Journal of Neurology, Neurosurgery, and Psychiatry最新文献

Background: Brain atrophy is increasingly used as an outcome measure in clinical trials in relapsing-remitting multiple sclerosis (RRMS), but little is known about how chronological age interacts with MS-specific effects. For instance, while annual brain atrophy rates typically increase with age in healthy individuals, MS patients tend to exhibit decreasing atrophy rates over time.

Methods: We investigated the relationship between age and brain volume in a large dataset of 4241 trial participants with RRMS. We used pooled individual-participant data from phase 3 clinical trials with 96 weeks follow-up, which included both active treatment and placebo/comparator arms. Participants were categorised into seven groups based on chronological age (18-24 years, 25-30 years, 31-35 years, 36-40 years, 41-45 years, 46-50 years, 51-56 years). We performed multilevel linear mixed-effects regression analyses to examine differences between age groups in normalised whole brain volume (NWBV), thalamus grey matter volume (NThGMV), grey matter volume (NGMV) and white matter volume at baseline and their changes over follow-up. We also studied how disease duration influenced these relationships using similar models.

Results: Older participants showed significantly lower NWBV, NGMV and NThGMV at baseline than younger participants. Most importantly, older participants exhibited lower rates of atrophy during follow-up, particularly in the thalamus. This association was consistent across all disease duration subgroups.

Conclusions: Older participants had more severe atrophy when enrolled into trials, but slower (thalamic) atrophy rates, independent of disease duration over time. Together, these findings emphasise that age should be taken into account when designing clinical trials that use brain atrophy as an outcome measure.

Background: No disorder-specific patient-reported outcome measure (PROM) has yet been validated for functional movement disorders (FMDs), leaving a critical gap in clinical care and research.

Objective: To validate the FMD questionnaire (FMDQ) in a prospectively recruited sample through a multicentre study.

Methods: Confirmatory factorial analysis (CFA) tested the assumed structure of the questionnaire with factors reflecting severity of motor symptoms, impairment of everyday activities, impact of non-motor symptoms and impairment of social functioning. Internal consistency and floor/ceiling effects were examined. The 36-item short form health survey (SF-36), patient health questionnaire-15 (PHQ-15), the fatigue assessment scale (FAS) and a clinician-rated scale corresponding to motor symptom items of the FMDQ (FMDQ-CR) were used to test criterion and construct validity. The minimally clinically important difference (MCID) was assessed through distribution-based and anchor-based methods in a convenience sample of patients with follow-up assessments.

Results: Complete datasets from 157 patients were analysed; follow-up assessments were available from 30 patients. CFA confirmed that a four-factor model provides a better fit to the data compared with a more restrictive one-factor model. Internal consistency was appropriate for all factors/subscales. No floor or ceiling effects were detected. Criterion and content validity were supported by significant correlations with respective SF-36 subscores, PHQ-15, FAS and FMDQ-CR. Anchor-based MCID was estimated at 8 to 20 points, with the central value aligning with the distribution-based MCID of 12 points (8% of the total score range).

Conclusions: The FMDQ is a psychometrically robust PROM, making it a useful tool for clinical practice and treatment trials.

Background: Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder caused by survival motor neuron (SMN1) deletion. While loss of ambulation in SMA type III typically occurs at a median age of 13.4 years, outcomes in the treatment era remain unclear. This study aims to address that gap by investigating ambulation outcomes in individuals with type III receiving disease-modifying therapies.

Methods: This retrospective study analysed prospectively collected international data. Time-dependent Cox models assessed the association between treatment initiation and age at loss of ambulation, adjusting for age at onset, sex, SMN2 copies, birth year and country. Treatment was modelled as a time-dependent covariate to avoid immortal time bias. Descriptive analyses used Mann-Whitney U and χ² tests.

Results: Among 555 individuals with type III, treatment halved the risk of ambulation loss (HR=0.50), with median loss at 44 vs 32 years in treated and untreated groups. Later onset, ≥4 SMN2 copies and female sex were also protective. The treatment effect was significant in type IIIA (HR=0.34) but not IIIB, with no significant interactions by sex, country or SMN2, though effects remained directionally protective.

Conclusions: Treatment in type III reduced the risk of ambulation loss by 50%, extending median ambulation by 12 years, with the greatest benefit in type IIIA. Later onset, female sex and higher SMN2 copy number were also protective but did not modify treatment effect. These findings underscore the value of early treatment and support its broad use to preserve ambulation across clinical subgroups.

Polyneuropathy, Organomegaly, Endocrinopathy, M-protein and Skin changes (POEMS) syndrome is a rare multisystemic disorder associated with plasma cell dyscrasia, most commonly presenting with peripheral neuropathy. Due to its complex and heterogeneous clinical presentation, misdiagnosis is frequent, particularly with chronic inflammatory demyelinating polyradiculoneuropathy, which often leads to delays in appropriate management. Peripheral nerve involvement in POEMS syndrome is predominantly demyelinating, typically accompanied by early axonal degeneration. Specific clinical, neurophysiological and imaging features are key to differentiating POEMS from other acquired demyelinating neuropathies. Elevated levels of vascular endothelial growth factor (VEGF) play a central role in its pathophysiology, promoting disruption of the blood-nerve barrier and contributing to the systemic manifestations. Accurate diagnosis requires a multidisciplinary approach and is often supported by laboratory testing, including VEGF measurement and monoclonal protein screening as well as advanced imaging techniques. Therapeutic strategies are guided by disease extent and include radiotherapy for localised lesions, systemic chemotherapy and autologous haematopoietic stem cell transplantation for disseminated disease. Early identification and intervention are essential to prevent irreversible nerve damage and optimise long-term functional outcomes. Prompt recognition of characteristic findings not only enables appropriate treatment but may also significantly improve patient prognosis.

Background: The optimal strategy after discontinuation of B-cell depleting therapies like ocrelizumab in people with multiple sclerosis (pwMS) remains uncertain, particularly regarding delayed disease reactivation, disability progression and required treatment duration before cessation.

Methods: In this prospective two-centre observational cohort study with propensity score-matched (PSM) analysis, we evaluated recurrence of disease activity and disability worsening after ocrelizumab discontinuation. PwMS fulfilling the 2017 McDonald criteria were enrolled between January 2018 and December 2023 at two German MS centres. Participants received ocrelizumab for ≥12 months with no inflammatory activity in the preceding 12 months. Of 655 eligible patients (continuers, n=578; discontinuers, n=77), 290 were included after 4:1 PSM. The primary exposure was discontinuation, mainly due to infection concerns during COVID-19 (81%) or hypogammaglobulinaemia (16%). Main outcomes were time to combined inflammatory activity (CIA) and progression independent of relapse activity (PIRA). Receiver operating characteristic (ROC) identified optimal treatment duration.

Results: After median follow-up of 28.5 months, there was no significant difference in CIA risk between groups (HR: 0.91, 95% CI 0.08 to 10.79) or for PIRA (HR: 4.8, 95% CI 0.38 to 60.2). Beyond 24 months after discontinuation, disease activity remained stable, with a numerical rise that did not reach statistical significance. ROC analysis suggested no further reduction of activity beyond 29-30 months of therapy, but increasing reactivation risk after >32 months off-treatment.

Conclusions: For stable pwMS, ocrelizumab discontinuation after about 30 months on-treatment appears safe short-term, though vigilant monitoring is warranted beyond 2 years off-treatment due to potential delayed reactivation.

Background: Predicting response to treatment and long-term disability in multiple sclerosis (MS) remains challenging. In other complex diseases, combining genetic risk variants has enabled the detection of relevant clinical endophenotypes associated with important outcomes, but this strategy has never been applied to MS.

Methods: We applied unsupervised hierarchical clustering to genomic risk scores in a prospective Welsh MS cohort (n=1455) and replicated the findings in the postmortem Netherlands Brain Bank (NBB) MS (NBB-MS) cohort (n=272). Disease progression was assessed using survival analysis to determine the time to Expanded Disability Status Scale (EDSS) milestones.

Results: Three genomic clusters were identified, each with similar genetic profiles. Baseline demographics did not differ between clusters. Welsh patients in cluster 1 attained EDSS 6 and EDSS 8 significantly later than clusters 2 and 3 (by 6 years, p=3×10^-3 and 13 years, p=0.02, respectively). These findings were replicated in the NBB-MS cohort (6-year delay to EDSS 6 for cluster 1 vs 2, p=0.04). Genomic clustering independently predicted disease progression (HRs 1.3-2.0, all p<0.05), beyond established risk factors. Clusters 2 and 3 showed a greater annual increase in T2 lesion load on serial MR imaging (p=0.04). In cluster 2, patients receiving disease-modifying treatments had delayed progression to EDSS 6 (p=3×10^-³), while no such benefit was observed in clusters 1 or 3. Cluster 2 patients also had earlier onset of symptoms, including dysphagia (p=0.02) and spasticity (p=8×10^-⁴) in the NBB-MS cohort.

Conclusions: Genetic clustering reveals clinically meaningful MS subtypes with distinct prognoses and treatment responses, highlighting its potential role in precision medicine for MS management.