Respiratory function in LAMA2-related muscular dystrophy and SELENON-related congenital myopathy, a 1.5-year natural history study

INTRODUCTION: LAMA2-related muscular dystrophy (LAMA2-MD) and SELENON(SEPN1)-related congenital myopathy (SELENON-RM) are rare neuromuscular diseases with respiratory impairment from a young age. Prospective natural history studies are needed for prevalence estimations, respiratory characterization, optimizing clinical care and selecting outcome measures for trial readiness.METHODS: Our prospective 1.5-year natural history study included spirometry (forced vital capacity (FVC); difference between upright and supine vital capacity (dVC)), respiratory muscle strength tests (sniff nasal inspiratory pressure (SNIP)) (age≥5 years), and diaphragm ultrasound (thickness; thickening; echogenicity; all ages).RESULTS: Twenty-six LAMA2-MD patients (M = 8, median 21 [9; 31] years) and 11 SELENON-RM patients (M = 8, 20 [10; 33] years) were included. At baseline, 17 (85 %) LAMA2-MD (FVC%: 59 % [33; 68]) and all SELENON-RM patients (FVC%: 34 % [31; 46]) had an impaired respiratory function (FVC%&lt;80 %). Nine (35 %) LAMA2-MD and eight (73 %) SELENON-RM patients received mechanical ventilation at baseline, and two additional SELENON-RM patients started during follow-up. Contrarily to LAMA2-MD, SELENON-RM patients had severe diaphragm atrophy (diaphragm thickness z-score: 2.5 [-3.1; -2.1]) and dysfunction (diaphragm thickness ratio: 1.2 [1.0; 1.7]; dVC: 30 % [7.7; 41]). SNIP was low in both neuromuscular diseases and correlated with motor function. In SELENON-RM, respiratory function decreased during follow-up.CONCLUSION: The majority of LAMA2-MD and all SELENON-RM patients had respiratory impairment. SELENON-RM patients showed lower respiratory function which was progressive, more prevalent mechanical ventilation, and more severe diaphragm atrophy and dysfunction than LAMA2-MD patients. Spirometry (FVC%, dVC) and respiratory muscle strength tests (SNIP) are useful in clinical care and as outcome measure in clinical trials.CLINICAL TRIAL NUMBER: NCT04478981.</p

Long-term follow-up of respiratory function in facioscapulohumeral muscular dystrophy

OBJECTIVE: To evaluate the 5-year change in respiratory function in patients with facioscapulohumeral muscular dystrophy (FSHD). METHODS: Genetically confirmed patients with FSHD aged ≥ 18 years were examined twice over five years. Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were measured using hand-held spirometry with a face mask. Several clinical outcome measures were correlated to respiratory function. RESULTS: Ninety-two patients were included (57% male, age 18–75 years). At baseline, the spirometry outcomes of 41 patients showed a restrictive ventilatory pattern (FVC  10% predicted. The subgroup of 15 patients was more severely affected at baseline (p = 0.002 for FSHD clinical score and 0.007 for Ricci score). They developed more frequently spinal and thorax deformities (p < 0.001 for kyphoscoliosis and 0.012 for pectus excavatum) and had a larger decline in axial muscle function (p = 0.020). Only weak correlations were found between the change in FVC% predicted and the change in clinical scores between baseline and follow-up. INTERPRETATION: Respiratory function remained stable in most patients with FSHD, but a subgroup of patients showed a pronounced deterioration. They showed more severe muscle weakness including the leg muscles at baseline (Ricci score ≥ 6), had spinal and thorax deformities and a relatively fast decline in axial muscle function at follow-up

Visuomotor processing is altered after peripheral nerve damage in neuralgic amyotrophy

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

Incidence of neuralgic amyotrophy (parsonage turner syndrome) in a primary care setting - A prospective cohort study

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

Immunogenicity and Protective Capacity of a Virosomal Respiratory Syncytial Virus Vaccine Adjuvanted with Monophosphoryl Lipid A in Mice

Respiratory Syncytial Virus (RSV) is a major cause of viral brochiolitis in infants and young children and is also a significant problem in elderly and immuno-compromised adults. To date there is no efficacious and safe RSV vaccine, partially because of the outcome of a clinical trial in the 1960s with a formalin-inactivated RSV vaccine (FI-RSV). This vaccine caused enhanced respiratory disease upon exposure to the live virus, leading to increased morbidity and the death of two children. Subsequent analyses of this incident showed that FI-RSV induces a Th2-skewed immune response together with poorly neutralizing antibodies. As a new approach, we used reconstituted RSV viral envelopes, i.e. virosomes, with incorporated monophosphoryl lipid A (MPLA) adjuvant to enhance immunogenicity and to skew the immune response towards a Th1 phenotype. Incorporation of MPLA stimulated the overall immunogenicity of the virosomes compared to non-adjuvanted virosomes in mice. Intramuscular administration of the vaccine led to the induction of RSV-specific IgG2a levels similar to those induced by inoculation of the animals with live RSV. These antibodies were able to neutralize RSV in vitro. Furthermore, MPLA-adjuvanted RSV virosomes induced high amounts of IFNγ and low amounts of IL5 in both spleens and lungs of immunized and subsequently challenged animals, compared to levels of these cytokines in animals vaccinated with FI-RSV, indicating a Th1-skewed response. Mice vaccinated with RSV-MPLA virosomes were protected from live RSV challenge, clearing the inoculated virus without showing signs of lung pathology. Taken together, these data demonstrate that RSV-MPLA virosomes represent a safe and efficacious vaccine candidate which warrants further evaluation

The effect of inspired oxygen fraction on peak oxygen uptake during arm exercise

Item does not contain fulltextIt has been shown that peak oxygen uptake (O(2)peak) during leg exercise is enhanced by an increased inspiratory oxygen fraction ( FiO(2)), indicating that oxygen supply is the limiting factor. Whether oxygen supply is a limiting factor in arm exercise performance is unknown. The purpose of this study, therefore, was to examine the effect of different levels of FiO(2 )on O(2)peak during arm exercise in healthy individuals. Nine men successfully performed three incremental arm-cranking exercise tests with FiO(2)15%, FiO(2)21% and FiO(2)50% applied in counterbalanced order. A significant FiO(2 )dependency was observed for O(2)peak ( p=0.02) and power output ( p=0.03) and post hoc tests revealed a significant difference in O(2)peak between 15 and 50% FiO(2 )( p=0.02), but not between 15 and 21% FiO(2), and 21 and 50% FiO(2). The results of this study show that O(2)peak is enhanced with increasing FiO(2), and suggest that O(2)peak during arm exercise is limited by oxygen supply rather than by the metabolic machinery within the muscle itself