SELENON-Related Myopathy Across the Life Span, a Cross-Sectional Study for Preparing Trial Readiness.

BACKGROUND: SELENON(SEPN1)-related myopathy (SELENON-RM) is a rare congenital neuromuscular disease characterized by proximal and axial muscle weakness, spinal rigidity, scoliosis and respiratory impairment. No curative treatment options exist, but promising preclinical studies are ongoing. Currently, natural history data are lacking, while selection of appropriate clinical and functional outcome measures is needed to reach trial readiness. OBJECTIVE: We aim to identify all Dutch and Dutch-speaking Belgian SELENON-RM patients, deep clinical phenotyping, trial readiness and optimization of clinical care. METHODS: This cross-sectional, single-center, observational study comprised neurological examination, functional measurements including Motor Function Measurement 20/32 (MFM-20/32) and accelerometry, questionnaires, muscle ultrasound, respiratory function tests, electro- and echocardiography, and dual-energy X-ray absorptiometry. RESULTS: Eleven patients with genetically confirmed SELENON-RM were included (20±13 (3-42) years, 73% male). Axial and proximal muscle weakness were most pronounced. The mean MFM-20/32 score was 71.2±15.1%, with domain 1 (standing and transfers) being most severely affected. Accelerometry showed a strong correlation with MFM-20/32. Questionnaires revealed impaired quality of life, pain and problematic fatigue. Muscle ultrasound showed symmetrically increased echogenicity in all muscles. Respiratory function, and particularly diaphragm function, was impaired in all patients, irrespective of the age. Cardiac assessment showed normal left ventricular systolic function in all patients but abnormal left ventricular global longitudinal strain in 43% of patients and QRS fragmentation in 80%. Further, 80% of patients showed decreased bone mineral density on dual-energy X-ray absorptiometry scan and 55% of patients retrospectively experienced fragility long bone fractures. CONCLUSIONS: We recommend cardiorespiratory follow-up as a part of routine clinical care in all patients. Furthermore, we advise vitamin D supplementation and optimization of calcium intake to improve bone quality. We recommend management interventions to reduce pain and fatigue. For future clinical trials, we propose MFM-20/32, accelerometry and muscle ultrasound to capture disease severity and possibly disease progression.

Cerebral Adaptation Associated with Peripheral Nerve Recovery in Neuralgic Amyotrophy: A Randomized Controlled Trial.

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).

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.

Long-term use of implanted peroneal functional electrical stimulation for stroke-affected gait: the effects on muscle and motor nerve.

BACKGROUND: Peripheral changes to muscle and motor nerves occur following stroke, which may further impair functional capacity. We investigated whether a year-long use of an implanted peroneal FES system reverses stroke-related changes in muscles and motor nerves in people with foot drop in the chronic phase after supratentorial stroke. METHODS: Thirteen persons with a chronic stroke (mean age 56.1 years, median Fugl-Meyer Assessment leg score 71%) were included and received an implanted peroneal FES system (ActiGait®). Quantitative muscle ultrasound (QMUS) images were obtained bilaterally from three leg muscles (i.e. tibialis anterior, rectus femoris, gastrocnemius). Echogenicity (muscle ultrasound gray value) and muscle thickness were assessed over a one-year follow-up and compared to age-, sex-, height- and weight-corrected reference values. Compound motor action potentials (CMAPs) and motor evoked potentials (MEPs) were obtained from the tibialis anterior muscle. Generalized estimated equation modeling was used to assess changes in QMUS, CMAPs and MEPs outcomes over the follow-up period. RESULTS: Echogenicity of the tibialis anterior decreased significantly during the follow-up on the paretic side. Z-scores changed from 0.88 at baseline to - 0.15 after 52 weeks. This was accompanied by a significant increase in muscle thickness on the paretic side, where z-scores changed from - 0.32 at baseline to 0.48 after 52 weeks. Echogenicity of the rectus femoris normalized on both the paretic and non-paretic side (z-scores changed from - 1.09 and - 1.51 to 0.14 and - 0.49, respectively). Amplitudes of CMAP and MEP (normalized to CMAP) were reduced during follow-up, particularly on the paretic side (ΔCMAP = 20% and ΔMEP = 14%). CONCLUSIONS: We show that the structural changes to muscles following stroke are reversible with FES and that these changes might not be limited to electrically stimulated muscles. No evidence for improvement of the motor nerves was found.

The influence of concentration/meditation on autonomic nervous system activity and the innate immune response: a case study.

OBJECTIVE: In this case study, we describe the effects of a particular individual's concentration/meditation technique on autonomic nervous system activity and the innate immune response. The study participant holds several world records with regard to tolerating extreme cold and claims that he can influence his autonomic nervous system and thereby his innate immune response. METHODS: The individual's ex vivo cytokine response (stimulation of peripheral blood mononuclear cells with lipopolysaccharide [LPS]) was determined before and after an 80-minute full-body ice immersion during which the individual practiced his concentration/meditation technique. Furthermore, the individual's in vivo innate immune response was studied while practicing his concentration/mediation technique during human endotoxemia (intravenous administration of 2 ng/kg LPS). The results from the endotoxemia experiment were compared with a historical cohort of 112 individuals who participated in endotoxemia experiments in our institution. RESULTS: The ex vivo proinflammatory and anti-inflammatory cytokine response was greatly attenuated by concentration/meditation during ice immersion, accompanied by high levels of cortisol. In the endotoxemia experiment, concentration/meditation resulted in increased circulating concentrations of catecholamines, and plasma cortisol concentrations were higher than in any of the previously studied participants. The individual's in vivo cytokine response and clinical symptoms after LPS administration were remarkably low compared with previously studied participants. CONCLUSIONS: The concentration/meditation technique used by this particular individual seems to evoke a controlled stress response. This response is characterized by sympathetic nervous system activation and subsequent catecholamine/cortisol release, which seems to attenuate the innate immune response.

Atypical dystonic shoulder movements following neuralgic amyotrophy.

Peripherally induced movement disorders are relatively rare. Here, we present 3 patients who suffered a lesion of the brachial plexus because of neuralgic amyotrophy and developed involuntary movements of their shoulder muscles. The nature of the involuntary movements, which did not easily comply with classic descriptions of hyperkinetic movement disorders, is probably best referred to as dystonia.