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Background: SELENON-related myopathy (SELENON-RM) is a rare congenital myopathy characterized by slowly progressive axial muscle weakness, rigidity of the spine, scoliosis, and respiratory insufficiency. Laminin-a2-related muscular dystrophy (LAMA2-MD) has a similar clinical phenotype, which ranges from severe, early-onset congenital muscular dystrophy type 1A (MDC1A) to milder forms presenting as childhood- or adult-onset limb-girdle type muscular dystrophy. The first 1.5-year natural history follow-up showed that 90% of the patients had low bone quality, respiratory impairments were found in all SELENON-RM and most of the LAMA2-MD patients, and many had cardiac risk factors. However, further extensive knowledge on long-term natural history data, and clinical and functional outcome measures is needed to reach trial readiness. Therefore, we extended the natural history study with 3- and 5-year follow-up visits (Extended LAST STRONG)., Methods: The Extended LAST STRONG is a long-term natural history study in Dutch-speaking patients of all ages diagnosed with genetically confirmed SELENON-RM or LAMA2-MD, starting in September 2023. Patients visit our hospital twice over a period of 2 years to complete a 5-year follow up from the initial LAST-STRONG study. At both visits, they undergo standardized neurological examination, hand-held dynamometry (age ≥ 5 years), functional measurements, muscle ultrasound, respiratory assessments (spirometry, maximal inspiratory and expiratory pressure, sniff nasal inspiratory pressure; age ≥ 5 years), Dual-energy X-ray absorptiometry (DEXA-)scan (age ≥ 2 years), X-ray of the left hand (age ≤ 17 years), lower extremity MRI (age ≥ 10 years), accelerometry for 8 days (age ≥ 2 years), and questionnaires (patient report and/or parent proxy; age ≥ 2 years). All examinations are adapted to the patient's age and functional abilities. Disease progression between all subsequent visits and relationships between outcome measures will be assessed., Discussion: This study will provide valuable insights into the 5-year natural history of patients with SELENON-RM and LAMA2-MD and contribute to further selecting relevant and sensitive to change clinical and functional outcome measures. Furthermore, this data will help optimize natural history data collection in clinical care and help develop clinical care guidelines., Trial Registration: This study protocol including the patient information and consent forms has been approved by medical ethical reviewing committee ('METC Oost-Nederland'; https://www.ccmo.nl/metcs/erkende-metcs/metc-oost-nederland , file number: 2023-16401). It is registered at ClinicalTrials.gov (NCT06132750; study registration date: 2023-10-05; study first passed date: 2023-11-15)., (© 2024. The Author(s).)

Three forms of muscular dystrophy-dystroglycanopathies are linked to the ribitol pathway. These include mutations in the isoprenoid synthase domain-containing protein ( ISPD ), fukutin-related protein ( FKRP ), and fukutin ( FKTN ) genes. The aforementioned enzymes are required for generation of the ribitol phosphate linkage in the O-glycan of alpha-dystroglycan. Mild cases of dystroglycanopathy present with slowly progressive muscle weakness, while in severe cases the eyes and brain are also involved. Previous research showed that ribose increased the intracellular concentrations of cytidine diphosphate-ribitol (CDP-ribitol) and had a therapeutic effect. Here, we report the safety and effects of oral ribose supplementation during 6 months in a patient with limb girdle muscular dystrophy type 2I (LGMD2I) due to a homozygous FKRP mutation. Ribose was well tolerated in doses of 9 g or 18 g/day. Supplementation with 18 g of ribose resulted in a decrease of creatine kinase levels of 70%. Moreover, metabolomics showed a significant increase in CDP-ribitol levels with 18 g of ribose supplementation ( p  < 0.001). Although objective improvement in clinical and patient-reported outcome measures was not observed, the patient reported subjective improvement of muscle strength, fatigue, and pain. This case study indicates that ribose supplementation in patients with dystroglycanopathy is safe and highlights the importance for future studies regarding its potential effects., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)

Background and Objectives: LAMA2 -related muscular dystrophy ( LAMA2 -MD) is a rare neuromuscular disease characterized by proximal and axial muscle weakness, rigidity of the spine, scoliosis, and respiratory impairment. 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. We aim for deep clinical phenotyping, establishment of a well-characterized baseline cohort for prospective follow-up and recruitment for future clinical trials, improvement of clinical care, and selection of outcome measures for reaching trial readiness., Methods: We performed a cross-sectional, single-center, observational study. This study included neurologic examination and functional measurements among others the Motor Function Measure 20/32 (MFM-20/32) as primary outcome measure, accelerometry, questionnaires, muscle ultrasound, respiratory function tests, electrocardiography and echocardiography, and dual-energy X-ray absorptiometry., Results: Twenty-seven patients with genetically confirmed LAMA2 -MD were included (21 ± 13 years; M = 9; ambulant = 7). Axial and proximal muscle weakness was most pronounced. The mean MFM-20/32 score was 42.0% ± 29.4%, with domain 1 (standing and transfers) being severely affected and domain 3 (distal muscle function) relatively spared. Physical activity as measured through accelerometry showed very strong correlations to MFM-20/32 (Pearson correlation, -0.928, p < 0.01). Muscle ultrasound showed symmetrically increased echogenicity, with the sternocleidomastoid muscle most affected. Respiratory function was impaired in 85% of patients without prominent diaphragm dysfunction and was independent of age. Ten patients (37%) needed (non)invasive ventilatory support. Cardiac assessment revealed QRS fragmentation in 62%, abnormal left ventricular global longitudinal strain in 25%, and decreased left ventricular ejection fraction in 14% of patients. Decreased bone quality leading to fragility fractures was seen in most of the patients., Discussion: LAMA2 -MD has a widely variable phenotype. Based on the results of this cross-sectional study and current standards of care for congenital muscular dystrophies, we advise routine cardiorespiratory follow-up and optimization of bone quality. We propose MFM-20/32, accelerometry, and muscle ultrasound for assessing disease severity and progression. For definitive clinical recommendations and outcome measures, natural history data are needed., Clinical Trials Registration: This study was registered at clinicaltrials.gov (NCT04478981, 21 July 2020). The first patient was enrolled in September 2020., Competing Interests: The authors report no relevant disclosures. Go to Neurology.org/NG for full disclosures, (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Neuralgic amyotrophy (NA) is a common peripheral nerve disorder caused by auto-immune inflammation of nerves in the brachial plexus territory, characterized by acute pain and weakness of the shoulder muscles, followed by motor impairment. Recent work has confirmed that NA patients with residual motor dysfunction have abnormal cerebral sensorimotor representations of their affected upper extremity., Objective: To determine whether abnormal cerebral sensorimotor representations associated with NA can be altered by specialized, multidisciplinary outpatient rehabilitation focused on relearning motor control., Methods: 27 NA patients with residual lateralized symptoms in the right upper extremity participated in a randomized controlled trial, comparing 17 weeks of multidisciplinary rehabilitation ( n  = 16) to usual care ( n  = 11). We used task-based functional MRI and a hand laterality judgment task, which involves motor imagery and is sensitive to altered cerebral sensorimotor representations of the upper extremity., Results: Change in task performance and related brain activity did not differ significantly between the multidisciplinary rehabilitation and usual care groups, whereas the multidisciplinary rehabilitation group showed significantly greater clinical improvement on the Shoulder Rating Questionnaire. Both groups, however, showed a significant improvement in task performance from baseline to follow-up, and significantly increased activity in visuomotor occipito-parietal brain areas, both specific to their affected upper extremity., Conclusions: Abnormal cerebral sensorimotor representations of the upper extremity after peripheral nerve damage in NA can recover toward normality. As adaptations occurred in visuomotor brain areas, multidisciplinary rehabilitation after peripheral nerve damage may be further optimized by applying visuomotor strategies. This study is registered at ClinicalTrials.gov (NCT03441347).

Neuralgic amyotrophy is a common peripheral nerve disorder caused by autoimmune inflammation of the brachial plexus, clinically characterized by acute pain and weakness of the shoulder muscles, followed by motor impairment. Despite recovery of the peripheral nerves, patients often have residual motor dysfunction of the upper extremity, leading to persistent pain related to altered biomechanics of the shoulder region. Building on clinical signs that suggest a role for cerebral mechanisms in these residual complaints, here we show and characterize cerebral alterations following neuralgic amyotrophy. Neuralgic amyotrophy patients often develop alternative motor strategies, which suggests that (mal)adaptations may occur in somatomotor and/or visuomotor brain areas. Here, we tested where changes in cerebral sensorimotor representations occur in neuralgic amyotrophy, while controlling for altered motor execution due to peripheral neuropathy. We additionally explore the relation between potential cerebral alterations in neuralgic amyotrophy and clinical symptoms. During functional MRI scanning, 39 neuralgic amyotrophy patients with persistent, lateralized symptoms in the right upper extremity and 23 matched healthy participants solved a hand laterality judgement task that can activate sensorimotor representations of the upper extremity, across somatomotor and visuomotor brain areas. Behavioural and cerebral responses confirmed the involvement of embodied, sensorimotor processes across groups. Compared with healthy participants, neuralgic amyotrophy patients were slower in hand laterality judgement and had decreased cerebral activity specific to their affected limb in two higher-order visual brain regions: the right extrastriate cortex and the parieto-occipital sulcus. Exploratory analyses revealed that across patients, extrastriate activity specific to the affected limb decreased as persistent pain increased, and affected limb-related parieto-occipital activity decreased as imagery performance of the affected limb became slower. These findings suggest that maladaptive cerebral plasticity in visuomotor areas involved in sensorimotor integration plays a role in residual motor dysfunction and subsequent persistent pain in neuralgic amyotrophy. Rehabilitation interventions that apply visuomotor strategies to improve sensorimotor integration may help to treat neuralgic amyotrophy patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: To 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., Design: A mixed method study alongside a randomised controlled trial., Setting: University hospital, rehabilitation centre and community health centre., Participants: 29 patients with a neuromuscular disease and chronic fatigue and 13 healthcare professionals participated in this mixed methods study., Intervention: Multidisciplinary 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 Measures: Quantitative 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., Results: Patients 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., Conclusions: The 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 Number: NCT02208687., Competing Interests: Competing interests: YV was sponsored by the Netherlands Organisation for Health Research and Development (ZonMw), National Rehabilitation Fund and Centre of Expertise ‘Sneller Herstel’ (HAN) and the Dutch FSHD Foundation. EHCC was sponsored by the Netherlands Organisation for Health Research and Development (ZonMw), National Rehabilitation Fund and Centre of Expertise ‘Sneller Herstel’ (HAN) the Dutch FSHD Foundation. She also reports grants from the Prinses Beatrix Spierfonds. BGMvE was sponsored by the Netherlands Organisation for Health Research and Development (ZonMw), National Rehabilitation Fund and Centre of Expertise ‘Sneller Herstel’ (HAN). He also reports grants from the EU Horizon 2020 research and innovation programme (Murab), the Netherlands Organisation for Scientific Research, the Netherlands Organisation for Health Research and Development, Global FSH, Prinses Beatrix Spierfonds, Stichting Spieren voor Spieren, Association Francaise contre les Myopathies, Fulcrum and the Dutch FSHD Foundation. ACHG was sponsored by the Netherlands Organisation for Health Research and Development (ZonMw), National Rehabilitation Fund and Centre of Expertise ‘Sneller Herstel’ (HAN). He also reports grants from the Netherlands Organisation for Scientific Research (ZonMw), the Netherlands Organsation for Health Research and Development, Prinses Beatrix Spierfonds, National Rehabilitation Fund, Ipsen, Merz and Otto Bock. JTG reports grants from Prinses Beatrix Spierfonds and Fulcrum Therapeutics. TS, MJLG and MWGNvdS declare that there is no conflict of interest., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: SELENON (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 the LAMA2 gene (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., Methods: LAST 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., Discussion: Our 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., Conclusion: Our natural history study is an essential step for reaching trial readiness in SELENON-RM and LAMA2-MD., Trial Registration: This study has been approved by medical ethical reviewing committee Region Arnhem-Nijmegen (NL64269.091.17, 2017-3911) and is registered at ClinicalTrial.gov ( NCT04478981 )., (© 2021. The Author(s).)

Following publication of the original article [1], the authors reported that the headers in Table 2 in their paper were omitted.

Background: Strength testing of the serratus anterior muscle with hand held dynamometry (HDD) in supine subjects has low reproducibility, and is influenced by compensatory activity of other muscles like the pectoralis major and upper trapezius. Previously, two manual maximum voluntary isometric contraction tests of the serratus anterior muscle were reported that recruited optimal surface electromyography (sEMG) activity in a sitting position. We adapted three manual muscle tests to make them suitable for HHD and investigated their validity and reliability., Methods: Twenty-one healthy adults were examined by two assessors in one supine and two seated positions. Each test was repeated twice. Construct validity was determined by evaluating force production (assessed with HHD) in relation to sEMG of the serratus anterior, upper trapezius and pectoralis major muscles, comparing the three test positions. Intra- and interrater reliability were determined by calculating intra-class correlation coefficients (ICC) smallest detectable change (SDC) and standard error of measurement (SEM)., Results: Serratus anterior muscle sEMG activity was most isolated in a seated position with the humerus in 90° anteflexion in the scapular plane. This resulted in the lowest measured force levels in this position with a mean force of 296 N (SEM 15.8 N). Intrarater reliability yielded an ICC of 0.658 (95% CI 0.325; 0.846) and an interrater reliability of 0.277 (95% CI -0.089;0.605). SDC was 127 Newton, SEM 45.8 Newton., Conclusion: The results indicate that validity for strength testing of the serratus anterior muscle is optimal with subjects in a seated position and the shoulder flexed at 90° in the scapular plane. Intrarater reliability is moderate and interrater reliability of this procedure is poor. However the high SDC values make it difficult to use the measurement in repeated measurements.

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.

Background: Weakness caused by motor neuron degeneration in amyotrophic lateral sclerosis (ALS) may result in avoidance of physical activity, resulting in deconditioning and reduced health-related quality of life (HRQoL)., Objective: To study the effectiveness of aerobic exercise therapy (AET) on disease-specific and generic HRQoL in ambulatory patients with ALS., Methods: We conducted a multicenter, assessor-blinded, randomized controlled trial. Using a biphasic randomization model, ambulatory ALS patients were assigned (1:1) to AET+usual care (UC), or UC. AET consisted of a 16-week aerobic cycling exercise program. Primary outcome measures were the 40-item ALS assessment questionnaire (ALSAQ-40), and the mental component summary (MCS) and physical component summary (PCS) scores of the short-form survey (SF-36), using linear mixed effects models. Per-protocol (PP) analysis was performed for those patients who attended ≥75% of the training sessions; controls were matched (1:1) by propensity score matching., Results: Of 325 screened patients, 57 were randomized: 27 to AET+UC and 30 to UC. No significant mean slope differences between groups were observed for ALSAQ-40 (-1.07; 95% confidence interval [CI] -2.6 to 0.5, P=0.172) nor for SF-36 MCS (0.24; -0.7 to 1.1, P=0.576) or PCS (-0.51; -1.4 to 0.38, P=0.263). There were no adverse events related to the AET. PP-analyses showed significantly less deterioration in ALSAQ-40 (-1.88, -3.8 to 0.0, P=0.046) in AET+UC compared to UC., Conclusions: AET+UC was not superior to UC alone in preserving HRQoL in ambulatory ALS patient. However, the study was unfortunately underpowered, because only 10 patients completed the protocol. AET+UC may preserve disease-specific HRQoL in slow progressors., Clinical Trial Registration Number: Netherlands National Trial Register (NTR): 1616.

Background: Non-invasive ventilation (NIV) improves survival and quality of life in amyotrophic lateral sclerosis (ALS) patients. The timing of referral to a home ventilation service (HVS), which is in part based on respiratory function tests, has shown room for improvement. It is currently unknown which respiratory function test predicts an appropriate timing of the initiation of NIV., Methods: We analysed, retrospectively, serial data of five respiratory function tests: forced vital capacity (FVC), peak cough flow (PCF), maximum inspiratory and expiratory pressure (MIP and MEP) and sniff nasal inspiratory pressure (SNIP) in patients with ALS. Patients who had had at least one assessment of respiratory function and one visit at the HVS, were included. Our aim was to detect the test with the highest predictive value for the need for elective NIV in the following 3 months. We analysed time curves, currently used cut-off values for referral, and respiratory function test results between 'NIV indication' and 'no-NIV indication' patients., Results: One hundred ten patients with ALS were included of whom 87 received an NIV indication; 11.5% had one assessment before receiving an NIV indication, 88.5% had two or more assessments. The NIV indication was based on complaints of hypoventilation and/or proven (nocturnal) hypercapnia. The five respiratory function tests showed a descending trend during disease progression, where SNIP showed the greatest decline within the latest 3 months before NIV indication (mean = -22%). PCF at the time of referral to the HVS significantly discriminated between the groups 'NIV-indication' and 'no NIV-indication yet' patients at the first HVS visit: 259 (±92) vs. 348 (±137) L/min, p = 0.019. PCF and SNIP showed the best predictive characteristics in terms of sensitivity., Conclusion: SNIP showed the greatest decline prior to NIV indication and PCF significantly differentiated 'NIV-indication' from 'no NIV-indication yet' patients with ALS. Currently used cut-off values might be adjusted and other respiratory function tests such as SNIP and PCF may become part of routine care in patients with ALS in order to avoid non-timely initiation of (non-invasive) ventilation.

Background: More than half of the patients harbouring the m.3243A > G mutation were found to have trouble maintaining balance when walking in a recent study by our group. Others demonstrated that these patients had an abnormal gait pattern, as quantified by gait analysis. Gait analysis is an emerging method to quantify subtle changes in walking pattern, also during therapeutic interventions. Therefore, we aimed to test the reliability and reproducibility of gait analysis and select the most suitable protocol for this group of patients using a GAITRite electronic walkway. Four different protocols were tested: normal walking, dual task, post exercise and after a ten minutes of rest., Results: In total 36 patients with the m.3243A > G mutation and 50 healthy controls were enrolled in this study. Overall high intra class correlation coefficients were found in all experimental conditions for both patients and healthy controls indicating good reproducibility. Marked differences in gait between patients and controls were observed and were in line with the only available exploratory study performed. There was a good correlation between both the overall NMDAS score, NMDAS subscale scores, both markers for disease severity, and specific gait parameters., Conclusions: The observed reliability of the test makes GAITRite a suitable instrument for intervention studies in patients with mitochondrial disease.

Objective: Neuralgic amyotrophy is considered a rare peripheral nervous system disorder but in practice seems grossly under recognized, which negatively affects care for these patients. In this study we prospectively counted the one-year incidence rate of classic neuralgic amyotrophy in a primary care setting., Methods: In a prospective cohort study during the year 2012 we registered all new cases of neck, shoulder or arm complaints from two large primary care centers serving a population of 14,118. Prior to study, general practitioners received a short training on how to diagnose classic neuralgic amyotrophy. Neuralgic amyotrophy was defined according to published criteria irrespective of family history. Only patients with a classic phenotype were counted as definite cases. After inclusion, patients with suspected neuralgic amyotrophy who had not yet seen a neurologist were offered neurologic evaluation for diagnostic confirmation., Results: Of the 492 patients identified with new onset neck, shoulder or arm complaints, 34 were suspected of having neuralgic amyotrophy. After neurologic evaluation the diagnosis was confirmed in 14 patients. This amounts to a one-year incidence rate for classic neuralgic amyotrophy of 1 per 1000., Conclusions: Our findings suggest that neuralgic amyotrophy is 30-50 times more common than previously thought. Unawareness of the disorder and its clinical presentation seems the most likely explanation for this difference. An incidence rate of 1 per 1000 and the long-term sequelae many patients suffer warrant more vigilance in diagnosing the disorder, to pave the way for timely treatment and prevent complications.

Background: Chronic fatigue is present in more than 60% of the patients with a neuromuscular disease and can be their most disabling symptom. In combination with other impairments, fatigue often results in low levels of physical activity and decreased social participation, leading to high societal costs. 'Energetic' is a self-management group program aimed at improving social participation, physical endurance and alleviating fatigue in these patients. The primary aim of this study is to evaluate the effectiveness and cost-effectiveness of the Energetic program., Methods/design: A multicentered, assessor-blinded, two-armed randomized controlled trial is conducted with evaluations at inclusion and four, seven and fifteen months later. The study includes patients with a neuromuscular disease and chronic fatigue and, when present, their caregivers. The participants are randomized (ratio 1:1) to either an intervention group, receiving the Energetic program, or a control group, receiving usual care (i.e., no specific intervention). The Energetic program covers four months and includes 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. Two months after cessation of the program a booster session is provided. The primary outcome is the perceived performance score of the Canadian Occupational Performance Measure (COPM). Secondary outcomes include the COPM-satisfaction score, and measures of fatigue, physical endurance, activity engagement, mood, and self-efficacy. Caregiver burden is also evaluated as a secondary outcome. Health-related quality of life and medical and societal costs are assessed to estimate cost-effectiveness of the program., Discussion: The Energetic study is the first randomized controlled trial to evaluate the effectiveness and cost-effectiveness of a combined physical and self-management group training program for improving social participation, physical endurance and alleviating fatigue in patients with neuromuscular diseases. It will generate new insights in (cost-)effective rehabilitation strategies for these incurable conditions., Trial Registration: Clinicaltrials.gov NCT02208687 .

The pathophysiology of orthostatic hypotension in Parkinson's disease (PD) is incompletely understood. The primary focus has thus far been on failure of the baroreflex, a central mediated vasoconstrictor mechanism. Here, we test the role of two other possible factors: 1) a reduced peripheral vasoconstriction (which may contribute because PD includes a generalized sympathetic denervation); and 2) an inadequate plasma volume (which may explain why plasma volume expansion can manage orthostatic hypotension in PD). We included 11 PD patients with orthostatic hypotension (PD + OH), 14 PD patients without orthostatic hypotension (PD - OH), and 15 age-matched healthy controls. Leg blood flow was examined using duplex ultrasound during 60° head-up tilt. Leg vascular resistance was calculated as the arterial-venous pressure gradient divided by blood flow. In a subset of 9 PD + OH, 9 PD - OH, and 8 controls, plasma volume was determined by indicator dilution method with radiolabeled albumin ((125)I-HSA). The basal leg vascular resistance was significantly lower in PD + OH (0.7 ± 0.3 mmHg·ml(-1)·min) compared with PD - OH (1.3 ± 0.6 mmHg·ml(-1)·min, P < 0.01) and controls (1.3 ± 0.5 mmHg·ml(-1)·min, P < 0.01). Leg vascular resistance increased significantly during 60° head-up tilt with no significant difference between the groups. Plasma volume was significantly larger in PD + OH (3,869 ± 265 ml) compared with PD - OH (3,123 ± 377 ml, P < 0.01) and controls (3,204 ± 537 ml, P < 0.01). These results indicate that PD + OH have a lower basal leg vascular resistance in combination with a larger plasma volume compared with PD - OH and controls. Despite the increase in leg vascular resistance during 60° head-up tilt, PD + OH are unable to maintain their blood pressure.

Maintaining blood pressure during orthostatic challenges is primarily achieved by baroreceptor-mediated activation of the sympathetic nervous system, which can be divided into preganglionic and postganglionic parts. Despite their preganglionic autonomic failure, spinal cord-injured individuals demonstrate a preserved peripheral vasoconstriction during orthostatic challenges. Whether this also applies to patients with postganglionic autonomic failure is unknown. Therefore, we assessed leg vasoconstriction during 60° head-up tilt in five patients with pure autonomic failure (PAF) and two patients with autonomic failure due to dopamine-β-hydroxylase (DBH) deficiency. Ten healthy subjects served as controls. Leg blood flow was measured using duplex ultrasound in the right superficial femoral artery. Leg vascular resistance was calculated as the arterial-venous pressure gradient divided by blood flow. DBH-deficient patients were tested off and on the norepinephrine pro-drug l-threo-dihydroxyphenylserine (l-DOPS). During 60° head-up tilt, leg vascular resistance increased significantly in PAF patients [0.40 ± 0.38 (+30%) mmHg·ml(-1)·min(-1)]. The increase in leg vascular resistance was not significantly different from controls [0.88 ± 1.04 (+72%) mmHg·ml(-1)·min(-1)]. In DBH-deficient patients, leg vascular resistance increased by 0.49 ± 0.01 (+153%) and 1.52 ± 1.47 (+234%) mmHg·ml(-1)·min(-1) off and on l-DOPS, respectively. Despite the increase in leg vascular resistance, orthostatic hypotension was present in PAF and DBH-deficient patients. Our results demonstrate that leg vasoconstriction during orthostatic challenges in patients with PAF or DBH deficiency is not abolished. This indicates that the sympathetic nervous system is not the sole or pivotal mechanism inducing leg vasoconstriction during orthostatic challenges. Additional vasoconstrictor mechanisms may compensate for the loss in sympathetic nervous system control.

Autonomic dysreflexia is a hypertensive episode in spinal cord-injured individuals induced by exaggerated sympathetic activity and thought to be alpha-adrenergic mediated. alpha-Adrenoceptor antagonists have been a rational first choice; nevertheless, calcium channel blockers are primarily used in autonomic dysreflexia management. However, alpha-adrenoceptor blockade may leave a residual vasoconstrictor response to sympathetic nonadrenergic transmission unaffected. The aim was to assess the alpha-adrenergic contribution and, in addition, the role of supraspinal control to leg vasoconstriction during exaggerated sympathetic activity provoked by autonomic dysreflexia in spinal cord-injured individuals and by a cold pressure test in control individuals. Upper leg blood flow was measured using venous occlusion plethysmography during supine rest and during exaggerated sympathetic activity in 6 spinal cord-injured individuals and 7 able-bodied control individuals, without and with phentolamine (alpha-adrenoceptor antagonist) and nicardipine (calcium channel blocker) infusion into the right femoral artery. Leg vascular resistance was calculated. In spinal cord-injured individuals, phentolamine significantly reduced the leg vascular resistance increase during autonomic dysreflexia (8+/-5 versus 24+/-13 arbitrary units; P=0.04) in contrast to nicardipine (15+/-10 versus 24+/-13 arbitrary units; P=0.12). In controls, phentolamine completely abolished the leg vascular resistance increase during a cold pressure test (1+/-2 versus 18+/-14 arbitrary units; P=0.02). The norepinephrine increase during phentolamine infusion was larger (P=0.04) in control than in spinal cord-injured individuals. These results indicate that the leg vascular resistance increase during autonomic dysreflexia in spinal cord-injured individuals is not entirely alpha-adrenergic mediated and is partly explained by nonadrenergic transmission, which may, in healthy subjects, be suppressed by supraspinal control.

Background: orthostatic hypotension is common in older men and associated with morbidity and mortality. During orthostatic challenges, older men maintain their blood pressure by an augmented increase in total peripheral resistance. Changes in the leg vascular bed contribute importantly to blood pressure regulation during orthostatic challenges, partly because of blood pooling in the legs. Little is known about the contribution of the leg vascular bed to the augmented increase in total peripheral resistance., Objective: to examine tilt-induced peripheral vasoconstriction in the leg vascular bed of young and older men., Methods: we measured forearm and calf blood flow in 12 young and 12 older men, using venous occlusion plethysmography during 30 degrees head-up tilt (HUT). Forearm and calf vascular resistance were calculated as mean arterial blood pressure divided by blood flow., Results: during HUT, calf and forearm vascular resistance increased in older and young men. The increase in forearm vascular resistance was similar between older (40 +/- 6%) and young men (51 +/- 12%). However, the increase in calf vascular resistance was lower in older (96 +/- 15%) than in young men (175 +/- 30%)., Conclusion: advancing age leads to an attenuated tilt-induced increase in calf vascular resistance, which may contribute to age-related orthostatic hypotension.

Leg vascular resistance is calculated as the arterial-venous pressure gradient divided by blood flow. During orthostatic challenges it is assumed that the hydrostatic pressure contributes equally to leg arterial, as well as to leg venous pressure. Because of venous valves, one may question whether, during orthostatic challenges, a continuous hydrostatic column is formed and if leg venous pressure is equal to the hydrostatic pressure. The purpose of this study was, therefore, to measure intravenous pressure in the great saphenous vein of 12 healthy individuals during 30 degrees and 70 degrees head-up tilt and compare this with the calculated hydrostatic pressure. The height difference between the heart and the right medial malleolus level represented the hydrostatic column. The results demonstrate that there were no differences between the measured intravenous pressure and the calculated hydrostatic pressure during 30 degrees (47.2 +/- 1.0 and 46.9 +/- 1.5 mmHg, respectively) and 70 degrees head-up tilt (83.9 +/- 0.9 and 85.1 +/- 1.2 mmHg, respectively). Steady-state levels of intravenous pressure were reached after 95 +/- 12 s during 30 degrees and 161 +/- 15 s during 70 degrees head-up tilt. In conclusion, the measured leg venous pressure is similar to the calculated hydrostatic pressure during orthostatic challenges. Therefore, the assumption that hydrostatic pressure contributes equally to leg arterial as well as to leg venous pressure during orthostatic challenges can be made.

Objective: To report a rare cause of spinal cord injury., Study Design: Case report., Case Report: A 36-year-old woman presented with acute onset of paresis of the upper and lower extremity (level C5, ASIA B) the day after delivering a healthy daughter (39 weeks' gestation). Prior to giving birth, she was admitted with gestational hypertension. Directly postpartum, blood pressure increased markedly, and hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome was diagnosed. The next day, tetraplegia developed. Magnetic resonance imaging showed multiple epidural and subdural hematomas in the cervical and thoracic spinal canal extending from C2 to T8, with displacement and compression of the cord. Three weeks after treatment with intravenous labetalol, she made a significant recovery (level T1, ASIA D)., Conclusions: This rare cause of spinal cord injury shows the importance of closely monitoring pregnant patients with hypertension complicated with HELLP syndrome both pre- and postpartum.

Venous occlusion strain gauge plethysmography (VOP) is based on the assumption that the veins are occluded and arterial inflow is undisturbed by the venous cuff pressure. Literature is not clear concerning the pressure that should be used. The purpose of this study was to determine the optimal venous occlusion pressure at which the highest arterial inflow is achieved in the forearm, calf, and leg by using VOP. We hypothesized that, for each limb segment, an optimal (range of) venous cuff pressure can be determined. Arterial inflow in each limb segment was measured in nine healthy individuals by VOP by using pressures ranging from 10 mmHg up to diastolic blood pressure. Arterial inflows were similar at cuff pressures between 30 and 60 mmHg for the forearm, leg, and calf. Arterial inflow in the forearm was significantly lower at 10 mmHg compared with the other cuff pressures. In addition, arterial inflows at 20 mmHg tended to be lower in each limb segment than flow at higher cuff pressures. In conclusion, no single optimum venous cuff pressure, at which a highest arterial inflow is achieved, exists, but rather a range of optimum cuff pressures leading to a similar arterial inflow. Venous cuff pressures ranging from 30 mmHg up to diastolic blood pressure are recommended to measure arterial inflow by VOP.

The purpose of the present study was to determine the effect of a spinal cord injury (SCI) on resting vascular resistance in paralyzed legs in humans. To accomplish this goal, we measured blood pressure and resting flow above and below the lesion (by using venous occlusion plethysmography) in 11 patients with SCI and in 10 healthy controls (C). Relative vascular resistance was calculated as mean arterial pressure in millimeters of mercury divided by the arterial blood flow in milliliters per minute per 100 milliliters of tissue. Arterial blood flow in the sympathetically deprived and paralyzed legs of SCI was significantly lower than leg blood flow in C. Because mean arterial pressure showed no differences between both groups, leg vascular resistance in SCI was significantly higher than in C. Within the SCI group, arterial blood flow was significantly higher and vascular resistance significantly lower in the arms than in the legs. To distinguish between the effect of loss of central neural control vs. deconditioning, a group of nine SCI patients was trained for 6 wk and showed a 30% increase in leg blood flow with unchanged blood pressure levels, indicating a marked reduction in vascular resistance. In conclusion, vascular resistance is increased in the paralyzed legs of individuals with SCI and is reversible by training.

The purpose of this study was to assess the relationship between inactivity and shear stress, the frictional force of blood against the endothelium, in spinal cord injury (SCI) subjects. SCI group offers a unique "model of nature" to study the effects of inactivity. Nine SCI subjects with upper (SCI-U) and 5 with a lower (SCI-L) motoneuron lesion and 10 able-bodied controls (C) were included. A venous blood sample was withdrawn to determine blood viscosity. Red blood cell velocities and arterial diameters of the common carotid artery (CCA) and common femoral artery (CFA) were measured by using echo-Doppler ultrasound in a supine position. No differences were observed in wall shear stress in the CCA between groups. In the CFA, peak and mean wall shear stress were significantly increased in SCI (14.1 and 1.2 Pa, respectively) compared with C (10.2 and 0.9 Pa, respectively). Because SCI-U and SCI-L showed no differences in shear stress levels, inactivity and not nerve degeneration seems to cause the elevated shear stress levels in the CFA in SCI. However, the lack of central neural control as a causal factor cannot be ruled out.