BMJ Neurology Open最新文献

Background: Menopausal changes in adipose tissue distribution and adipokine profiles may influence immune activity in multiple sclerosis (MS). We investigated relationships between adipokines, inflammation and disease severity in menopausal women with MS and evaluated changes in adipokines during menopausal hormone therapy (MHT).

Methods: 16 menopausal women with MS (participants with MS, PwMS) and 15 age-matched healthy controls were assessed for the associations of adipokines with inflammatory markers, and clinical, radiological and fluid biomarkers of MS severity. Adipokine levels were monitored over 1 year of oral MHT in baseline-controlled design.

Results: In PwMS, body mass index and leptin-to-adiponectin ratio correlated with circulating high-sensitivity C reactive protein (hs-CRP), tumour necrosis factor (TNF)-α and interleukin-6 (ρ=0.51-0.66, p<0.05). The associations with hs-CRP and TNF-α were independent of age, disease duration, follicle-stimulating hormone and vitamin D. Serum vitamin D inversely correlated with hs-CRP, TNF-α and interferon-γ (ρ=-0.64-0.65, p<0.01). Adipsin showed strong correlation with neurofilament light chain (ρ=0.72, p=0.002) and decreased during MHT (3 months: p=0.007; 12 months: p=0.04).

Conclusions: Adipokine imbalance and lower vitamin D levels were associated with systemic inflammation in PwMS. Adipsin emerged as a promising biomarker, with potential relevance for disease monitoring and therapeutic modulation via hormonal pathways. These findings support further exploration of multibiomarker profiling to guide personalised care in menopausal MS.

Background: Neurological complications are increasingly recognised in Sjögren's Syndrome, yet their prevalence and determinants remain incompletely characterised. This study aimed to evaluate the frequency, patterns and clinical associations of neurological involvement in patients with primary Sjögren's syndrome (pSS).

Methods: A retrospective analysis was performed on 49 patients diagnosed with pSS according to 2016 ACR/EULAR criteria. Clinical, laboratory, neuroimaging and electrophysiological data were reviewed. Neurological involvement was defined using attribution-based criteria. Statistical analyses included multivariable logistic regression, with Bonferroni correction for multiple comparisons.

Results: Neurological complications were present in 65.3% (32/49) of patients. Among these, 21 (65.6%) had isolated peripheral nervous system (PNS) involvement, 4 (12.5%) isolated central nervous system (CNS) involvement and 7 (21.9%) combined PNS-CNS involvement. The most frequent manifestations were headache attributed to pSS (61.2% of the total cohort) and peripheral neuropathy (44.9%). Among the 22 patients who underwent brain MRI, white matter lesions were observed in 45.5%, and 9.1% showed multiple sclerosis-like lesions. Electrophysiological studies (n=23) revealed sensory neuropathy in 26.1% and motor neuropathy in 13.0%. No bivariate associations remained significant after Bonferroni correction. However, multivariable regression identified higher EULAR Sjögren's Syndrome Disease Activity Index scores (OR 1.21, p=0.03), positive antithyroid antibodies (OR 4.8, p=0.04) and joint pain (OR 5.2, p=0.02) as independent predictors of neurological involvement. Disease was controlled in 91.8% of cases, with 6.1% showing persistent activity and 2.0% mortality.

Conclusion: Neurological complications are common in pSS and associated with higher systemic disease activity. Peripheral neuropathy and pSS-attributed headache predominate, while MRI often reveals non-specific white matter changes. Multivariable analysis, but not univariate testing, identified key correlates of neurological involvement, underscoring the importance of comprehensive disease assessment. Prospective studies with standardised neurological phenotyping are needed.

Introduction: In 2015, pivotal trials demonstrated that endovascular thrombectomy (EVT) in patients who had a large vessel occlusion stroke improves functional outcome. We report 10-year trends and outcomes from our centre, which provides EVT to 2.8 million people in northern New Zealand.

Methods: We performed an audit of all patients who underwent EVT between 1 March 2015 and 1 March 2025 using the compulsory National Stroke Reperfusion Therapy Registry. Baseline characteristics, treatment variables and 3-month outcomes were analysed. Functional independence was defined as a modified Rankin scale score of 0-2.

Results: 2184 patients were treated with EVT (48% women; mean age 67.6 years), with the number of treated patients increasing year-on-year. 1404 (63.8%) required interhospital transfer (638 (29.2%) via air ambulance). 1868 (85.5%) had successful reperfusion (Thrombolysis in Cerebral Infarction 2b-3). 1015 (46.5%) received intravenous thrombolysis. At day 90, 1095 (51.9%) patients were functionally independent, 1506 (72.8%) were living at home and 327 (15.5%) had died.

Conclusion: EVT outcomes in New Zealand align with international results despite supra-regional logistical challenges. The growing number of treated cases reflects improved access to EVT across different regions and an expansion of eligibility criteria. Our study supports the continued development and provision of large hub-and-spoke EVT services.

Background: Variants in the vaccinia-related kinase 1 (VRK1) gene have been linked to a spectrum of lower motor neuron disorders, typically characterised by distal muscle weakness and atrophy. Homozygous c.961C>T (p.Arg321Cys) is a rare mutation associated with a slowly progressive distal spinal muscular atrophy phenotype, usually presenting with normal or mildly elevated creatine kinase (CK) levels.

Case presentation: A 29-year-old man born to consanguineous parents presented with a 2 year history of progressive lower limb weakness. Examination revealed distal lower limb muscle wasting, absent ankle reflexes and brisk knee and upper limb reflexes. CK was elevated at 17 791 IU/L (normal<190). Neurophysiology showed a motor neuropathy with chronic active denervation, and MRI showed fatty atrophy and oedema in lower limb muscles. Muscle biopsies revealed neurogenic atrophy, scattered necrotic myofibres, pseudo-dystrophic changes and reduced sarcolemmal dysferlin. Genetic testing identified a homozygous VRK1 (c.961C>T, p.Arg321Cys) variant.

Conclusions: This report expands the VRK1 phenotype to include marked hyperCKaemia. Elevated CK levels are typically associated with inflammatory myopathies, though they can be seen in primary diseases of the motor neurons. A lack of sarcolemmal dysferlin could underlie myofibre sensitivity to minor trauma and cause elevated CK levels in chronic muscle denervation.

Background: Myasthenia gravis (MG) is a rare autoimmune disorder that affects neuromuscular transmission, leading to muscle weakness. While most patients respond to standard treatments, approximately 15% remain refractory, prompting interest in alternative therapies. This study examined the use of rituximab in patients with refractory MG at a single centre in Latvia, intending to broaden discussions on treatment strategies.

Materials and methods: The prospective cohort study was conducted at Pauls Stradiņš Clinical University Hospital from November 2022 to March 2024. Refractory MG was defined as failure to achieve adequate disease control despite standard immunosuppressive therapy, including patients with persistent symptoms, recurrent crises or intolerance to medications. Myasthenia Gravis Composite Score (MGCS), Myasthenia Gravis Activities of Daily Living and Myasthenia Gravis Quality of Life (scores at baseline and monthly for 6 months) were completed. Glucocorticosteroid doses were also recorded. Data were analysed using descriptive statistics and Wilcoxon signed-rank test, considering p<0.05 significant.

Results: 98 patients with MG were evaluated to identify treatment-refractory cases. A total of nine patients with refractory MG (median disease duration 7 years, range 1-12) were included and received a single low dose of rituximab. Among the nine patients treated, seven were acetylcholine receptor-positive and two were muscle-specific kinase antibody-seropositive. 6 months after treatment, the median MGCS decreased from 11.5 (IQR 7.3-17.8) to 7.5 (IQR 3.8-8.0) (p=0.025). The median daily corticosteroid dose decreased from 15.0 mg (IQR 10.0-20.9) to 8.5 mg (IQR 5.0-12.5) (p=0.036). There were no exacerbations of MG or significant adverse reactions.

Conclusions: Our findings suggest that rituximab may be a promising treatment option for refractory MG. The notable clinical benefits and safety profile make rituximab a valuable addition to this challenging autoimmune disorder treatment options. Further research is needed to refine patient selection and dosing for optimal treatment outcomes.

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.