects a decrease in the number of attached actin-myosin cross-bridges during activation. Myosin concentration was reduced in IBM fibers. Because reduced specific force contributes to muscle weakness in patients with IBM, therapeutic strategies that augment muscle fiber strength may provide benefit to patients with IBM.

ObjectiveTo assess the relation between age at onset and disease severity in facioscapulohumeral muscular dystrophy (FSHD).MethodsIn this prospective cross-sectional study, we matched adult patients with FSHD with an early disease onset with 2 sex-matched FSHD control groups with a classic onset; the first group was age matched, and the second group was disease duration matched. Genetic characteristics, muscle performance, respiratory functioning, hearing loss, vision loss, epilepsy, educational level, and work status were compared with the 2 control groups.ResultsTwenty-eight patients with early-onset FSHD were age (n = 28) or duration (n = 27) matched with classic-onset patients. Patients with early-onset FSHD had more severe muscle weakness (mean FSHD clinical score 11 vs 5 in the age-matched and 9 in the duration-matched group, p < 0.05) and a higher frequency of wheelchair dependency (57%, 0%, and 30%, respectively, p < 0.05). In addition, systemic features were more frequent in early-onset FSHD, most important, hearing loss, decreased respiratory function and spinal deformities. There was no difference in work status. Genetically, the shortest D4Z4 repeat arrays (2–3 units) were found exclusively in the early-onset group, and the largest repeat arrays (8–9 units) were found only in the classic-onset groups. De novo mutations were more frequent in early-onset patients (46% vs 4%).ConclusionsPatients with early-onset FSHD more often have severe muscle weakness and systemic features. The disease severity is greater than in patients with classic-onset FSHD who are matched for disease duration, suggesting that the progression is faster in early-onset patients.

Aims Evaluate safety, tolerability, pharmacokinetics (PK) and target engagement (TE) of losmapimod in blood and muscle in facioscapulohumeral dystrophy (FSHD). Methods This study included Part A: 10 healthy volunteers randomized to single oral doses of losmapimod (7.5 mg then 15 mg; n = 8) or placebo (both periods; n = 2); Part B: 15 FSHD subjects randomized to placebo (n = 3), or losmapimod 7.5 mg (n = 6) or 15 mg (n = 6); and Part C: FSHD subjects received open-label losmapimod 15 mg (n = 5) twice daily for 14 days. Biopsies were performed in FSHD subjects at baseline and Day 14 in magnetic resonance imaging-normal appearing (Part B) and affected muscle identified by abnormal short-tau inversion recovery sequence + (Part C). PK and TE, based on pHSP27:total HSP27, were assessed in muscle and sorbitol-stimulated blood. Results PK profiles were similar between healthy volunteers and FSHD subjects, with mean Cmax and AUC0-12 for 15 mg in FSHD subjects (Part B) of 85.0 ± 16.7 ng*h/mL and 410 ± 50.3 ng*h/mL, respectively. Part B and Part C PK results were similar, and 7.5 mg results were approximately dose proportional to 15 mg results. Dose-dependent concentrations in muscle (42.1 ± 10.5 ng/g [7.5 mg] to 97.2 ± 22.4 ng/g [15 mg]) were observed, with plasma-to-muscle ratio from ~0.67 to ~1 at estimated tmax of 3.5 hours postdose. TE was observed in blood and muscle. Adverse events (AEs) were mild and self-limited. Conclusion Losmapimod was well tolerated, with no serious AEs. Dose-dependent PK and TE were observed. This study supports advancing losmapimod into Phase 2 trials in FSHD. Clinical trial registration Clinical trial identifier ToetsingOnline: NL68539.056.18 Nederlands Trials Register NL8000.

Summary Background Treatment with one standard dose (2 g/kg) of intravenous immunoglobulin is insufficient in a proportion of patients with severe Guillain-Barre syndrome. Worldwide, around 25% of patients severely affected with the syndrome are given a second intravenous immunoglobulin dose (SID), although it has not been proven effective. We aimed to investigate whether a SID is effective in patients with Guillain-Barre syndrome with a predicted poor outcome. Methods In this randomised, double-blind, placebo-controlled trial (SID-GBS), we included patients (≥12 years) with Guillain-Barre syndrome admitted to one of 59 participating hospitals in the Netherlands. Patients were included on the first day of standard intravenous immunoglobulin treatment (2 g/kg over 5 days). Only patients with a poor prognosis (score of ≥6) according to the modified Erasmus Guillain-Barre syndrome Outcome Score were randomly assigned, via block randomisation stratified by centre, to SID (2 g/kg over 5 days) or to placebo, 7–9 days after inclusion. Patients, outcome adjudicators, monitors, and the steering committee were masked to treatment allocation. The primary outcome measure was the Guillain-Barre syndrome disability score 4 weeks after inclusion. All patients in whom allocated trial medication was started were included in the modified intention-to-treat analysis. This study is registered with the Netherlands Trial Register, NTR 2224/NL2107. Findings Between Feb 16, 2010, and June 5, 2018, 327 of 339 patients assessed for eligibility were included. 112 had a poor prognosis. Of those, 93 patients with a poor prognosis were included in the modified intention-to-treat analysis: 49 (53%) received SID and 44 (47%) received placebo. The adjusted common odds ratio for improvement on the Guillain-Barre syndrome disability score at 4 weeks was 1·4 (95% CI 0·6–3·3; p=0·45). Patients given SID had more serious adverse events (35% vs 16% in the first 30 days), including thromboembolic events, than those in the placebo group. Four patients died in the intervention group (13–24 weeks after randomisation). Interpretation Our study does not provide evidence that patients with Guillain-Barre syndrome with a poor prognosis benefit from a second intravenous immunoglobulin course; moreover, it entails a risk of serious adverse events. Therefore, a second intravenous immunoglobulin course should not be considered for treatment of Guillain-Barre syndrome because of a poor prognosis. The results indicate the need for treatment trials with other immune modulators in patients severely affected by Guillain-Barre syndrome. Funding Prinses Beatrix Spierfonds and Sanquin Plasma Products.

Background and ObjectivesData on the natural history of facioscapulohumeral dystrophy (FSHD) in childhood are limited and critical for improved patient care and clinical trial readiness. Our objective was to describe the disease course of FSHD in children.MethodsWe performed a nationwide, single-center, prospective cohort study of FSHD in childhood assessing muscle functioning, imaging, and quality of life over 2 years of follow-up.ResultsWe included 20 children with genetically confirmed FSHD who were 2 to 17 years of age. Overall, symptoms were slowly progressive, and the mean FSHD clinical score increased from 2.1 to 2.8 (p = 0.003). The rate of progression was highly variable. At baseline, 16 of 20 symptomatic children had facial weakness; after 2 years, facial weakness was observed in 19 of 20 children. Muscle strength did not change between baseline and follow-up. The most frequently and most severely affected muscles were the trapezius and deltoid. The functional exercise capacity, measured with the 6-minute walk test, improved. Systemic features were infrequent and nonprogressive. Weakness-associated complications such as lumbar hyperlordosis and dysarthria were common, and their prevalence increased during follow-up. Pain and fatigue were frequent complaints in children, and their prevalence also increased during follow-up. Muscle ultrasonography revealed a progressive increase in echogenicity.DiscussionFSHD in childhood has a slowly progressive but variable course over 2 years of follow-up. The most promising outcome measures to detect progression were the FSHD clinical score and muscle ultrasonography. Despite this disease progression, an improvement on functional capacity may still occur as the child grows up. Pain, fatigue, and a decreased quality of life were common symptoms and need to be addressed in the management of childhood FSHD. Our data can be used to counsel patients and as baseline measures for treatment trials in childhood FSHD.

Aims The aim of this study was to determine electrocardiographic (ECG) criteria predicting abnormal infrahissian conduction in patients with myotonic dystrophy type 1 (DM1), as these criteria could be used to identify the need for an electrophysiological study (EPS). Methods and results A retrospective multicentre study was conducted including DM1-affected individuals who underwent EPS between 2007 and 2018. For each individual, EPS indication, His-ventricle (HV) interval, resting ECG parameters prior to EPS, left ventricular ejection fraction (LVEF), neurological status, and DM1 DNA analysis results were collected. Electrocardiographic parameters of patients with a normal HV interval were compared with ECG parameters of patients with a prolonged HV interval. Logistic regression was performed to determine predictors for a prolonged HV interval of ≥70 ms on EPS and diagnostic accuracy of ECG parameters was ascertained. Among 100 DM1-affected individuals undergoing EPS, 47 had a prolonged HV interval. The sole presence of a PR interval >200 ms [odds ratio (OR) 8.45, confidence interval (CI) 2.64–27.04] or a QRS complex >120 ms (OR 9.91, CI 3.53–27.80) on ECG were independent predictors of a prolonged HV interval. The combination of both parameters had a positive predictive value of 78% for delayed infrahissian conduction on EPS. His-ventricle interval was independent of DM1 genetic mutation size, neuromuscular status, and LVEF. Conclusion The combination of a prolonged PR interval and widened QRS complex on ECG accurately predicts abnormal infrahissian conduction on EPS in patients with DM1. These ECG parameters could be used as a screening tool to determine the need for referral to a specialized multidisciplinary neuromuscular team with EPS capacity.

BackgroundThe European OPTIMISTIC clinical trial has demonstrated a significant, yet heterogenous effect of Cognitive Behavioural Therapy (CBT) for Myotonic Dystrophy type 1 (DM1) patients. One of its remaining aims was the assessment of efficacy and adequacy of clinical outcome measures, including the relatively novel primary trial outcome, the DM1-Activ-c questionnaire.ObjectivesAssessment of the relationship between the Rasch-built DM1-Activ-c questionnaire and 26 commonly used clinical outcome measurements. Identification of variables associated with CBT response in DM1 patients.MethodsRetrospective analysis of the to date largest clinical trial in DM1 (OPTIMISTIC), comprising of 255 genetically confirmed DM1 patients randomized to either standard care or CBT with optionally graded exercise therapy. Correlations of 27 different outcome measures were calculated at baseline (cross-sectional) and of their respective intervention induced changes (longitudinal). Bootstrap enhanced Elastic-Net (BeEN) regression was validated and implemented to select variables associated with CBT response.ResultsIn cross-sectional data, DM1-Activ-c correlated significantly with the majority of other outcome measures, including Six Minute Walk Test and Myotonic Dystrophy Health Index. Fewer and weaker significant longitudinal correlations were observed. Nine variables potentially associated with CBT response were identified, including measures of disease severity, executive cognitive functioning and perceived social support.ConclusionsThe DM1-Activ-c questionnaire appears to be a well suited cross-sectional instrument to assess a variety of clinically relevant dimensions in DM1. Yet, apathy and experienced social support measures were less well captured. CBT response was heterogenous, requiring careful selection of outcome measures for different disease aspects.

Contains fulltext : 232919.pdf (Publisher’s version ) (Closed access) Nemaline myopathy type 6 (NEM6), KBTBD13-related congenital myopathy is caused by mutated KBTBD13 protein that interacts improperly with thin filaments/actin, provoking impaired muscle-relaxation kinetics. We describe muscle morphology in 18 Dutch NEM6 patients and correlate it with clinical phenotype and pathophysiological mechanisms. Rods were found in in 85% of biopsies by light microscopy, and 89% by electron microscopy. A peculiar ring disposition of rods resulting in ring-rods fiber was observed. Cores were found in 79% of NEM6 biopsies by light microscopy, and 83% by electron microscopy. Electron microscopy also disclosed granulofilamentous protein material in 9 biopsies. Fiber type 1 predominance and prominent nuclear internalization were found. Rods were immunoreactive for α-actinin and myotilin. Areas surrounding the rods showed titin overexpression suggesting derangement of the surrounding sarcomeres. NEM6 myopathology hallmarks are prominent cores, rods including ring-rods fibers, nuclear clumps, and granulofilamentous protein material. This material might represent the histopathologic epiphenomenon of altered interaction between mutated KBTBD13 protein and thin filaments. We claim to classify KBTBD13-related congenital myopathy as rod-core myopathy.

Contains fulltext : 229514.pdf (Publisher’s version ) (Open Access) BACKGROUND: Specific force, that is the amount of force generated per unit of muscle tissue, is reduced in patients with facioscapulohumeral muscular dystrophy (FSHD). The causes of reduced specific force and its relation with FSHD disease severity are unknown. METHODS: Quantitative muscle magnetic resonance imaging (MRI), measurement of voluntary maximum force generation and quadriceps force-frequency relationship, and vastus lateralis muscle biopsies were performed in 12 genetically confirmed patients with FSHD and 12 controls. RESULTS: Specific force was reduced by ~33% in all FSHD patients independent of disease severity. Quadriceps force-frequency relationship shifted to the right in severe FSHD compared to controls. Fiber type distribution in vastus lateralis muscle biopsies did not differ between groups. CONCLUSIONS: Reduced quadriceps specific force is present in all FSHD patients regardless of disease severity or fatty infiltration. Early myopathic changes, including fibrosis, and non-muscle factors, such as physical fatigue and musculoskeletal pain, may contribute to reduced specific force.

Contains fulltext : 235675.pdf (Publisher’s version ) (Open Access) Patient-relevant outcome measures for facioscapulohumeral muscular dystrophy (FSHD) are needed. The motor function measure (MFM) is an ordinal-based outcome measure for neuromuscular disorders, but its suitability to measure FSHD patients is questionable. Here, we performed Rasch analyses on MFM data from 194 FSHD patients to assess clinimetric properties in this patient group. Both the total scale and its three domains were analyzed (D1: standing position and transfers; D2: axial and proximal motor function; D3: distal motor function). Fit to the Rasch model, sample-item targeting, individual item fit, threshold ordering, sex- and age-based differential item functioning, response dependency and unidimensionality were assessed. Rasch analysis revealed multiple limitations of the MFM for FSHD, the most important being a large ceiling effect and suboptimal sample-item targeting, which were most pronounced for domains D2 and D3. There were disordered thresholds for most items, often resulting in items functioning in a dichotomous fashion. It was not possible to remodel the MFM into a Rasch-built interval scale. Remodeling of domain D1 into an interval scale with adequate fit statistics was achieved, but sample-item targeting remained suboptimal. Therefore, the MFM should be used with caution in FSHD patients, as it is not optimally suited to measure functional abilities in this patient group.

ObjectiveTo obtain insight into experiences of patients with a neuromuscular disease and chronic fatigue and their healthcare professionals regarding content and delivery of a multidisciplinary outpatient self-management group programme to improve social participation. This will inform future implementation.DesignA mixed method study alongside a randomised controlled trial.SettingUniversity hospital, rehabilitation centre and community health centre.Participants29 patients with a neuromuscular disease and chronic fatigue and 13 healthcare professionals participated in this mixed methods study.InterventionMultidisciplinary group programme, called Energetic, consisted of a 4 months intervention with weekly meetings and covered four modules: (1) individually tailored aerobic exercise training; (2) education about aerobic exercise; (3) self-management training in applying energy conservation strategies and (4) implementation and relapse prevention in daily life.Main measuresQuantitative data were collected by a questionnaire measuring patients’ (n=25, all completed the programme) satisfaction with the perceived results, content and delivery of the programme. Qualitative data were collected by individual and focus group interviews to gain insight in the experiences of patients (n=18), next of kin (n=2) and healthcare professionals (n=13) with facilitators and barriers to programme implementation.ResultsPatients were satisfied with the number and length of the sessions, the different modules and the therapists. Analysis of the interviews led to five themes: (1) the combination of modules makes a complete picture, (2) the programme is physically and mentally intensive, (3) the group setting is valuable, (4) small variations in delivery occur in different settings, (5) therapists are coaches. Suggestions for programme improvement include a combination of face to face and e-health, enhancement of therapists’ skills in guiding group interventions and inclusion of more booster sessions to evaluate and maintain self-management competencies.ConclusionsThe Energetic programme could be implemented in different healthcare settings and group settings, and a combination of modules proved to be a facilitator for improving self-management.Trial registration numberNCT02208687.

Contains fulltext : 238097.pdf (Publisher’s version ) (Open Access) INTRODUCTION: Malignant hyperthermia (MH) and exertional rhabdomyolysis (ERM) have long been considered episodic phenotypes occurring in response to external triggers in otherwise healthy individuals with variants in RYR1. However, recent studies have demonstrated a clinical and histopathological continuum between patients with RYR1-related congenital myopathies and those with ERM or MH susceptibility. Furthermore, animal studies have shown non-neuromuscular features such as a mild bleeding disorder and an immunological gain-of-function associated with MH/ERM related RYR1 variants raising important questions for further research. Awareness of the neuromuscular disease spectrum and potential multisystem involvement in RYR1-related MH and ERM is essential to optimize the diagnostic work-up, improve counselling and and future treatment strategies for patients affected by these conditions. This study will examine in detail the nature and severity of continuous disease manifestations and their effect on daily life in patients with RYR1-related MH and ERM. METHODS: The study protocol consists of four parts; an online questionnaire study, a clinical observational study, muscle imaging, and specific immunological studies. Patients with RYR1-related MH susceptibility and ERM will be included. The imaging, immunological and clinical studies will have a cross-sectional design, while the questionnaire study will be performed three times during a year to assess disease impact, daily living activities, fatigue and pain. The imaging study consists of muscle ultrasound and whole-body magnetic resonance imaging studies. For the immunological studies, peripheral mononuclear blood cells will be isolated for in vitro stimulation with toll-like receptor ligands, to examine the role of the immune system in the pathophysiology of RYR1-related MH and ERM. DISCUSSION: This study will increase knowledge of the full spectrum of neuromuscular and multisystem features of RYR1-related MH and ERM and will establish a well-characterized baseline cohort for future studies on RYR1-related disorders. The results of this study are expected to improve recognition of RYR1-related symptoms, counselling and a more personalized approach to patients affected by these conditions. Furthermore, results will create new insights in the role of the immune system in the pathophysiology of MH and ERM. TRIAL REGISTRATION: This study was pre-registered at ClinicalTrials.gov (ID: NCT04610619).

ObjectiveTo assess the association between variant repeat (VR) interruptions in patients with myotonic dystrophy type 1 (DM1) and clinical symptoms and outcome measures after cognitive behavioral therapy (CBT) intervention.MethodsAdult patients with DM1 were recruited within the OPTIMISTIC trial (NCT02118779). Disease-related history, current clinical symptoms and comorbidities, functional assessments, and disease- and health-related questionnaires were obtained at baseline and after 5 and 10 months. After genetic analysis, we assessed the association between the presence of VR interruptions and clinical symptoms' long-term outcomes and compared the effects of CBT in patients with and without VR interruptions. Core trial outcome measures analyzed were: 6-minute walking test, DM1-Activ-C, Checklist Individual Strength Fatigue Score, Myotonic Dystrophy Health Index, McGill-Pain questionnaire, and Beck Depression inventory—fast screen. Blood samples for DNA testing were obtained at the baseline visit for determining CTG length and detection of VR interruptions.ResultsVR interruptions were detectable in 21/250 patients (8.4%)—12 were assigned to the standard-of-care group (control group) and 9 to the CBT group. Patients with VR interruptions were significantly older when the first medical problem occurred and had a significantly shorter disease duration at baseline. We found a tendency toward a milder disease severity in patients with VR interruptions, especially in ventilation status, mobility, and cardiac symptoms. Changes in clinical outcome measures after CBT were not associated with the presence of VR interruptions.ConclusionsThe presence of VR interruptions is associated with a later onset of the disease and a milder phenotype. However, based on the OPTIMISTIC trial data, the presence of VR interruptions was not associated with significant changes on outcome measures after CBT intervention.Trial Registration InformationClinicalTrials.govNCT02118779.

Item does not contain fulltext Background Patients with myotonic dystrophy type 1 (DM1) increased their physical activity and exercise capacity following a behavioral intervention. However, it is unknown what is altered in muscles of patients with DM1 as a result of this intervention. The increased exercise capacity suggests that decelerated fat infiltration or increased muscle cross-sectional area (CSA) could be involved. Purpose To assess the effect of this activity-stimulating behavioral intervention on the lower extremity muscles of patients with DM1 with longitudinal quantitative muscle MRI. Materials and Methods In this prospective trial, participants with DM1 were randomized to a behavioral intervention (n = 14) or continued regular care (standard care; n = 13); no age-matched pairing was performed. Participants underwent MRI of the lower extremities at baseline and 10-month follow-up (January 2015 to March 2016). Fat fraction (FF), muscle CSA, and muscle water T2 (T2water) as markers for fat infiltration, muscle mass, and alteration in tissue water distribution (edema), respectively, were assessed with a chemical shift-encoded Dixon sequence and multiecho spin-echo sequence. Longitudinal within-group and between-group changes were assessed with paired-samples t tests and multivariable regression models. Results A total of 27 patients with DM1 (15 men) were evaluated. Patient age was comparable between groups (intervention, 45 years +/- 13 [standard deviation]; standard care, 5 years +/- 12; P = .96). Muscle CSA increased 5.9 cm(2) +/- 7.8 in the intervention group during the 10-month follow-up (P = .03) and decreased 3.6 cm(2) +/- 7.2 in the standard care group (P = .13). After 10 months, the mean difference between the groups was 9.5 cm(2) (P = .01). This effect was stronger in muscles with baseline FF below the mean +/- standard deviation of unaffected volunteers (-0.4 cm(2) +/- 0.15; P < .001). FF increased 0.9% +/- 1.0 in the intervention group (P = .02) and 1.2% +/- 1.2 for standard care (P = .02), with no between-group difference (P = .56). T2water did not change significantly in either group (intervention, P = .08; standard care, P = .88). Conclusion A behavioral intervention targeting physical activity increased lower extremity muscle cross-sectional area in patients with myotonic dystrophy, preferentially in healthy-appearing muscle. (c) RSNA, 2020 Online supplemental material is available for this article.

ObjectiveTo investigate single muscle fiber contractile performance in muscle biopsies from patients with facioscapulohumeral muscular dystrophy (FSHD), one of the most common hereditary muscle disorders.MethodsWe collected 50 muscle biopsies (26 vastus lateralis, 24 tibialis anterior) from 14 patients with genetically confirmed FSHD and 12 healthy controls. Single muscle fibers (n = 547) were isolated for contractile measurements. Titin content and titin phosphorylation were examined in vastus lateralis muscle biopsies.ResultsSingle muscle fiber specific force was intact at saturating and physiologic calcium concentrations in all FSHD biopsies, with (FSHDFAT) and without (FSHDNORMAL) fatty infiltration, compared to healthy controls. Myofilament calcium sensitivity of force is increased in single muscle fibers obtained from FSHD muscle biopsies with increased fatty infiltration, but not in FSHD muscle biopsies without fatty infiltration (pCa50: 5.77–5.80 in healthy controls, 5.74–5.83 in FSHDNORMAL, and 5.86–5.90 in FSHDFAT single muscle fibers). Cross-bridge cycling kinetics at saturating calcium concentrations and myofilament cooperativity did not differ from healthy controls. Development of single muscle fiber passive tension was changed in all FSHD vastus lateralis and in FSHDFAT tibialis anterior, resulting in increased fiber stiffness. Titin content was increased in FSHD vastus lateralis biopsies; however, titin phosphorylation did not differ from healthy controls.ConclusionMuscle weakness in patients with FSHD is not caused by reduced specific force of individual muscle fibers, even in severely affected tissue with marked fatty infiltration of muscle tissue.

Contains fulltext : 229739.pdf (Publisher’s version ) (Closed access) The nondystrophic myotonias are rare muscle hyperexcitability disorders caused by gain-of-function mutations in the SCN4A gene or loss-of-function mutations in the CLCN1 gene. Clinically, they are characterized by myotonia, defined as delayed muscle relaxation after voluntary contraction, which leads to symptoms of muscle stiffness, pain, fatigue, and weakness. Diagnosis is based on history and examination findings, the presence of electrical myotonia on electromyography, and genetic confirmation. In the absence of genetic confirmation, the diagnosis is supported by detailed electrophysiological testing, exclusion of other related disorders, and analysis of a variant of uncertain significance if present. Symptomatic treatment with a sodium channel blocker, such as mexiletine, is usually the first step in management, as well as educating patients about potential anesthetic complications.

Objective. To determine psychometric properties, a cut-off score for severe fatigue and normative data for the 4-item Short Fatigue Questionnaire (SFQ) derived from the multi-dimensional fatigue questionnaire Checklist Individual Strength (CIS). Methods. Data of previous studies investigating the prevalence of fatigue in ten chronic conditions (n = 2985) and the general population (n = 2288) was used to determine the internal consistency (Cronbach's alpha) of the SFQ, its relation with other fatigue measures (EORTC QLQ-30 fatigue subscale and digital fatigue diary), a cut-off score for severe fatigue (ROC analysis) and to examine whether the four SFQ items truly measure the same construct. Norms were calculated for ten patient groups and the Dutch general population. Results. Cronbach's alpha of the SFQ were excellent in almost all groups. Pearson's correlations between the SFQ and the EORTC-QLQ-C30 fatigue subscale and a fatigue diary were respectively 0.76 and 0.68. ROC analysis showed an area under the curve of 0.982 (95% CI: 0.979–0.985) and cut-off score of 18 was suggested which showed a good sensitivity (0.984) and specificity (0.826) as well as excellent values for the positive and negative prediction values within all groups using the CIS as golden standard. Factor analysis showed a one factor solution (Eigenvalue: 3.095) with factor loadings of all items on the factor being greater than 0.87. Conclusion. The SFQ is an easy to use, reliable and valid instrument to screen for severe fatigue in clinical routine and research.

ObjectiveWith drug trials starting soon, responsive, relevant, and patient-friendly biomarkers are highly needed in facioscapulohumeral dystrophy (FSHD). Our objective was to assess muscle ultrasound (MUS) as an imaging biomarker in patients with FSHD.MethodsOne-year observational, longitudinal study of both quantitative and qualitative MUS changes in FSHD.ResultsTwenty-two patients with symptomatic FSHD1 underwent a clinical examination and MUS at baseline and after 1-year follow-up. The qualitative MUS sum score increased from 18.59 to 20.32 (p = 0.005) and the quantitative MUS sum z scores increased from 19.96 to 24.72 (p = 0.003). The clinical scores did not change over 1 year. Muscle echogenicity correlated with the FSHD clinical score at baseline (r = 0.61, p = 0.002).ConclusionsMUS shows a significant increase in echogenicity in FSHD over 1 year. Both quantitative and qualitative MUS correlate cross-sectionally with clinical severity in FSHD and identify structural muscle changes in a clinically stable group of patients. MUS thus seems a potentially responsive biomarker that could be standardized between centers. We recommend its use in therapeutic trials.Classification of evidenceThis study provides Class I evidence that in patents with FSHD1, MUS findings correlate with baseline FSHD clinical scores.

Contains fulltext : 217232.pdf (Publisher’s version ) (Open Access) Neuralgic amyotrophy is a common peripheral nerve disorder caused by acute autoimmune inflammation of the brachial plexus. Subsequent weakness of the stabilizing shoulder muscles leads to compensatory strategies and abnormal motor control of the shoulder. Despite recovery of peripheral nerves and muscle strength over time, motor dysfunction often persists. Suboptimal motor recovery has been linked to maladaptive changes in the central motor system in several nervous system disorders. We therefore hypothesized that neuralgic amyotrophy patients with persistent motor dysfunction may have altered cerebral sensorimotor representations of the affected upper limb. To test this hypothesis, 21 neuralgic amyotrophy patients (mean age 45 ± 12 years, 5 female) with persistent lateralized symptoms in the right upper limb and 20 age- and sex-matched healthy controls, all right-handed, performed a hand laterality judgement task in a cross-sectional comparison. Previous evidence has shown that to solve this task, subjects rely on sensorimotor representations of their own upper limb, using a first-person imagery perspective without actual motor execution. This enabled us to investigate altered central sensorimotor representations while controlling for altered motor output and altered somatosensory afference. We found that neuralgic amyotrophy patients were specifically less accurate for laterality judgments of their affected right limb, as compared to healthy controls. There were no significant group differences in reaction times. Both groups used a first-person imagery perspective, as evidenced by changes in reaction times as a function of participants’ own arm posture. We conclude that cerebral sensorimotor representations of the affected upper limb are altered in neuralgic amyotrophy patients. This suggests that maladaptive central neuroplasticity may occur in response to peripheral nerve damage, thereby contributing to motor dysfunction. Therapies focused on altering cerebral sensorimotor representations may help to treat peripheral nerve disorders such as neuralgic amyotrophy. 11 p.

Contains fulltext : 220138.pdf (Publisher’s version ) (Closed access) Objective: In the autosomal dominant, multisystem, chronic progressive disease myotonic dystrophy type 1 (DM1), cognitive deficits may originate from disrupted functional brain networks. We aimed to use network analysis of resting-state electro-encephalography (EEG) recordings of patients with DM1 and matched unaffected controls to investigate changes in network organization in large-scale functional brain networks and correlations with cognitive deficits. Methods: In this cross-sectional study, 28 adult patients with genetically confirmed DM1 and 26 age-, sex- and education-matched unaffected controls underwent resting-state EEG and neuropsychological assessment. We calculated the Phase Lag Index (PLI) to determine EEG frequency-dependent functional connectivity between brain regions. Functional brain networks were characterized by applying concepts from graph theory and compared between-groups. Network topology was evaluated using the minimum spanning tree (MST). We evaluated correlations between network metrics and neuropsychological tests that showed statistically significant between-group differences. Results: Functional connectivity estimated as whole-brain median PLI for DM1 patients versus healthy controls was higher in theta band (0.141 [0.050] versus 0.125 [0.018], p = 0.029), and lower in the upper alpha band (0.154 [0.048] versus 0.182 [0.073], p = 0.038), respectively. Functional MST-constructed networks in DM1 patients were significantly dissimilar from healthy controls in the delta, (p = 0.009); theta, (p = 0.009); lower alpha, (p = 0.036); and upper alpha, (p = 0.008) bands. In evaluation of local MST network measures, trends toward networks with higher global integration in the theta band and lower global integration in the upper alpha band were observed. Compared to unaffected controls, DM1 patients performed worse on tests of attention, motor function, executive function and visuospatial memory. Visuospatial memory correlated with the global median PLI in the upper alpha band; the Stroop interference test correlated with betweenness centrality in this band. Conclusion: This study supports the hypothesis that brain changes in DM1 give rise to disrupted functional network organization, as modelled with EEG-based networks. Further study may help unravel the relations with clinical brain-related DM1 symptoms. Significance: EEG network analysis has potential to help understand brain related DM1 phenotypes. Funding This work was supported by the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 305697 (OPTIMISTIC) and the Marigold Foundation. 10 p.

To determine how much of the clinical variability in facioscapulohumeral muscular dystrophy type 1 (FSHD1) can be explained by the D4Z4 repeat array size, D4Z4 methylation and familial factors, we included 152 carriers of an FSHD1 allele (23 single cases, 129 familial cases from 37 families) and performed state-of-the-art genetic testing, extensive clinical evaluation and quantitative muscle MRI. Familial factors accounted for 50% of the variance in disease severity (FSHD clinical score). The explained variance by the D4Z4 repeat array size for disease severity was limited (approximately 10%), and varied per body region (facial muscles, upper and lower extremities approximately 30%, 15% and 3%, respectively). Unaffected gene carriers had longer repeat array sizes compared to symptomatic individuals (7.3 vs 6.0 units, P = 0.000) and slightly higher Delta1 methylation levels (D4Z4 methylation corrected for repeat size, 0.96 vs -2.46, P = 0.048). The D4Z4 repeat array size and D4Z4 methylation contribute to variability in disease severity and penetrance, but other disease modifying factors must be involved as well. The larger effect of the D4Z4 repeat array on facial muscle involvement suggests that these muscles are more sensitive to the influence of the FSHD1 locus itself, whereas leg muscle involvement seems highly dependent on modifying factors.

Pain is a common but often ignored symptom in patients with myotonic dystrophy type 2 (DM2). In this explorative study, we assessed qualitative and quantitative aspects of pain in DM2 using 4 questionnaires and quantitative sensory testing. A disease control group (fibromyalgia [FMS]) as well as healthy controls were used to compare the results, because pain in DM2 shows many clinical similarities to pain in FMS. Thirty-four patients with genetically confirmed DM2 (71% female, mean age 54 years), 28 patients with FMS, and 33 healthy controls were included, age- as well as sex-matched. Pain prevalence was 65% in DM2, 100% in FMS (P

Item does not contain fulltext INTRODUCTION: Electrical impedance myography (EIM) is a noninvasive technique for measuring muscle composition and a potential physiological biomarker for facioscapulohumeral muscular dystrophy (FSHD). METHODS: Thirty-two participants with genetically confirmed and clinically affected FSHD underwent EIM in 7 muscles bilaterally. Correlations between EIM and baseline clinical measures were used to select EIM variables of interest in FSHD, and EIM and clinical measures were followed for 1 year. RESULTS: There were no significant changes in the EIM variables. Although 50-kHZ reactance correlated the strongest with clinical measures at baseline, the 50-211-kHZ phase ratio demonstrated lower within-subject 12-month variability, potentially offering sample size savings for FSHD clinical trial planning. DISCUSSION: EIM did not identify significant disease progression over 12 months. It is currently unclear whether this is because of limitations of the technology or the slow rate of disease progression in this cohort of FSHD patients over this period of time. Muscle Nerve 58: 213-218, 2018.

Aim: To assess the long-term natural course of early-onset facioscapulohumeral dystrophy (FSHD), which is important for patient management and trial-readiness, and is currently lacking.Methods: We had the unique opportunity to evaluate 10 patients with early-onset FSHD after 22 years follow-up. Patients underwent a semi-structured interview, physical examination and additional genotyping.Results: Nine initial study participants (median age 37 years) were included, one patient died shortly after first publication. At first examination, one patient was wheelchair dependent, one patient walked aided, and eight patients walked unaided. After 22 years, four patients were wheelchair dependent, three walked aided, and two walked unaided. Systemic features, including hearing loss (56%), intellectual disability (44%), and a decreased respiratory function (56%), were frequent. Patients participated socially and economically with most patients living in a regular house (n = 6) and/or having a paid job (n = 4).Discussion: Patients with early-onset FSHD generally had a severe phenotype compared to classical onset FSHD. However, after 22 years of follow up they showed a wide variation in severity and, despite these physical limitations, participated socially and economically. These observations are important for patient management and should be taken into account in clinical trials. (C) 2018 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

ObjectivesTo characterise the pattern and spectrum of involvement on muscle MRI in a large cohort of patients with sarcoglycanopathies, which are limb-girdle muscular dystrophies (LGMD2C–2F) caused by mutations in one of the four genes coding for muscle sarcoglycans.MethodsLower limb MRI scans of patients with LGMD2C–2F, ranging from severe childhood variants to milder adult-onset forms, were collected in 17 neuromuscular referral centres in Europe and USA. Muscle involvement was evaluated semiquantitatively on T1-weighted images according to a visual score, and the global pattern was assessed as well.ResultsScans from 69 patients were examined (38 LGMD2D, 18 LGMD2C, 12 LGMD2E and 1 LGMD2F). A common pattern of involvement was found in all the analysed scans irrespective of the mutated gene. The most and earliest affected muscles were the thigh adductors, glutei and posterior thigh groups, while lower leg muscles were relatively spared even in advanced disease. A proximodistal gradient of involvement of vasti muscles was a consistent finding in these patients, including the most severe ones.ConclusionsMuscle involvement on MRI is consistent in patients with LGMD2C–F and can be helpful in distinguishing sarcoglycanopathies from other LGMDs or dystrophinopathies, which represent the most common differential diagnoses. Our data provide evidence about selective susceptibility or resistance to degeneration of specific muscles when one of the sarcoglycans is deficient, as well as preliminary information about progressive involvement of the different muscles over time.

Item does not contain fulltext PURPOSE: To examine the effect of mindfulness-based stress reduction training (MBSR) on the mental health of medical students during clinical clerkships. METHOD: Between February 2011 and May 2014, the authors conducted a cluster-randomized controlled trial of clerkships as usual (CAU) and clerkships with additional MBSR in medical students during their first year of clinical clerkships at a Dutch university medical center. MBSR consisted of eight weekly two-hour sessions, comprising didactic teaching, meditation exercises, and group dialogues. Students completed online assessments at baseline and after 3, 7, 12, 15, and 20 months. Outcome measures were psychological distress, positive mental health, life satisfaction, physician empathy, mindfulness skills, and dysfunctional cognitions as measured by validated tools. RESULTS: Of 232 eligible students, 167 students (72%) participated and were randomized by clerkship group into MBSR (n = 83) or CAU (n = 84). The MBSR group reported a small reduction of psychological distress (P = .03, Cohen's d = 0.20) and dysfunctional cognitions (P = .05, Cohen's d = 0.18) and a moderate increase of positive mental health (P = .002, Cohen's d = 0.44), life satisfaction (P = .01, Cohen's d = 0.51), and mindfulness skills (P = .05, Cohen's d = 0.35) compared with CAU during the 20-month follow-up. The authors detected no significant effect on physician empathy (P = .18, Cohen's d = 0.27). CONCLUSIONS: MBSR appeared feasible and acceptable to medical clerkship students and resulted in a small to moderate improvement of mental health compared with CAU over the 20-month follow-up.

Objective:To add quantitative muscle MRI to the clinical trial toolbox for facioscapulohumeral muscular dystrophy (FSHD) by correlating it to clinical outcome measures in a large cohort of genetically and clinically well-characterized patients with FSHD comprising the entire clinical spectrum.Methods:Quantitative MRI scans of leg muscles of 140 patients with FSHD1 and FSHD2 were assessed for fatty infiltration and TIRM hyperintensities and were correlated to multiple clinical outcome measures.Results:The mean fat fraction of the total leg musculature correlated highly with the motor function measure, FSHD clinical score, Ricci score, and 6-minute walking test (correlation coefficients −0.845, 0.835, 0.791, −0.701, respectively). Fat fraction per muscle group correlated well with corresponding muscle strength (correlation coefficients up to −0.82). The hamstring muscles, adductor muscles, rectus femoris, and gastrocnemius medialis were affected most frequently, also in early stage disease and in patients without leg muscle weakness. Muscle involvement was asymmetric in 20% of all muscle pairs and fatty infiltration within muscles showed a decrease from distal to proximal of 3.9%. TIRM hyperintense areas, suggesting inflammation, were found in 3.5% of all muscles, with and without fatty infiltration.Conclusions:We show a strong correlation between quantitative muscle MRI and clinical outcome measures. Muscle MRI is able to detect muscle pathology before clinical involvement of the leg muscles. This indicates that quantitative leg muscle MRI is a promising biomarker that captures disease severity and motor functioning and can thus be included in the FSHD trial toolbox.

Ophthalmological abnormalities in facioscapulohumeral dystrophy may lead to treatable vision loss, facilitate diagnostics, could help unravelling the pathophysiology and serve as biomarkers. In this study, we provide a detailed description of the ophthalmological findings in a well-defined cohort of patients with facioscapulohumeral dystrophy using state of the art retina imaging techniques. Thirty-three genetically confirmed patients (aged 7–80 years) and 24 unrelated healthy controls (aged 6–68 years) underwent clinical ophthalmological examination, fundus photography, optical coherence tomography/angiography, genotyping and neurological examination. All patients had normal corrected visual acuity and normal intraocular pressure. In 27 of the 33 patients, weakness of the orbicularis oculi was observed. Central retinal pathology, only seen in patients and not in healthy controls, included twisting (tortuosity) of the retinal arteries in 25 of the 33 patients and retinal pigment epithelium defects in 4 of the 33 patients. Asymmetrical foveal hypoplasia was present in three patients, and exudative abnormalities were observed in one patient. There was a correlation between the severity of retinal tortuosity and the D4Z4 repeat array size (R2 = 0.44, P, Ophthalmological abnormalities are an important aspect of facioscapulohumeral dystrophy. We show that retinal abnormalities such as arterial tortuosity are frequent and mostly subclinical in facioscapulohumeral dystrophy. The severity of retinal tortuosity correlated with the genetic defect, thereby providing clinical evidence for an underlying genetic linkage between the retina and facioscapulohumeral dystrophy., Graphical Abstract Graphical Abstract

Background: Home mechanical ventilation (HMV) is a questionable treatment in patients with myotonic dystrophy type 1 (DM1), due to a presumed poor adherence, minor symptomatic improvement and uncertainty regarding a survival benefit. We aimed to investigate indications, adherence and survival related to HMV in a relatively large cohort of DM1 patients. Methods: In this retrospective study we evaluated 234 DM1 patients who visited the HMV centre of the University Medical Centre Utrecht between 1996 and 2018. We collected results of pulmonary function test, indications for and compliance with HMV, and survival data. To analyse the effect of HMV on survival a cox regression analysis was used. Results: In total 234 patients were analysed of whom 118 started HMV. In 13 patients ventilation was started in an acute setting. Other patients started electively because of daytime (n=72) or nocturnal hypercapnia (n=33). Adequate adherence (≥ 4 hours per night) was found in 99 patients (84%). In 34 patients (28%) ventilatory support was stopped prematurely due to as patients’ expectations were not reached (n=22), or due to intolerance in eight patients, or other reasons (n=4). HMV did not improve survival, even not in patients with hypercapnia at daytime (p=0.64). The analyses was corrected for age and vital capacity. Conclusion: Home mechanical ventilation in DM1 patients is tolerated well in most patients with a reliable adherence. Survival was not improved by mechanical ventilation, even not in patients with daytime hypercapnia. Further research is needed to identify whether a subgroup of DM1 patients exists who benefit from HMV.

Background Neuralgic amyotrophy (NA) is a distinct peripheral neurological disorder of the brachial plexus with a yearly incidence of 1/1000, which is characterised by acute severe upper extremity pain. Weakness of the stabilising shoulder muscles in the acute phase leads to compensatory strategies and abnormal motor control of the shoulder - scapular dyskinesia. Despite peripheral nerve recovery, scapular dyskinesia often persists, leading to debilitating residual complaints including pain and fatigue. Evidence suggests that persistent scapular dyskinesia in NA may result from maladaptive cerebral neuroplasticity, altering motor planning. Currently there is no proven effective causative treatment for the residual symptoms in NA. Moreover, the role of cerebral mechanisms in persistent scapular dyskinesia remains unclear. Methods NA-CONTROL is a single-centre, randomised controlled trial comparing specific rehabilitation to usual care in NA. The rehabilitation programme combines relearning of motor control, targeting cerebral mechanisms, with self-management strategies. Fifty patients will be included. Patients are recruited through the Radboud university medical center Nijmegen, the Netherlands. Patients with a (suspected) diagnosis of NA, with lateralized symptoms and scapular dyskinesia in the right upper extremity, who are 18 years or older and not in the acute phase can be included. The primary outcome is the Shoulder Rating Questionnaire score, which measures functional capability of the upper extremity. Secondary clinical outcomes include measures of pain, fatigue, participation, reachable workspace, muscle strength and quality of life. In addition, motor planning is assessed with first-person motor imagery and functional magnetic resonance imaging. In a sub-study the patients are compared to 25 healthy participants, to determine the involvement of cerebral mechanisms. This will enable interpretation of cerebral changes associated with the rehabilitation programme and functional impairments in NA. Discussion NA-CONTROL is the first randomised trial to investigate the effect of specific rehabilitation on residual complaints in NA. It also is the first study into the cerebral mechanisms that might underlie persistent scapular dyskinesia in NA. It thus may aid the further development of mechanism-based interventions for disturbed motor control in NA and in other peripheral neurological disorders. Trial registration ClinicalTrials.gov, NCT03441347. Registered on 20 February 2018. Electronic supplementary material The online version of this article (10.1186/s13063-019-3556-4) contains supplementary material, which is available to authorized users.

ObjectiveTo determine the value of quantitative MRI in providing imaging biomarkers for disease in 20 different upper and lower leg muscles of patients with myotonic dystrophy type 1 (DM1).MethodsWe acquired images covering these muscles in 33 genetically and clinically well-characterized patients with DM1 and 10 unaffected controls. MRIs were recorded with a Dixon method to determine muscle fat fraction, muscle volume, and contractile muscle volume, and a multi-echo spin-echo sequence was used to determine T2 water relaxation time (T2water), reflecting putative edema.ResultsMuscles in patients with DM1 had higher fat fractions than muscles of controls (15.6 ± 11.1% vs 3.7 ± 1.5%). In addition, patients had smaller muscle volumes (902 ± 232 vs 1,097 ± 251 cm3), smaller contractile muscle volumes (779 ± 247 vs 1,054 ± 246 cm3), and increased T2water (33.4 ± 1.0 vs 31.9 ± 0.6 milliseconds), indicating atrophy and edema, respectively. Lower leg muscles were affected most frequently, especially the gastrocnemius medialis and soleus. Distribution of fat content per muscle indicated gradual fat infiltration in DM1. Between-patient variation in fat fraction was explained by age (≈45%), and another ≈14% was explained by estimated progenitor CTG repeat length (r2 = 0.485) and somatic instability (r2 = 0.590). Fat fraction correlated with the 6-minute walk test (r = −0.553) and muscular impairment rating scale (r = 0.537) and revealed subclinical muscle involvement.ConclusionThis cross-sectional quantitative MRI study of 20 different lower extremity muscles in patients with DM1 revealed abnormal values for muscle fat fraction, volume, and T2water, which therefore may serve as objective biomarkers to assess disease state of skeletal muscles in these patients.ClinicalTrials.gov identifierNCT02118779.