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: Clinical guidelines recommend physical activity (PA) to prevent diabetic peripheral neuropathy (DPN). However, these recommendations lack specificity in terms of optimal PA intensity and duration. We aimed to determine associations between PA, DPN and painful DPN (pDPN).

Methods: In a cross-sectional study of persons with diabetes, PA was assessed with a wrist-worn accelerometer, recording time spent at different milli-gravity (mG) intensity levels with categories set as light (45-100 mG), moderate (100-400 mG), or vigorous (>400 mG). DPN was defined by Michigan Neuropathy Screening Instrument questionnaire and pDPN by presence of bilateral foot pain.

Results: In 2878 participants (mean (SD) age: 58.6 (7.1) years, 39.1% female), time spent above 75 mG decreased DPN odds (OR, 95% CI) (0.97, 0.95 to 0.997). Further, more time spent performing moderate (0.95, 0.91 to 0.99) or vigorous (0.40, 0.22 to 0.70) PA decreased DPN odds. Overall, PA did not affect pDPN; however, among females, more time spent above 50 mG (0.92, 0.87 to 0.98) decreased pDPN odds.

Conclusions: Increased PA decreased DPN likelihood, and in females, pDPN likelihood. Whether lack of PA occurs secondary to the presence of DPN or contributes to DPN remains to be determined.

Background: Regulatory authorities have raised concerns about potential teratogenic and neurodevelopmental disorders (NDDs) risks associated with paternal valproate use during spermatogenesis, leading to restrictions. We aimed to investigate the association between paternal valproate exposure during spermatogenesis and the risk of NDDs in offspring in Sweden and Norway.

Methods: We conducted a population-based cohort study of two nationwide cohorts from Sweden and Norway, including all singleton live births (≥22 gestational weeks) from 2007 to 2020. Paternal monotherapy exposure to valproate, lamotrigine or levetiracetam was defined as ≥1 prescription filled for only one of these medications during the 3 months prior to conception. NDDs were identified from health registers from age 1 through 2022. Cox proportional hazards models were used to estimate adjusted HRs (aHRs), accounting for relevant confounders. A random-effects meta-analysis combined results from both countries.

Results: The Swedish cohort included 1588 children with paternal valproate and 3093 with lamotrigine/levetiracetam monotherapy, while the Norwegian cohort included 463 and 1109, respectively. Compared with paternal lamotrigine/levetiracetam monotherapy, paternal valproate exposure was not associated with increased pooled risk of any NDD (aHR, 1.06; 95% CI 0.81 to 1.22), including autism spectrum disorder (aHR, 1.29; 95% CI 0.89 to 1.85), attention-deficit/hyperactivity disorder (aHR, 0.98; 95% CI 0.76 to 1.25), intellectual disability (aHR, 1.20; 95% CI 0.65 to 2.21; Sweden only) or psychological development disorders (aHR, 1.28; 95% CI 0.84 to 1.97). Findings remained consistent in dose-response analyses and when restricted to fathers with epilepsy.

Conclusions: In this large Nordic study, paternal valproate use during spermatogenesis was not associated with increased risk of NDDs in offspring, suggesting current regulatory restrictions may warrant re-evaluation.

Background: Motor asymmetry is a hallmark of Parkinson's disease (PD), but ~20% of patients present with symmetric motor signs, which are associated with faster disease progression and poorer dopaminergic response. The impact of motor symmetry on activities of daily living (ADL) outcomes following subthalamic deep brain stimulation (STN-DBS) remains unclear. We hypothesised that patients with symmetric PD experience less ADL improvement post-STN-DBS than asymmetric PD patients.

Methods: This was a prospective, quasi-experimental, non-randomised, controlled, international multicentre study with a 6-month follow-up. The primary outcome was the Scales for Outcomes in Parkinson's Disease-Motor ADL scale. Secondary outcomes included Unified Parkinson's Disease Rating Scale motor examination and Parkinson's Disease Questionnaire-8 (PDQ-8). We defined symmetric PD as a right-to-left hemibody motor score equalling 1. We analysed within-group longitudinal changes, between-group outcome differences, effect size and correlations between PDQ-8 and motor changes. We confirmed results in a propensity-score matched subcohort with well-balanced demographic and clinical parameters.

Results: We included 200 patients with asymmetric and 54 with symmetric PD. In symmetric PD, ADL remained stable, which was not associated with the observed PDQ-8 improvement. In contrast, in asymmetric PD, ADL improved with a moderate effect size, which correlated moderately with PDQ-8 improvement. In symmetric PD, the absolute risk of experiencing no clinically relevant postoperative ADL improvement was 23.8% higher.

Conclusions: This study provides class IIb evidence of worse ADL outcome of STN-DBS in patients with symmetric compared with asymmetric PD. Clinicians should counsel patients with symmetric PD on their elevated risk of ADL non-response when discussing STN-DBS as a treatment option.

Background: Neurofascin 155 autoimmune nodopathy (NF155 AN) is a recently recognised immune-mediated neuropathy distinct from chronic inflammatory demyelinating polyneuropathy. While adult-onset cases have been increasingly reported, the juvenile-onset form remains poorly characterised.

Methods: We retrospectively analysed 36 patients with NF155 AN, focusing on detailed characterisation of 16 juvenile-onset cases. Their clinical and laboratory data were reviewed.

Results: Juvenile-onset patients presented with sensorimotor neuropathy characterised by distal predominant weakness, tremor and sensory ataxia. Motor symptoms were the presenting feature in 75% of patients, which significantly differed from the adult cases (p=0.0015). Postural tremor was more frequent in juvenile patients (94%), while cranial nerve involvement was less common (19%). Electrophysiologically, absent compound muscle action potentials in lower limbs were significantly more prevalent in juvenile patients (peroneal: 78%; tibial: 66%; p<0.001 for both). Symmetrical spinal root/plexus hypertrophy on MR neurography and characteristic pathological findings were observed in both groups. Intravenous immunoglobulin response was generally poor, while delayed rituximab initiation still led to clinical improvement in the juvenile-onset group. Juvenile patients showed trends towards better functional outcomes.

Conclusions: Juvenile-onset NF155 AN is distinguished by motor-predominant onset, frequent tremor and characteristic electrophysiological abnormalities, yet demonstrates favourable prognosis with B-cell targeted therapy. Early recognition and timely diagnosis are essential for optimal outcomes.

Background: Becker muscular dystrophy (BMD) is a rare X-linked neuromuscular disorder predominantly affecting males. While respiratory function has been characterised in small cohorts over limited time frames, comprehensive long-term longitudinal data remain lacking, as do established care guidelines to inform respiratory surveillance in BMD.

Methods: In this retrospective analysis, we present a large longitudinal analysis of respiratory function in patients with BMD, based on 1360 spirometry measurements from a single-centre cohort of 152 patients. Analysed assessments spanned paediatric to adult ages (3.4-86.3 years), with a mean follow-up duration of 11 years per patient.Linear mixed-effects models were used to study longitudinal changes in respiratory function.

Results: Respiratory decline in BMD appears gradual and variable, typically not affecting children (<18 years of age).Respiratory support was infrequent (11.2%), always non-invasive and limited to nocturnal use.Loss of ambulation emerged as a strong predictor of faster decline in forced vital capacity percentage of predicted (FVC%) (estimate -0.58%/year, p=0.002), with the requirement for assistive walking devices marking a critical transitional stage.Upper limb function, assessed via the PUL 2.0 entry item, correlated significantly with FVC%, particularly among non-ambulant patients (rho=0.60, p=0.02). Cardiac involvement showed a limited effect on respiratory function, likely driven by patients with more advanced cardiomyopathy.No consistent genotype-phenotype correlations were observed.

Conclusion: These findings provide important evidence to inform clinical management, supporting the recommendation of individualised respiratory monitoring strategies and contributing to the design and interpretation of clinical trials in BMD.

Background: Women with multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD) and highly active disease may benefit from early post partum reinitiation of disease-modifying therapy (DMT), but safety data to monoclonal antibody (mAb) use while breastfeeding are limited. This study examined infant development and health following potential mAb exposure during breastfeeding.

Methods: A prospective monocentric cohort study of infants, born in 2013-2022, in the German MS and Pregnancy Registry, followed up 6-36 months post partum via telephone interviews. 183 infants breastfed during maternal mAb therapy (mAb use during breastfeeding (mAb-BF)) were matched 1:1 (DMT pregnancy exposure) to infants of DMT-naïve mothers (no-DMT-BF). Primary outcomes included developmental delay, systemic antibiotic use, hospitalisation, severe infection and growth. Adjusted regression models estimated the beta coefficient, OR or rate ratio with 95% CI.

Results: The study included 366 infants. Among 183 mAb-BF infants, most were breastfed on natalizumab (n=125), followed by ocrelizumab (n=34), rituximab (n=11) and ofatumumab (n=10); three had multiple exposures. Developmental delays occurred in 8.2% mAb-BF and in 7.1% no-DMT-BF infants (p=0.844). A comparable number of infants used a systemic antibiotic (n=33/183, 18.0% vs n=29/183, 15.8%; p=0.676), were hospitalised (n=18/183, 9.8% vs 19/183, 10.4%; p=1.000) or had a severe infection (n=14/183, 7.7% vs n=13/183, 7.1%; p=1.000). The physical growth and adjusted model outcomes were also similar.

Conclusions: The results indicate that infants of mothers with neuroimmunological diseases, breastfed under mAbs, did not experience negative consequences for their development and health within the initial 6-36 months of life. This may encourage mothers with highly active disease to breastfeed.

Background: Most patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) require maintenance treatment. We aimed to determine whether combined treatment with intravenous immunoglobulin (IVIg) and intravenous methylprednisolone (IVMP) increases remission rates compared with IVIg and placebo.

Methods: We performed a randomised, double-blind, placebo-controlled study. Adults with CIDP who were treatment naive, relapsed after a remission or required continued treatment after a single IVIg dose were included. Participants were treated with IVMP (1000 mg) or placebo (sodium chloride) every 3 weeks for 18 weeks. All participants received IVIg treatment consisting of a loading dose (2 g/kg) and serial maintenance treatments (1 g/kg). The primary outcome was remission, defined as sustained improvement on disability scales at 52 weeks without need for further treatment.

Results: Enrolment was halted after the inclusion of 77 of the 96 planned participants because of safety concerns: four thromboembolic events occurred in the IVIg/IVMP group compared with none in the IVIg/placebo group. 14 of 37 (38%) participants in the IVIg/IVMP group were in remission at 52 weeks compared with 11 out of 40 (28%) in the IVIg/placebo group, with a difference of 10% (95% CI -11 to 31; p=0.47). Several secondary outcomes showed a greater magnitude of improvement in disability and impairment at 18 and 52 weeks in the IVIg/IVMP group.

Conclusions: The study was prematurely stopped due to safety concerns after four thromboembolic events in the IVIg plus IVMP group. Combined treatment did not lead to significantly more frequent remissions than IVIg alone in the doses used in this study.

Trial registration number: ISRCTN15893334.

Objective: This study aimed to evaluate the cumulative benefits of Food and Drug Administration (FDA)-approved monoclonal antibodies (mABs), administered at FDA-approved dosing regimens in slowing cognitive decline compared with placebo and acetylcholinesterase inhibitor (AChEI), and the dynamic relationships between cognitive decline, amyloid reduction and whole brain volume (WBV) changes in mAB treatment.

Methods: Five major databases were systematically searched for double-blinded randomised controlled trials of patients with mild cognitive impairment due to Alzheimer's disease (AD) or mild AD treated with mAB or AChEI for at least 6 months. The primary outcomes were the change in cognitive function measured by Alzheimer's Disease Assessment Scale-cognitive subscale 14-Item (ADAS-Cog) and Clinical Dementia Rating Scale-Sum of Boxes (CDR-SOB). The secondary outcomes included amyloid burden and WBV changes.

Results: There were 6479 participants across seven mAB trials, and 4993 participants in nine AChEI trials. Compared with placebo, the pooled percentage of cognitive slowing was 27.6% (95% CI 24.6% to 30.9%), and the pooled progression delay was 5.52 months over 19.5 months (1.40 to 9.65) on CDR-SOB in patients treated with mABs. For cognitive trajectories on ADAS-Cog, mAB progressively attenuated cognitive decline, whereas AChEI exhibited a smaller effect with large uncertainty and eventually provided no benefits. Additionally, the rates of cognitive decline and amyloid reduction stabilised over time, while WBV initially showed a rapid decline but progressively slowed. Finally, WBV decline was not associated with worsening cognitive function. Instead, a 1 cm³ reduction in WBV was linked to a 0.0975-point reduction in CDR-SOB (0.0614 to 0.1336).

Conclusions: In prodromal to mild AD, mAB therapy provided greater cumulative cognitive benefits than placebo and AChEI, and WBV reduction may reflect a treatment-related process rather than a detrimental sequela.

Prospero registration number: CRD42024628107.