Current Opinion in Neurology

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Progress in the therapy of myasthenia gravis: getting closer to effective targeted immunotherapies

imagePurpose of review
To provide an update on immunomodulating and immunosuppressive therapies in myasthenia gravis and highlight newly approved, or pending approval, therapies with new biologics.
Recent findings
Preoperative IVIg is not needed to prevent myasthenic crisis in stable myasthenia gravis patients scheduled for surgery under general anesthesia, based on controlled data. Rituximab, if initiated early in new-onset myasthenia gravis, can lead to faster and more sustained remission even without immunotherapies in 35% of patients at 2 years. Biomarkers determining the timing for follow-up infusions in Rituximab-responding AChR-positive patients are discussed. Most patients with MuSK-positive myasthenia gravis treated with Rituximab have sustained long-term remission with persistent reduction of IgG4 anti-MuSK antibodies. Eculizumb in the extension REGAIN study showed sustained long-term pharmacological remissions and reduced exacerbations. Three new biologic agents showed promising results in phase-II controlled myasthenia gravis trials: Zilucoplan, a subcutaneous macrocyclic peptide inhibiting complement C5; Efgartigimod, an IgG1-derived Fc fragment binding to neonatal FcRn receptor; and Rozanolixizumab, a high-affinity anti-FcRn monoclonal antibody. Finally, the safety of ongoing myasthenia gravis immunotherapies during COVID19 pandemic is discussed.
Summary
New biologics against B cells, complement and FcRn receptor, are bringing us closer to successful targeted immunotherapies in the chronic management of myasthenia gravis promising an exciting future for antibody-mediated neurological diseases.

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https://journals.lww.com/co-neurology/Fulltext/2020/10000/Progress_in_the_therapy_of_myasthenia_gravis_.3.aspx

Where are we moving in the classification of idiopathic inflammatory myopathies?

imagePurpose of review
Discoveries of myositis-specific antibodies, transcriptomic signatures, and clinicoseropathological correlation support classification of idiopathic inflammatory myopathies (IIM) into four major subgroups: dermatomyositis, immune-mediated necrotizing myopathy (IMNM), antisynthetase syndrome (ASS), and inclusion body myositis (IBM) whereas leaving polymyositis as a historical nonspecific diagnosis of exclusion. This review summarizes and comments on recent knowledge regarding the major subgroup of IIM.
Recent findings
Type 1 interferon (IFN1) pathway activation is the most prominent in dermatomyositis whereas type 2 interferon (IFN2) pathway activation is high in IBM and ASS; neither pathway is distinct in IMNM. Myxovirus-resistant protein A, IFN1 surrogate marker, is now one of definite dermatomyositis muscle biopsy criteria in the new 2018 European Neuromuscular Centre classification of dermatomyositis; the classification emphasizes on different categorization with and without dermatomyositis-specific antibody result. Novel HLA loci associated with anti-TIF1-γ, anti-Mi-2, and anti-Jo-1 antibodies in Caucasian population are identified. Associations of chaperon-assisted selective autophagy (CASA) and complement-mediated autoimmunity in IMNM as well as highly differentiated T cells in IBM are discovered.
Summary
Current IIM classification requires integrated clinicoseropathological approaches. Additional information, such as transcriptomics, HLA haplotyping, and potential biomarkers help tailoring categorization that may have future diagnostic and therapeutic implications.

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https://journals.lww.com/co-neurology/Fulltext/2020/10000/Where_are_we_moving_in_the_classification_of.9.aspx

The prospects of targeting DUX4 in facioscapulohumeral muscular dystrophy

imagePurpose of review
Facioscapulohumeral muscular dystrophy (FSHD) is a neuromuscular disorder, which is caused by incomplete repression of the transcription factor double homeobox 4 (DUX4) in skeletal muscle. To date, there is no DUX4-targeting treatment to prevent or delay disease progression. In the present review, we summarize developments in therapeutic strategies with the focus on inhibiting DUX4 and DUX4 target gene expression.
Recent findings
Different studies show that DUX4 and its target genes can be repressed with genetic therapies using diverse strategies. Additionally, different small compounds can reduce DUX4 and its target genes in vitro and in vivo.
Summary
Most studies that show DUX4 repression by genetic therapies have only been tested in vitro. More efforts should be made to test them in vivo for clinical translation. Several compounds have been shown to prevent DUX4 and target gene expression in vitro and in vivo. However, their efficiency and specificity has not yet been shown. With emerging clinical trials, the clinical benefit from DUX4 repression in FSHD will likely soon become apparent.

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https://journals.lww.com/co-neurology/Fulltext/2020/10000/The_prospects_of_targeting_DUX4_in.14.aspx

The elusive promise of myostatin inhibition for muscular dystrophy

imagePurpose of review
Recent terminations of clinical trials of myostatin inhibitors in muscular dystrophy have raised questions about the predictiveness of mouse models for this therapeutic strategy.
Recent findings
A variety of myostatin inhibitors have been developed for preclinical and clinical studies. These inhibitors have ameliorated the phenotype of many but not all mouse models of muscular dystrophy. However, randomized double-blinded placebo controlled trials in both pediatric and adult muscular dystrophies have, as of yet, not demonstrated functional improvement.
Summary
The present article will review the preclinical promise of myostatin inhibitors, the clinical trial experience to date of these inhibitors in muscular dystrophy, and the potential reasons for the lack of observed translation.

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https://journals.lww.com/co-neurology/Fulltext/2020/10000/The_elusive_promise_of_myostatin_inhibition_for.12.aspx

Amyotrophic lateral sclerosis: update on clinical management

imagePurpose of review
The current review will provide recent updates in the clinical management of amyotrophic lateral sclerosis (ALS).
Recent findings
Although there is no cure for ALS, there are new treatments, growing knowledge of genetics, development of clinical staging systems, and the recent coronavirus disease 2019 pandemic that have recently impacted the clinical management of ALS. Increased understanding of genetics has helped provide insights into pathophysiology, the staging systems and clinical measures help to provide tools for monitoring disease clinically, and the recent coronavirus disease 2019 pandemic has provided opportunities to develop telemedicine and remote monitoring of disease thereby increasing accessibility to care and reducing burden of travel to centers for people living with the disease and their caregivers.
Summary
ALS is a progressive neurodegenerative disease that causes degeneration of the motor neurons which leads to paralysis and respiratory failure. Despite the lack of a cure, multidisciplinary care, proactive respiratory management, nutritional care and management of symptoms as well as pharmacological interventions that can improve quality of life and survival.

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https://journals.lww.com/co-neurology/Fulltext/2020/10000/Amyotrophic_lateral_sclerosis__update_on_clinical.15.aspx

Molecular pathogenesis of spinal bulbar muscular atrophy (Kennedy's disease) and avenues for treatment

imagePurpose of review
The aim of this study was to illustrate the current understanding and avenues for developing treatment in spinal and bulbar muscular atrophy (SBMA), an inherited neuromuscular disorder caused by a CAG trinucleotide repeat expansion in the androgen receptor (AR) gene.
Recent findings
Important advances have been made in characterizing the molecular mechanism of the disease, including the disruption of protein homeostasis, intracellular trafficking and signalling pathways. Biomarkers such as MRI quantification of muscle volume and fat fraction have been used to track disease progression, and will be useful in future clinical studies. Therapies tested and under development have been based on diverse strategies, including targeting mutant AR gene expression, stability and activity, and pathways that mitigate disease toxicity.
Summary
We provide an overview of the recent advances in understanding the SBMA disease mechanism and highlight efforts to translate these insights into well tolerated and effective therapy.

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https://journals.lww.com/co-neurology/Fulltext/2020/10000/Molecular_pathogenesis_of_spinal_bulbar_muscular.13.aspx

Biomarkers in amyotrophic lateral sclerosis: a review of new developments

imagePurpose of review
This review draws together the most recent findings in ALS biomarker research from biochemical, imaging and neurophysiology techniques.
Recent findings
The potential of circulating RNA is highlighted, including new retrieval techniques. With ongoing genetic clinical trials, the need for pharmacodynamic biomarkers is essential. There is a strong case for neurofilament proteins being validated in ALS; their biomarker profile is discussed. Oxidative stress and neuroinflammation studies offer insight into disease mechanisms and offer good biomarker potential. Recent metabolic studies include investigation of lipid profiles, creatinine and ferritin. The potential of chitinase proteins as pharmacodynamic and prognostic biomarkers is highlighted. The role of tau and amyloidβ is debated, as evidenced by the articles presented here. Proteomic approaches provide unbiased discoveries of novel biomarkers, together with confirmation of previous findings. The use of imaging techniques is outlined to demonstrate selective atrophy, volume loss, muscle and tract involvement. In-vivo imaging is discussed with reference to histone deacetylase, oxidative stress, neuroinflammation and metabolic changes. New applications of electrophysiology demonstrate objective muscle biomarkers and brain network perturbations.
Summary
The biomarker research field continues to provide insight into the disease. Multicentre collaborations are needed to validate these promising recent findings.

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https://journals.lww.com/co-neurology/Fulltext/2020/10000/Biomarkers_in_amyotrophic_lateral_sclerosis__a.18.aspx