BMJ Neurology Open最新文献

Background: Variants in the FHL1 gene are associated with a spectrum of rare X-linked hereditary myopathies. This study describes the clinical presentation and genetic basis of a novel FHL1 variant identified in a Chinese family with an inherited myopathy, aiming to delineate its phenotypic and genotypic characteristics.

Methods: Clinical data were collected from two symptomatic family members. The proband underwent a muscle biopsy. Genetic analysis was performed using whole-exome sequencing and Sanger sequencing of peripheral blood DNA. Bioinformatic tools were employed to predict the pathogenicity of the variant and its impact on protein structure and stability. Wild-type and mutant FHL1 constructs were transfected into 293 T cells to compare mRNA and protein expression levels via quantitative PCR and Western blot.

Results: Affected family members exhibited progressive lower limb weakness and muscle atrophy. Muscle biopsy revealed mild myopathic changes without reducing bodies. A heterozygous FHL1 c.505T>C (p.C169R) variant was identified in the proband and other affected family members, while her nephew carried a hemizygous variant. Bioinformatics analysis predicted the variant to be damaging, and structural analysis indicated altered secondary structure and reduced protein stability. While mRNA levels remained unchanged in transfected 293 T cells, mutant FHL1 protein expression was significantly reduced in this heterologous system.

Conclusion: The FHL1 c.505T>C (p.C169R) variant is likely pathogenic and associated with a familial myopathy. The reduction in mutant protein expression may contribute to the disease mechanism. This finding expands the spectrum of FHL1-related myopathy reported in the Chinese population and underscores the importance of integrated genetic and clinical analyses for diagnosis.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an inflammatory, immune-mediated neuropathy of the peripheral nerves and nerve roots. CIDP is unlikely to be a discrete disease entity, but rather a spectrum of related conditions, in which cell-mediated and humoral mechanisms act synergistically to cause damage to peripheral nerves. The 2021 guideline of the European Academy of Neurology/Peripheral Nerve Society on the diagnosis and treatment of CIDP has modified the CIDP spectrum to include typical CIDP and four well-defined CIDP variants. Patients with CIDP usually respond well to immunoglobulin therapy, steroids or plasmapheresis; however, 20-30% do not respond well, and approximately 15% remain refractory to all treatment modalities. Rituximab, mycophenolate mofetil and cyclophosphamide are of therapeutic benefit for some of these patients. Patients with some CIDP variants respond less well to immunotherapy, suggesting a difference in the pathogenic mechanisms underlying these variants. Potential novel treatments trialled in CIDP, targeting functionally relevant disease mechanisms, include neonatal Fc receptor blockers and complement inhibitors. These new treatment approaches are needed to optimise disease outcomes in refractory patients, and as an alternative for patients with suboptimal response requiring high doses or experiencing side effects from first-line therapies. Increasing the therapeutic options for patients with CIDP, particularly for refractory patients, highlights the need for more accurate diagnosis of typical CIDP and CIDP variants, objective evidence of treatment response and the need for reliable clinical biomarkers.

Abstract:

Objective: Targeting interleukin-17A (IL-17A) represents a potential therapeutic strategy for myasthenia gravis (MG), but its clinical effects and immunomodulatory mechanisms remain incompletely defined. This study investigated the multidimensional efficacy and immune kinetic profile of secukinumab (SEC) in patients with MG.

Methods: We retrospectively enrolled acetylcholine receptor (AChR) antibody-positive (AChR-Ab⁺) generalised patients with MG (MG Foundation of America class IIa-IVb) treated at the Department of Neurology, Peking University People's Hospital between February 2023 and November 2024. All patients received SEC therapy (150 mg weekly for 4 weeks, followed by 150 mg every 4 weeks as maintenance for 24 weeks). Stable doses of conventional therapies (pyridostigmine, corticosteroids or immunosuppressive agents) were permitted. Longitudinal assessments were performed to evaluate changes in clinical scores (Quantitative MG (QMG) score, 15-item MG Quality of Life (MG-QOL15) scale, MG Activities of Daily Living (MG-ADL) scale), serum AChR-Ab titres, Th17/Tfh (T helper 17 cell/T follicular helper) cell frequencies and cytokine levels at multiple time points.

Results: A total of 29 patients with MG completed the study and were matched with 29 healthy controls. Following SEC treatment: (a) clinical outcomes: showed that by week 24, significant reductions from baseline were observed in QMG, MG-QOL15 and MG-ADL scores (reductions of 60.7%, 58.3% and 64.1%, respectively; all p<0.01). Significant clinical efficacy emerged by week 8 (25.0% reduction in QMG, p<0.01). (b) Correlations: the reduction in AChR-Ab titres strongly correlated with improvements in clinical scores (r=0.435-0.542, p<0.05). Furthermore, the decrease in Tfh cells showed a significant association with the decline in IL-6 levels (r=0.568-0.591, p<0.001).

Interpretation: In this study, SEC treatment was associated with rapid and sustained clinical improvement, as well as enhanced quality of life in patients with AChR-Ab⁺ MG. These benefits were correlated with modulation of the Th17/Tfh cell axis, downregulation of the IL-17A/IL-6 pathway and a reduction in autoantibody levels. These preliminary findings highlight the potential of IL-17A inhibition as a therapeutic strategy worthy of further investigation in MG.

Background and aims: Repeated evaluation for grading of symptoms and signs in distal symmetrical peripheral neuropathy (DSPN) is a core aspect of patient care and inflicts a burden on both the patient and the healthcare system. We designed the smartphone-based Neuropathy Tracker to enable patients to document symptoms and perform a guided self-examination of signs of neuropathy by themselves. We investigate the alignment and classification strength of this grading with grading performed by professionals.

Methods: We included 21 patients with DSPN and 18 controls. In a test-retest paradigm, the patients used the Neuropathy Tracker, and they had examinations by clinical professionals to grade their neuropathy using the Utah Early Neuropathy Scale (UENS) and the Total Neuropathy Score - Clinical Version (TNSc). Further, they had quantitative examinations of Temperature Thresholds and Nerve Conduction Studies for amplitudes of Sural Sensory Nerve Action Potentials.

Results: In a Bland-Altman analysis of differences between repeated tests, we found similar 95% confidence limits between Neuropathy Tracker and UENS, while TNSc had fewer wide limits. The comparison between the Neuropathy Tracker and UENS showed no bias in test score differences. Classification with receiver operating curve analysis showed Neuropathy Tracker to be slightly inferior to UENS and TNSc to classify neuropathy, but still with excellent ability, with area under curve values of 0.903±0.053.

Conclusions: Patient-administered neuropathy grading using the Neuropathy Tracker could add to the clinical evaluation in DSPN without an in-person visit to the outpatient clinic.

Functional neurological disorder (FND) is a common condition and outcome depends on good patient understanding. This article aims to summarise and simplify the prevailing model of FND, active inference, with key illustrative papers.

Background: The m.3243A>G mitochondrial DNA variant is the most common cause of adult mitochondrial disease and is associated with a heterogeneous clinical phenotype. The retina and optic nerve are among the most metabolically active tissues, making them vulnerable to mitochondrial dysfunction. Optical coherence tomography (OCT) studies have demonstrated retinal nerve fibre layer (RNFL) thinning in mitochondrial and other neurodegenerative diseases. We investigated whether temporal RNFL thinning is associated with central nervous system (CNS) involvement in individuals with the m.3243A>G variant.

Methods: High-resolution OCT was used to assess peripapillary RNFL thickness and perform macular segmentation. Participants were categorised into normal RNFL (n=14) or temporal RNFL thinning (n=15) groups. Demographic data, mean-corrected m.3243A>G heteroplasmy, Newcastle Mitochondrial Disease Adult Scale (NMDAS) scaled scores and NMDAS neurological traits were compared.

Results: Temporal RNFL thinning was significantly associated with neurological features (Fisher's exact test, p=0.027). In multivariable analysis, RNFL thinning and age were independent predictors of neurological involvement. Macular OCT revealed concomitant thinning of the ganglion cell-inner plexiform (GC-IPL) complex in the RNFL thinning group, with preservation of outer retinal layers, supporting primary retinal ganglion cell vulnerability. No significant associations were found between RNFL thinning and m.3243A>G heteroplasmy or NMDAS scaled scores.

Conclusion: Temporal RNFL thinning, accompanied by GC-IPL loss, is associated with neurological involvement in m.3243A>G-related mitochondrial disease, supporting its potential as a non-invasive biomarker of CNS dysfunction. Longitudinal studies are needed to determine whether these retinal changes are progressive and predictive of neurological decline.

Background: Neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated diseases (MOGAD) impose psychological burdens on patients. Chronic illnesses create challenges for both patients and their partners, who also play a crucial role in managing disease-related stress. Despite its relevance, little is known about the role of dyadic coping (DC) in these conditions. This study investigates DC in NMOSD and MOGAD, aiming to provide clinical recommendations.

Methods: The CoMMOnsense-Study is a cross-sectional, prospective study of 59 NMOSD and 50 MOGAD patients and their respective partners, recruited from 15 centres of the German Neuromyelitis Optica Study Group registry. Participants completed self-report questionnaires on DC, depression, anxiety and quality of relationship. Correlation analyses were performed to compare findings based on antibody status. Subsequently, multivariate regression analyses were conducted to identify relevant predictors of DC.

Results: Patients with NMOSD and MOGAD demonstrated higher levels of depressive symptoms (NMOSD: p=0.007; MOGAD: p=0.023) and stress communication scores (NMOSD: p=0.022; MOGAD: p=0.013) than their partners. Negative coping was low across all subgroups (Stanine 1). Despite high DC and relationship quality, discrepancies were observed in the coping perceptions between partners.

Conclusions: Coping is highly shared within partnerships affected by NMOSD and MOGAD, while discrepancies in coping perceptions and protective buffering suggest the presence of unfavourable coping mechanisms. Reducing protective buffering and illness-related distortions shows potential areas for enhancing DC.

Background: Despite advances in multiple sclerosis (MS) management, the need for more accurate biomarkers remains critical. Conventional MRI, while essential for diagnosis, prognosis and disease monitoring, has limitations in capturing the full complexity of disease progression. This paper aims to identify biomarkers likely to be available in clinical practice by 2028, define a prospective organisational follow-up model for patients with MS, explore organisational requirements and propose solutions to facilitate their implementation. These insights aim to inform and anticipate future discussions among policymakers regarding the adoption of prospective biomarkers into clinical practice.

Methods: A multimethod qualitative design was employed, including a systematic literature review of 82 studies, two modified Delphi consensus processes and semistructured interviews with nine neurologists and three healthcare programming experts, applying the Structural, Technological, Organisational and Professional (STOP) framework. The STOP framework was used to assess structural, technological, organisational and professional requirements and to explore solutions.

Results: The research identified a prospective organisational follow-up model that integrates the most probable prospective biomarkers into clinical practice. The prospective organisational follow-up model defined an optimal testing frequency of Serum Neurofilament Light Chain and Glial Fibrillar Acidic Protein every 6 months, as well as Cognitive Tests and Optical Coherence Tomography every 12 months. Combining biomarkers and aligning them with MRI was seen as beneficial. Despite the validation of the model through a modified Delphi consensus process based on organisational feasibility and economic sustainability, structural and organisational challenges need to be addressed to ensure smoother integration into clinical practice.

Conclusions: This article aims to define an organisational model for the integration of prospective biomarkers into clinical follow-up in MS. It also explores potential strategies to facilitate their transition from research settings to routine clinical practice. The proposed approach provides a framework with potential for replication across various care pathways.

Background: Factors such as age and stroke severity are commonly used to predict poststroke functional outcomes and tailor stroke rehabilitation therapy. However, the role of personality in stroke rehabilitation and its influence on functional outcomes is unclear. This review aims to assess whether an association exists between personality and poststroke functional outcomes.

Methods: We searched Medline, AMED, APA PsychINFO, CENTRAL, CINAHL and Scopus for studies published between database inception and 22 October 2024. Studies were included if they recruited adults with stroke, used a validated method to assess personality and poststroke functional outcomes and were published in a peer-reviewed journal.

Results: Five studies were identified (n=424): four cohort and one cross-sectional. There were no major concerns regarding risk of bias. Methods of assessing personality and poststroke functional outcome both varied, with Eysenck's Personality Questionnaire and Barthel Index being the most frequently used. Extroversion, openness and lie-tendency were associated with improved poststroke functional outcomes, while type D personality was negatively associated with poststroke functional outcomes.

Conclusions: There is some evidence for an association between personality and poststroke functional outcomes, but this is limited by the small number of relevant studies and small sample sizes. Further studies are needed to investigate this potential relationship.

Prospero registration number: CRD42024592518.

Introduction: Statin therapy is known to reduce subsequent cardiovascular events in patients who had an ischaemic stroke and transient ischaemic attack (TIA). However, its effectiveness and safety in frail older adults with a recent stroke or TIA are uncertain, leading to variations in clinical practice. 'StAtins in Frail oldEr patients with ischemic Stroke or Transient ischemic attack-the Randomized Controlled Trial' (SAFEST-RCT) aims to investigate the effectiveness of initiating versus not initiating statin therapy in this vulnerable population, to optimise secondary prevention strategies.

Methods and analysis: This multicentre, prospective, randomised, open-label study aims to enrol 612 frail adults ≥70 years with a recent acute ischaemic stroke or TIA across 22 Dutch hospitals. The study compares prescribing versus not prescribing statins in terms of health-related quality of life, major adverse cardiovascular event-free survival and societal costs over a 2-year follow-up period.

Ethics and dissemination: The SAFEST-RCT protocol was approved by the Ethics Committee of Amsterdam UMC. It complies with the Declaration of Helsinki and is classified as a healthcare evaluation. Recruitment began in March 2025. Results will be published in open access journals, presented at conferences, shared via the Dutch Brain Injury Association and integrated into national guidelines to support implementation in routine care.

Trial registration number: NCT06785727.