Current Opinion in Neurology最新文献

Purpose of review: This review summarizes recent evidence on sleep disturbances in amyotrophic lateral sclerosis (ALS), emphasizing their role as intrinsic features of the disease process rather than consequence of motor decline.

Recent findings: Emerging data suggest that sleep disturbances such as sleep fragmentation, rapid eye movement sleep (REM) and non rapid eye movement sleep (NREM) alterations and circadian changes often precede classic motor symptoms. Structural and functional hypothalamic changes have been observed in early ALS, suggesting a direct role in sleep-wake dysregulation. In addition, impaired glymphatic clearance during sleep may contribute to neurodegeneration by impairing the removal of protein waste. Polysomnographic studies and cohort data support the presence of prodromal sleep abnormalities in both symptomatic patients and gene mutation carriers. Noninvasive ventilation has shown benefits not only in respiratory management but also in improving sleep quality and overall prognosis.

Summary: Sleep alterations in ALS are increasingly recognized as early indicators and potential modulators of disease progression. The hypothalamus and the glymphatic system emerge as key contributors to these disturbances, highlighting sleep as a therapeutic target. Understanding the role of sleep in ALS pathophysiology may aid in earlier diagnosis and novel intervention strategies aimed at modifying disease course.

Purpose of review: Myofibrillar myopathies (MFMs) are traditionally defined by histopathology, but recent genetic discoveries have broadened the spectrum of causative genes beyond Z-disk components. This review aims to address the resulting terminological inconsistency by proposing a refined, mechanism-based definition of MFM centered on its identity as a "Z-disk-opathy." This re-evaluation is timely and relevant for improving diagnostic clarity and guiding future research.

Recent findings: The literature increasingly reports MFM-like pathology in conditions caused by mutations in genes not directly encoding Z-disk structural proteins or their interacting chaperones. This review highlights the pathogenic mechanisms distinguishing true MFMs, which involve disruption of Z-disk protein structure or Z-disk protein homeostasis, from "myopathies with MFM pathology" that share histological features but stem from different molecular etiologies. Key themes include the dominant nature of mutations in Z-disk structural proteins and the critical role of chaperone dysfunction in MFM pathogenesis.

Summary: A refined definition classifying MFM as a "Z-disk-opathy" offers a clearer framework for diagnosis and mechanistic understanding. This distinction has significant implications for clinical practice, facilitating more accurate diagnosis, and for research, by supporting the development of targeted therapeutic strategies aimed at either restoring Z-disk proteostasis or mitigating the effects of aberrant protein accumulation.

Purpose of review: Small fiber neuropathies (SFN) are a heterogeneous group of disorders affecting the thinly myelinated Aδ and unmyelinated C-fibers. The clinical picture is dominated by neuropathic pain, often accompanied by autonomic symptoms of variable severity. The underlying causes encompass metabolic conditions like diabetes mellitus, immuno-mediated disorders, infection, exposure to toxins, and gain-of-function variants in the genes encoding the Nav1.7, Nav1.8, and Nav1.9 sodium channel subunits, though the list of associated diseases continues to grow. Recently, increased attention has focused on immune-mediated forms, which led to the identification of potentially treatable subgroups. These discoveries have advanced our understanding of pathophysiological mechanisms.

Recent findings: Recent studies have broadened the spectrum of underlying conditions associated with SFN, including immune-mediated forms and links to SARS-CoV-2 infection and vaccines. Studies on genetic variants linked to unique clinical presentations have also yielded new insights. Furthermore, emerging perspectives highlighted disorders involving small fiber pathology that lacks typical clinical features of neuropathic pain, challenging traditional diagnostic criteria.

Summary: Deepening our understanding of the causes underlying SFN advances the identification of potential therapeutic targets. The clinical presentation of SFN can vary significantly and may not consistently correlate with specific underlying conditions. Therefore, a systematic investigation of possible causes through a structured diagnostic assessment is critical to unveil additional contributing factors.

Purpose of review: Guillain-Barré syndrome (GBS) is a severe but treatable form of immune-mediated neuropathy. The purpose of this review is to provide an update on current immune treatments for GBS, highlight challenges in clinical practice and research, and discuss new developments in therapies that focus on reducing inflammation and preventing further nerve damage.

Recent findings: In 2023, a GRADE-based guideline was published on the diagnosis and treatment of GBS on behalf of EAN/PNS. Several clinical trials have been conducted in GBS recently, including studies with an observational comparative study design.

Summary: Since 30 years, intravenous immunoglobulins and plasma exchange are the only proven effective immune treatments for GBS. Despite these treatments, a substantial proportion of patients recover incompletely and have residual disability or complaints with a high impact on quality of life. New treatment trials focus on reducing immunoglobulin G antibodies to nerves and inhibition of complement activation. Observational comparative studies based on extensive and well defined cohorts are an alternative method to evaluate the effect of treatments in GBS. Several novel study designs are discussed that aim to facilitate the conduct of future trials with more sustainable use of data.

Purpose of review: Autoimmune nodopathies (AN) are a recognized distinct group of immune-mediated peripheral neuropathies with unique immunopathological features and therapeutic implications. This review synthesizes recent advances in their pathogenesis, diagnosis, and management, which have refined their clinical classification and informed targeted treatment strategies.

Recent findings: AN are characterized by autoantibodies targeting surface proteins in the nodal-paranodal area (anti-contactin-1, anti-contactin-associated protein 1, anti-neurofascin-155, anti-pan-neurofascin), predominantly of IgG4 subclass. Recent studies have delineated antibody subclass contributions to disease mechanisms and identified B-cell response patterns predictive of therapeutic outcomes. Despite clinical overlap with chronic inflammatory demyelinating polyradiculoneuropathy and Guillain-Barré syndrome, AN exhibit a distinct phenotype and a poor response to intravenous immunoglobulins. Multiple studies, including recent ones, report good response and long-term clinical remission with B-cell depleting therapies. Diagnostic assays such as cell-based assays and ELISA offer high accuracy, while biomarker-guided monitoring using antibody titers and serum neurofilament light chain supports individualized follow-up.

Summary: Emerging evidence consolidates AN as a nosologically and therapeutically distinct entity. Integration of immunopathological insights with biomarker-driven strategies enables precision diagnostics and targeted immunotherapy, improving clinical outcomes.

Purpose of review: This review synthesizes the recent advances in the application of nerve ultrasound (US) to inflammatory neuropathies, including chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor neuropathy (MMN), Guillain-Barré syndrome (GBS), neuralgic amyotrophy (NA), Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, Skin changes syndrome (POEMS), and anti-MAG neuropathy. The aim is to clarify nerve US clinical utility and guide its use in clinical practice.

Recent findings: Nerve US supports differential diagnosis through characteristic sonographic patterns. In CIDP, it aids in identifying atypical forms, predicting treatment response, and may have a role in follow-up. In MMN, nerve US shows diagnostic value. In GBS, it can help differentiate acute-onset CIDP. In NA, alterations can be detected within hours from the onset. Anti-MAG antibody neuropathy lacks well characterized US features. In POEMS and vasculitis, data are scarce and conflicting.

Summary: Nerve US is an established tool for diagnosing neuropathies, as it is noninvasive, accessible, reproducible, and complements electrophysiology. Its role is established in CIDP and its variants, while evidence supports its utility in MMN and the differential diagnosis of neuropathies with an inflammatory-like clinical presentation. In NA, nerve US may outperform neurophysiology. It appears less useful in GBS, POEMS, and anti-MAG neuropathy.

Purpose of review: Myotonic dystrophy type 1 (DM1) is a genetically mediated, multisystemic neuromuscular disorder with significant phenotypic heterogeneity. This review aimed to summarize recent advances in clinical understanding, natural history, and therapeutic development, with a focus on cardiac, respiratory, cognitive, and pediatric aspects of DM1.

Recent findings: Longitudinal studies are refining the natural history of both adult and pediatric DM1. Advances in biomarker discovery, including composite ribosomal nucleic acid splicing metrics and imaging findings, are improving disease monitoring and treatment assessment. Cardiac risk stratification is evolving, although respiratory management remains challenging due to adherence issues. Increasing attention is being given to cognitive and behavioral impairments, particularly in congenital and childhood-onset DM1. Although disease-modifying therapies remain in development, real-world data on symptomatic treatments such as mexiletine and nonpharmacological interventions, including exercise and cognitive behavioral therapy, provide valuable clinical insights.

Summary: Recent literature highlights substantial progress in understanding DM1 across different age groups and organ systems. Although no approved disease-modifying therapies exist, ongoing clinical trials and biomarker advancements offer hope. This review synthesizes these developments to inform clinical management and guide future research efforts.

Purpose of review: Here, we summarize the current knowledge about the genetics and proposed mechanisms of disease underlying skeletal muscle short tandem repeat (STR) expansion disorders.

Recent findings: The human genome contains up to 2 million STRs (also known as microsatellites), which are highly variable repetitions of two to six nucleotide-long DNA motifs. These elements, present in both coding and noncoding sequences, are highly instable, and their polymorphic variations have important roles in genes regulation and human phenotypic trait diversity. Importantly, expansion over a threshold size of a subset of these STR is the cause of approximately 60 neurological diseases, including some major muscle disorders such as myotonic dystrophy, oculopharyngodistal myopathy (OPDM) and oculopharyngeal muscular dystrophy. The discovery and characterisation of a number of these STR expansion disorders, in particular for OPDM, has been enabled in recent years by advanced genomic technologies.

Summary: Many recently described STR expansion disorders are now recognized and genetic testing of patients is possible on a research basis, clinical testing for these newly described repeat loci is not yet readily available and is complicated by the reduced penetrance seen in some families, rendering clinical interpretation more difficult. The phenotypic spectrums associated with these STR expansion disorders are also evolving as unbiased sequencing approaches identified expansions at known loci in individuals with phenotypes that are quite different to those in which the STR expansions were first characterized. The pathomechanisms associated with these newer STR expansion disorders is still poorly understood, however there is evidence of both RNA toxicity and polyGly toxicity. Additional STR expansions underlying skeletal muscle diseases are likely to be identified in coming years and may shed further light onto the complex genetics, epigenetics and disease mechanisms underlying these disorders.