Abstract: The terminal complement C5 inhibitor ravulizumab was engineered from the humanized monoclonal antibody eculizumab to have an extended half-life and duration of action. It binds to human terminal complement protein C5, inhibiting its cleavage into C5a and C5b, thus preventing the cascade of events that lead to architectural destruction of the postsynaptic neuromuscular junction membrane by the membrane attack complex, and consequent muscle weakness in patients with anti-acetylcholine receptor (AChR) antibody-positive generalized myasthenia gravis (gMG). The 26-week randomized, placebo-controlled period (RCP) of the phase 3 CHAMPION MG study demonstrated the rapid efficacy of ravulizumab in reducing MG symptoms. Weight-based dosing of ravulizumab every 8 weeks provided sustained efficacy, in terms of patient-reported (Myasthenia Gravis–Activities of Daily Living) and clinician-reported (Quantitative Myasthenia Gravis) endpoints in patients with anti-AChR antibody-positive gMG. Pharmacokinetic and pharmacodynamic analyses showed therapeutic serum ravulizumab concentrations (> 175 μg/mL) were achieved immediately after the first dose and were maintained throughout 26 weeks, irrespective of patient body weight; inhibition of serum free C5 was immediate, complete (< 0.5 μg/mL), and sustained in all patients. Interim results from the open-label extension (OLE) showed that after 60 weeks, efficacy was maintained in patients continuing on ravulizumab. Rapid and sustained improvements in efficacy, similar to those seen in patients initiating ravulizumab in the RCP, were observed after initiation of ravulizumab treatment in patients who switched from placebo in the RCP to ravulizumab in the OLE. The findings from the RCP and OLE support ravulizumab's favorable safety profile. In conclusion, ravulizumab has a simple weight-based administration and long dosing interval. Its targeted mechanism of action without generalized immunosuppression is reflected in its rapid onset of symptom improvement, sustained efficacy and good safety profile in the treatment of patients with anti-AChR antibody-positive gMG. Plain Language Summary: Ravulizumab in anti-AChR antibody-positive gMGRavulizumab was engineered from eculizumab to have an extended half-life and longer duration of action. It binds to terminal complement protein C5 to inhibit anti-AChR antibody-mediated activation of terminal complement and destruction of the neuromuscular junction.Pharmacokinetic/pharmacodynamic analyses support a simple weight-based administration and long dosing interval and show that therapeutic ravulizumab concentrations and complete inhibition of C5 were achieved immediately after the first dose.The 26-week randomized placebo-controlled period (RCP) of the CHAMPION MG study in patients with anti-AChR antibody-positive gMG showed that ravulizumab has rapid and sustained efficacy with good safety and tolerability across a broad range of patients.Ravulizumab's efficacy, safety, and tolerability were confirmed in interim analyses of the open-label extension study (including data for up to 60 weeks from the RCP baseline): efficacy was maintained in patients remaining on ravulizumab; rapid and sustained efficacy was established in patients switching from placebo to ravulizumab. Keywords: acetylcholine receptor antibody, complement, membrane attack complex, monoclonal antibody, terminal complement complex
Limited data exist regarding association between physical performance and in-hospital falls. This study was performed to investigate the association between physical performance and in-hospital falls in a high-risk population.
Cognitive and movement processes involved integration of several large-scale brain networks. Central to these integrative processes are connector hubs, brain regions characterized by strong connections with multiple networks. Growing evidence suggests that many neurodegenerative and psychiatric disorders are associated with connector hub dysfunctions. Using a network metric called functional connectivity overlap ratio, we investigated connector hub alterations in Parkinson's disease. Resting-state functional MRI data from 99 patients (male/female = 44/55) and 99 age- and sex-matched healthy controls (male/female = 39/60) participating in our cross-sectional study were used in the analysis. We have identified two sets of connector hubs, mainly located in the sensorimotor cortex and cerebellum, with significant connectivity alterations with multiple resting-state networks. Sensorimotor connector hubs have impaired connections primarily with primary processing (sensorimotor, visual), visuospatial, and basal ganglia networks, whereas cerebellar connector hubs have impaired connections with basal ganglia and executive control networks. These connectivity alterations correlated with patients' motor symptoms. Specifically, values of the functional connectivity overlap ratio of the cerebellar connector hubs were associated with tremor score, whereas that of the sensorimotor connector hubs with postural instability and gait disturbance score, suggesting potential association of each set of connector hubs with the disorder's two predominant forms, the akinesia/rigidity and resting tremor subtypes. In addition, values of the functional connectivity overlap ratio of the sensorimotor connector hubs were highly predictive in classifying patients from controls with an accuracy of 75.76%. These findings suggest that, together with the basal ganglia, cerebellar and sensorimotor connector hubs are significantly involved in Parkinson's disease with their connectivity dysfunction potentially driving the clinical manifestations typically observed in this disorder.
Multiple system atrophy (MSA) is an adult-onset, progressive neurodegenerative disorder. Patients with MSA show various phenotypes during the course of their illness, including parkinsonism, cerebellar ataxia, autonomic failure, and pyramidal signs. Patients with MSA sometimes present with isolated autonomic failure or motor symptoms/ signs. The median duration from onset to the concomitant appearance of motor and autonomic symptoms is approximately 2 years but can range up to 14 years. As the presence of both motor and autonomic symptoms is essential for the current diagnostic criteria, early diagnosis is difficult when patients present with isolated autonomic failure or motor symptoms/signs. In contrast, patients with MSA may show severe autonomic failure and die before the presentation of motor symptoms/signs, which are currently required for the diagnosis of MSA. Recent studies have also revealed that patients with MSA may show nonsupporting features of MSA such as dementia, hallucinations, and vertical gaze palsy. To establish early diagnostic criteria and clinically definitive categorization for the successful development of disease-modifying therapy or symptomatic interventions for MSA, research should focus on the isolated phase and atypical symptoms to develop specific clinical, imaging, and fluid biomarkers that satisfy the requirements for objectivity, for semi- or quantitative measurements, and for uncomplicated, worldwide availability. Several novel techniques, such as automated compartmentalization of the brain into multiple parcels for the quantification of gray and white matter volumes on an individual basis and the visualization of α-synuclein and other candidate serum and cerebrospinal fluid biomarkers, may be promising for the early and clinically definitive diagnosis of MSA.
Abstract Background Primary lateral sclerosis (PLS) is an extremely rare condition; therefore, to date no clinical studies have been conducted. The Primary Lateral Sclerosis Functional Rating Scale (PLSFRS) was developed in the United States of America. The PLSFRS is a crucial assessment scale for international collaborative research and future clinical trials for PLS. It is useful for evaluating medical conditions through face-to-face assessments and telephone interviews such as when a face-to-face assessment is not possible due to disasters or the burden of hospital visits. This study assessed the reliability and consistency of in-person and telephone interviews using the Japanese version of the PLSFRS. Methods We enrolled 19 Japanese patients who met the specific criteria for inclusion at the six collaborating institutions. The PLSFRS assessments were performed by two evaluators at defined time points and analyzed for intra-rater and inter-rater reliability and consistency between the in-person and telephone interviews. Results The Japanese version of the PLSFRS was developed by a specialized company and translator, and modified to consider the Japanese lifestyle through a consensus among motor neuron specialists. The quadratic-weighted kappa coefficients for the intra-rater and the inter-rater agreement were substantial (intra-rater: 0.691-1.000, inter-rater: 0.634-1.000). Moreover, the intraclass correlation coefficient for the PLSFRS total score was 0.997 (95% confidence interval, 0.992–0.999). Conclusions This study provides results regarding the Japanese version of the PLSFRS intra-rater and inter-rater reliability and consistency between in-person and telephone interviews.
We performed (1)H-MR spectroscopy ((1)H-MRS) on multiple brain regions to determine the metabolite pattern and diagnostic utility of (1)H-MRS in multiple system atrophy (MSA).Examining single voxels at 3.0 T, we studied metabolic findings of the putamen, pontine base, and cerebral white matter in 24 MSA patients (predominant cerebellar ataxia (MSA-C), n = 13), parkinsonism (MSA-P), n = 11), in 11 age and duration matched Parkinson's disease patients (PD) and in 18 age matched control subjects.The N-acetylaspartate to creatine ratio (NAA/Cr) in MSA patients showed a significant reduction in the pontine base (p<0.0001) and putamen (p = 0.02) compared with controls. NAA/Cr in cerebral white matter also tended to decline in long standing cases. NAA/Cr reduction in the pontine base was prominent in both MSA-P (p<0.0001) and MSA-C (p<0.0001), and putaminal NAA/Cr reduction was significant in MSA-P (p = 0.009). It was also significant in patients who were in an early phase of their disease, and in those who showed no ataxic symptoms or parkinsonism, or did not show any MRI abnormality of the "hot cross bun" sign or hyperintense putaminal rims. NAA/Cr in MSA-P patients was significantly reduced in the pontine base (p = 0.001) and putamen (p = 0.002) compared with PD patients. The combined (1)H-MRS in the putamen and pontine base served to distinguish patients with MSA-P from PD more clearly.(1)H-MRS showed widespread neuronal and axonal involvement in MSA. The NAA/Cr reduction in the pontine base proved highly informative in the early diagnosis of MSA prior to MRI changes and even before any clinical manifestation of symptoms.
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