Journal of Neurology, Neurosurgery, and Psychiatry最新文献

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.

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.

BackgroundTarget trial emulation (TTE) offers a formal framework for causal inference using observational data, but its validity must be evaluated in each research domain by replicating randomised clinical trials (RCTs). We aimed to replicate eight RCTs evaluating the efficacy of disease-modifying therapies (DMTs) in multiple sclerosis (MS) using French registry data.

Methods: This multicentre, retrospective, observational study was conducted using data extracted in December 2023 from the Observatoire Français de la Sclérose en Plaques (OFSEP) database. For each emulated trial, patients were included when they initiated one of the DMT evaluated in the corresponding RCT and met its inclusion criteria. Clinical outcomes were the annualised relapse rate and 3-month confirmed Expanded Disability Status Scale progression. Radiological outcomes were new/enlarged T2-lesions and new gadolinium-enhanced T1-lesions on a brain MRI. A targeted maximum likelihood estimator was used to estimate the treatment effect adjusted for confounding factors between groups and corrected for censoring and missing outcome assessment.

Results: 14 111 patients were included in eight emulated trials: ASSESS (fingolimod vs glatiramer acetate), BEYOND (interferon beta vs glatiramer acetate), CONFIRM (dimethyl fumarate (DMF) vs glatiramer acetate), OPERA (ocrelizumab vs interferon beta), REGARD (interferon beta vs glatiramer acetate), RIFUND-MS (rituximab vs DMF), TENERE (teriflunomide vs interferon beta) and TRANSFORMS (fingolimod vs interferon beta). Treatment effects estimated in emulated trials were concordant with RCT findings in seven of eight trials for relapse rate, and in all six trials assessing disability progression. Radiological outcomes were more challenging to replicate; concordance was achieved in three of five trials for new T2-lesions, and one of four trials for new gadolinium-enhanced T1-lesions.

Conclusion: The combined use of a TTE methodology and high-quality registry data is a valid tool to evaluate treatment effectiveness in MS.

Background: Non-aneurysmal subarachnoid haemorrhage (NASAH) accounts for less than 20% of spontaneous subarachnoid haemorrhage (SAH). However, its epidemiological characteristics, risk factors and aetiology remain poorly defined.

Methods: All patients with spontaneous SAH admitted to a neurosurgical centre in Sweden over a 3.5-year period were prospectively enrolled in a database. Epidemiological data, risk factors, Fisher grade and follow-up radiological findings were analysed, comparing NASAH cases to aneurysmal SAH (aSAH).

Results: A total of 1532 patients with SAH were included, of whom 377 (24.6%) were diagnosed with NASAH. Five NASAH patients exhibited microaneurysms in the perforating arteries (MAPAs) of the vertebrobasilar circulation, identified on follow-up cone-beam CT angiography. Gender distribution and Fisher grade presentation differed significantly between the NASAH and aSAH groups (p<0.001). Risk factors, such as smoking, hypertension and alcohol overuse, were significantly more common in aSAH than NASAH. Conversely, diabetes mellitus (DM) was more prevalent in NASAH than in aSAH (p<0.001).

Conclusions: This is the largest epidemiological study of NASAH to date. The observed incidence of NASAH was higher than in the previous reports, suggesting either underdiagnosis in earlier studies or a changing proportion of aSAH to NASAH cases. The distinct differences in population characteristics and risk factors suggest that NASAH and aSAH arise from fundamentally different pathophysiological mechanisms. DM emerged as a risk factor for NASAH, and MAPAs were identified as one of the underlying sources of haemorrhage in this subgroup.

Background: Autologous haematopoietic stem cell transplantation (AHSCT) is increasingly used as a one-off disease-modifying therapy for aggressive forms of multiple sclerosis (MS). We report real-world effectiveness of AHSCT for MS in the UK.

Methods: This retrospective open-label study included patients with (pw)MS treated with AHSCT between 2002 and 2023 in 14 UK centres. Outcomes included relapse-free survival (RFS), MRI activity-free survival (MFS), progression-free survival (PFS) and no evidence of disease activity (NEDA-3). We assessed 6-month confirmed Expanded Disability Status Scale (EDSS) score progression or improvement compared with pre-treatment. Treatment-related mortality (TRM) was defined as death from any cause within 100 days post-autologous graft reinfusion.

Results: 364 pwMS were included (median age 40 years; 58% female). Of these, 271 pwMS had adequate neurological follow-up data: 168 (62%) had relapsing-remitting MS (pwRRMS) and 103 (38%) had progressive MS (pwPMS). Median disease duration from symptom onset was 10 years (IQR 6-14), EDSS 6 (IQR 4.0-6.5) and follow-up from AHSCT 46 months. At 2 and 5 years from AHSCT, RFS was 94.6% and 88.6%; MFS 93.1% and 80.1%; PFS 83.5% and 62.4%; NEDA-3 72.3% and 46.2%. pwRRMS had significantly higher rates of PFS (p=0.007) and NEDA-3 (p=0.001) than pwPMS. RRMS was a predictor of EDSS improvement, whose prevalence was 24.2% at 2 years and 20.4% at 5 years. TRM was 1.4% (n=5/364).

Conclusions: In this cohort with high EDSS at baseline and including pwPMS, AHSCT led to durable remission of inflammatory activity and stabilisation or improvement of neurological disability, particularly in pwRRMS.

Background: Treatment of progression independent of relapse activity (PIRA) is a relevant unmet need in multiple sclerosis (MS), being only modestly affected by disease-modifying treatments (DMTs) which target predominantly adaptive immunity in the periphery. As chemotherapy administered during autologous haematopoietic stem cell transplantation (AHSCT) is bioavailable within the central nervous system (CNS), the hypothesis that AHSCT could affect long-term PIRA was explored in aggressive relapsing-remitting (RR)-MS.

Methods: Retrospective propensity-score matched study including RR-MS patients who received BEAM/ATG AHSCT or started natalizumab (NTZ, ie, controls) at our centre in Florence in the period 2007-2018.

Main outcome: cumulative proportion of patients with PIRA during NTZ treatment epoch (ie, censoring controls at NTZ discontinuation) and whole follow-up (NTZ-other[o]DMTs, that is, including switch from NTZ to alternative DMTs).

Results: Thirty RR-MS were included in each group; median follow-up duration was 106 (6-209) months. NTZ was discontinued by 29/30 patients, who subsequently started alternative DMTs. Cumulative proportion of patients with PIRA did not differ between the two groups during the NTZ treatment epoch (p=0.990), but it was lower in AHSCT-treated compared with NTZ-oDMTs treated patients over the whole follow-up, being 10% vs 21% at year 5, and 10% versus 49% at year 10, respectively (p=0.020). AHSCT was superior to NTZ on relapses and NEDA-3, and to NTZ-oDMTs on all the secondary outcomes analysed. Baseline age and Expanded Disability Status Scale independently predicted PIRA in the whole cohort.

Conclusion: Timely treatment with AHSCT or DMTs targeting inflammation in both the peripheral and CNS compartments might prevent long-term PIRA in aggressive RR-MS.

Over recent decades, various hypotheses and theoretical frameworks have been advanced to elucidate the aetiology of normal pressure hydrocephalus (NPH). This reversible neurological condition, characterised by the classical clinical triad of gait disturbance, urinary incontinence and cognitive impairment, represents a multifactorial interplay of pathophysiological processes that co-occur, rather than originating from a single, defined cause. Despite extensive research efforts, the precise aetiology and underlying pathophysiological pathways remain indeterminate. Contributory factors such as dysfunction of the glymphatic system, diminished arterial pulsatility, metabolic and osmotic dysregulation, astrogliosis and neuroinflammatory processes are acknowledged as critical in the pathogenesis of NPH. Recent advancements in the understanding of these pathophysiological aberrations have substantially refined the conceptualisation of the NPH phenotype, enhancing the predictive accuracy for cerebrospinal fluid diversion interventions. This review addresses the definition and classification of NPH and emphasises future research directions aimed at further elucidating the molecular and physiological mechanisms underlying the disease. A comprehensive understanding of this syndrome is critical for informed clinical decision-making and optimising therapeutic outcomes. With the global increase in ageing populations, accurately differentiating NPH from other neurodegenerative disorders and managing overlapping comorbidities has become increasingly significant.