Neurology最新文献

Background and objectives: Patients with multiple sclerosis (MS) may demonstrate better disease control when treatment is initiated on high-efficacy disease-modifying therapies (DMTs) from onset. This subgroup analysis assessed the long-term efficacy and safety profile of the high-efficacy DMT ocrelizumab (OCR) as first-line therapy for early-stage relapsing MS (RMS).

Methods: Post hoc exploratory analyses of efficacy and safety were performed in a subgroup of treatment-naive patients with RMS who received ≥1 dose of OCR in the multicenter OPERA I/II (NCT01247324/NCT01412333) studies. Patients were randomized to OCR or interferon β-1a for 96 weeks (double-blind controlled treatment period [DBP]), before switching to OCR in the open-label extension (OLE). Efficacy assessments included no evidence of disease activity (NEDA-3), 24-week confirmed disability progression (CDP), MRI lesion activity, change in whole-brain volume; with safety outcomes assessed over a 9-year treatment period.

Results: Overall, 757 patients were included (interferon-treated n = 382, mean age 36.3 years, 65.7% female; OCR-treated n = 375, mean age 35.5 years, 64.0% female); 505 of 757 (66.7%) completed 9 years of follow-up. The difference in NEDA status between OCR-treated and interferon-treated patients achieved during the DBP (72.5% and 43.8%, respectively, odds ratio 3.48, 95% CI 2.52-4.81) was maintained throughout the 7-year OLE (48.2% vs 25.7%; odds ratio 2.72, 95% CI 1.94-3.82). No 24-week CDP was observed in 78.7% of OCR-treated patients over 9 years. Brain volume loss over the entire study period remained numerically higher among patients starting OCR later (p = 0.09 at OLE at week 336). During the DBP, safety profiles in both groups were similar; no new safety signals were observed during the OLE. Over >9 years of continuous OCR treatment, the rate of infections remained low and stable over time.

Discussion: A higher proportion of OCR-treated patients achieved NEDA status compared with interferon-treated patients during the DBP, which was maintained throughout the OLE. After switching to OCR, disability accrual and brain volume loss among interferon-treated patients became similar to the OCR-OCR group, but disability and brain volume loss accrued during interferon treatment were not recovered. Possible study limitations include assessment bias due to unmaintained blinding during the OLE. These data support OCR as first-line therapy for these patients.

Classification of evidence: This study provides Class II evidence that OCR delays disease progression in treatment-naïve patients with early-stage RMS.

Background and objectives: Type 2 diabetes mellitus (T2DM) is highly genetically determined, and polygenic susceptibility to T2DM (PSD) increases the risk of worse glycemic control and adverse vascular outcomes. Its role in stroke patients remains unknown. We aim to determine whether higher PSD is associated with worse glycemic control in stroke survivors.

Methods: We conducted a 2-stage genetic association study. In a cross-sectional design, we selected stroke survivors from the UK Biobank (enrollment between 2006 and 2010) to evaluate the relationship between PSD and glycemic control. Second, we replicated the results using data from All of Us (enrollment between 2018 and 2022). Exposures were low, intermediate, and high PSD, modeled through percentiles (<20, 20-80, >80) of a polygenic risk score of 2,522 independent risk variants associated with T2DM at genome-wide levels (p < 5 × 10^-8). Outcomes were hemoglobin A1c (HbA1c) levels, uncontrolled diabetes (HbA1c ≥7.0%), and resistant diabetes (uncontrolled despite antidiabetic treatment).

Results: Stage 1 included 6,908 stroke survivors (mean age 61 years, 42% female), including 977 (14%) with diabetes. Compared with low PSD, participants with high PSD had an increase of 0.49 in HbA1c (β = 0.49, standard error 0.03, p-trend <0.001), 6.9 times the odds of uncontrolled diabetes (odds ratio [OR] 6.92, 95% CI 4.71-10.52), and 7.8 times the odds of resistant diabetes (OR 7.76, 95% CI 4.92-12.89). Stage 2 (replication) confirmed the association with HbA1c in 4,451 stroke survivors, including 2,163 (49%) with diabetes (mean age 64 years, 53% female, p-trend <0.05 for all tests).

Discussion: Among stroke survivors, a higher PSD was associated with poorer glycemic control. Further research should determine precision medicine strategies using PSD to improve clinical management of stroke patients.

Background and objectives: Peripartum mood and anxiety disorders constitute the most frequent form of maternal morbidity in the general population, but little is known about peripartum mental illness in mothers with multiple sclerosis (MS). We compared the incidence and prevalence of peripartum mental illness among mothers with MS, epilepsy, inflammatory bowel disease (IBD), and diabetes and women without these conditions.

Methods: Using linked population-based administrative health data from ON, Canada, we conducted a cohort study of mothers with MS, epilepsy, IBD, and diabetes and without these diseases (comparators) who had a live birth with index dates, defined as 1 year before conception, between 2002 and 2017. Using validated definitions, we estimated the incidence and prevalence of mental illness (any, depression, anxiety, bipolar disorder, psychosis, substance use, suicide attempt) during the prenatal (PN) period (from conception to birth) and 3 years postpartum. We compared incidence and prevalence estimates between cohorts using simple incidence ratios (IRs) and prevalence ratios with 95% CIs and using Poisson regression models adjusting for confounders.

Results: We included 894,852 mothers (1,745 with MS; 5,954 with epilepsy; 4,924 with IBD; 13,002 with diabetes; 869,227 comparators). At conception, the mean (SD) maternal age was 28.6 (5.7) years. Any incident mental illness affected 8.4% of mothers with MS prenatally and 14.2% during the first postpartum year; depression and anxiety were the most common incident disorders. The first postpartum year was a higher risk period than the PN period (any mental illness IR 1.27; 95% CI 1.08-1.50). After adjustment, mothers with MS had an increased incidence of any mental illness during the PN (IR 1.26; 95% CI 1.11-1.44) and postpartum (IR 1.33; 95% CI 1.20-1.47, first postpartum year) periods than comparator mothers. Similarly, mothers with MS had an increased incidence of all specific mental illnesses except suicide attempt during the PN period vs comparator mothers. Any prevalent mental illness affected 42% of mothers with MS prenatally and 50.3% in the first postpartum year.

Discussion: Mothers with MS had an elevated incidence and prevalence of peripartum mental illness compared with comparator mothers, although residual confounding cannot be excluded. These findings emphasize the need for preventive interventions and early treatment of mental illness.

Background and objectives: Mitochondrial disorders are multiorgan disorders resulting in significant morbidity and mortality. We aimed to characterize death-associated factors in an international cohort of deceased individuals with mitochondrial disorders.

Methods: This cross-sectional multicenter observational study used data provided by 26 mitochondrial disease centers from 8 countries from January 2022 to March 2023. Individuals with genetically confirmed mitochondrial disorders were included, along with patients with clinically or genetically diagnosed Leigh syndrome. Collected data included demographic and genetic diagnosis variables, clinical phenotype, involvement of organs and systems, conditions leading to death, and supportive care. We defined pediatric and adult groups based on age at death before or after 18 years, respectively. We used Kruskal-Wallis with post hoc Dunn test with Bonferroni correction and Fisher exact test for comparisons, Spearman rank test for correlations, and multiple linear regression for multivariable analysis.

Results: Data from 330 deceased individuals with mitochondrial disorders (191 [57.9%] pediatric) were analyzed. The shortest survival times were observed in hepatocerebral syndrome (median 0.3, interquartile range [IQR] 0.2-0.6 years) and mitochondrial cardiomyopathy (median 0.3, IQR 0.2-5.2 years) and the longest in chronic progressive external ophthalmoplegia plus (median 26.5, IQR 22.8-40.2 years) and sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (median 21.0, IQR 13.8-28.5 years). Respiratory failure and pulmonary infections were the most common conditions associated with death (52/330, 15.7% and 46/330, 13.9%, respectively). Noninvasive ventilation was required more often in children (57/191, 29.8%) than adults (12/139, 8.6%, p < 0.001), as was nasogastric or gastric tube (131/191, 68.6% in children and 39/139, 28.1% in adults, p < 0.001). On multivariate analysis, individuals with movement disorders and nuclear gene involvement had increased odds of any respiratory support use (OR 2.42 (95% CI 1.17-5.22) and OR 2.39 (95% CI 1.16-5.07), respectively).

Discussion: This international collaboration highlights the importance of respiratory care and infection management and provides a reference for prognostication across different mitochondrial disorders.