对脑进行详细的神经病理学分析。患者有基因确认的ATP13A2纯合错义突变，死亡于38岁，即发病26年后。< / p > < /秒> The main brain neuropathologic findings were widespread neuronal and glial lipofuscin accumulation with no Lewy body–type inclusions and absence of α-synuclein–positive, tau-positive, β-amyloid–positive, and TDP-43 protein–positive pathologies. Sparse iron deposits were observed in several brain areas, but no obvious axonal spheroids were identified. This is to our knowledge the first KRS postmortem neuropathologic description. Iron deposits were found but not associated with increased axonal spheroids, as frequently observed in neurodegeneration with brain iron accumulation. ATP13A2 mutations have been described in patients with neuronal ceroid lipofuscinosis (CLN). Moreover, animal models with these mutations develop neurodegenerative disorders with CLN pathology. Therefore, our findings support that ATP13A2 mutations may be considered a genetic etiology of neuronal lipofuscinosis.
肌萎缩性侧索硬化症(ALS)的特征是大脑皮层、脑干和脊髓运动神经元的缺失。越来越多的证据表明，星形胶质细胞、小胶质细胞和少突胶质细胞通过功能丧失和毒性功能获得机制参与了ALS的发病机制。虽然大多数研究集中在小胶质细胞和星形胶质细胞的作用，但1,2少突细胞也可能在该疾病中起主要的致病作用3-6(图)。最近一项应用多基因风险评分方法的分析表明，参与神经元形态发生和膜运输的基因变异是ALS的一个主要遗传风险。7本研究还表明，在人类ALS危险基因中，少突胶质细胞亚型以及运动皮层中表达parvalbumin的gaba能神经元显著富集。7少突胶质细胞是影响als相关基因突变的靶点，其功能障碍可能通过多种机制影响运动神经元的存活。ALS的实验模型表明，少突胶质细胞前体无法完全分化成成熟的少突胶质细胞，导致它们无法提供代谢支持并使轴突有髓鞘化。3-6体外共培养研究表明，来自家族性ALS患者的诱导多能或神经祖细胞或其他突变的少突细胞，以及来自散发型ALS患者的少突细胞，与超氧化物歧化酶1 (SOD1)相关。也可能通过细胞接触机制在运动神经元死亡中发挥积极作用。5这些发现扩大了肌萎缩性侧索硬化症(ALS)神经保护的潜在细胞靶点
一名60岁的认知发育迟缓女性，表现为儿童期发作和左半边脸和眼睛的皮肤异常。检查显示脱发、裸侧痣、皮下脂肪堆积、突出(图1)。脑MRI示颅内脂肪瘤、左半脑畸形(图2)，证实脑颅皮肤脂肪瘤(ECCL)
.急性单侧听神经前庭病变常由侵犯迷路的炎症性疾病引起
我们饶有兴趣地阅读了Margot Geerts等人最近的文章。1作者评估了静脉注射免疫球蛋白(IVIG)对特发性小纤维神经病变(I-SFN)患者的疗效。金博宝app手机版某些I-SFN的病理生理机制可能涉及免疫机制。2既往研究表明，IVIG治疗对免疫介导的SFN有效3-5;然而，他们发现IVIG治疗对30例I-SFN患者无效。以往对SFN的研究使用IVIG至少连续5天，治疗后立即评估疼痛。另外，在本研究中，我们根据治疗慢性炎性脱髓鞘多神经病变的方案，连续给药2天，间隔3周，共4轮，但不给SFN。在第一次注射后的第1、12周和第6个月进行疼痛评估。1因此，如果作者像以前的研究一样遵循SF金博宝app手机版N的方案，3-5，他们可能对IVIG的疗效有不同的结论。作者应比金博宝app手机版较两种方案对IVIG使用的疗效。
我们想回应Mr. Franco Gemignani对我们的文章1关于非长度依赖性小纤维神经病(NLD-SFN)表型作为一种可能受益于静脉注射免疫球蛋白(IVIg)的情况的评论。我们完全同意，需要对NLD-SFN进行进一步研究，以确定IVIg在这些情况下是否具有治疗作用。有一些开放标签的临床研究暗示了潜在的治疗作用，1,2以及远端SFN病例研究显示IVIg的积极作用，而我们的RCT结果显示，IVIg治疗对特发性SFN患者的疼痛没有显著影响。这突出了病例报告或开放病例研究的缺陷以及双盲随机试验的重要性
我们饶有兴趣地阅读了评价静脉注射免疫球蛋白(IVIg)治疗特发性小纤维神经病变(I-SFN)疗效的首个随机对照试验的结果，并祝贺这一重要试验的作者金博宝app手机版
Day等在《抗体介导脑炎脑脊液生物标志物的前瞻性定量》一文中，1第二作者的名字应列为“Melanie L. Yarbrough”。作者对这金博宝app手机版个错误表示遗憾。< p>
Safety analyses are based on integrated clinical and laboratory data for all patients who received OCR in 11 clinical trials, including the controlled treatment and open-label extension (OLE) periods of the phase 2 and 3 trials, plus the phase 3b trials VELOCE, CHORDS, CASTING, OBOE, ENSEMBLE, CONSONANCE, and LIBERTO. For selected adverse events (AEs), additional postmarketing data were used. Incidence rates of serious infections (SIs) and malignancies were contextualized using multiple epidemiologic sources.
At data cutoff (January 2020), 5,680 patients with multiple sclerosis (MS) received OCR (18,218 patient-years [PY] of exposure) in clinical trials. Rates per 100 PY (95% confidence interval) of AEs (248; 246–251), serious AEs (7.3; 7.0–7.7), infusion-related reactions (25.9; 25.1–26.6), and infections (76.2; 74.9–77.4) were similar to those within the controlled treatment period of the phase 3 trials. Rates of the most common serious AEs, including SIs (2.01; 1.81–2.23) and malignancies (0.46; 0.37–0.57), were consistent with the ranges reported in epidemiologic data.
Continuous administration of OCR for up to 7 years in clinical trials, as well as its broader use for more than 3 years in the real-world setting, are associated with a favorable and manageable safety profile, without emerging safety concerns, in a heterogeneous MS population.
This analysis provides Class III evidence that long-term, continuous treatment with OCR has a consistent and favorable safety profile in patients with RMS and PPMS. This study is rated Class III because of the use of OLE data and historical controls.
We used the dataset from Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis (CombiRx) (clinicaltrials.gov identifier NCT00211887), a large phase 3 RCT, to compare the EDSS to the alternative outcomes T25FW and NHPT. We investigated disability worsening vs similarly defined improvement, unconfirmed vs confirmed and sustained disability change, and the presentation methods cumulative Kaplan-Meier survival curves vs cross-sectional disability worsening.
CombiRx included 1,008 participants. A comparison of confirmed and sustained worsening events showed that, throughout the trial, there were substantially fewer sustained than confirmed events, with a positive predictive value of confirmed for sustained worsening at 24 months of 0.73 for the EDSS, 0.73 for the T25FW, and 0.8 for the NHPT. More concerning were the findings that worsening on the EDSS occurred as frequently as similarly defined improvement throughout the 3 years of follow-up and that improvement rates increased in parallel with worsening rates. The T25FW showed low improvement rates of <10% throughout the trial. We also found that Kaplan-Meier survival analysis, the standard presentation and analysis method in modern RRMS trials, yields exaggerated estimates of disability worsening. With the Kaplan-Meier method, the proportion of patients with worsening events steadily increases until it reaches several-fold the number of events seen with more conservative analysis methods. For 3-month confirmed disability worsening up to 36 months, the Kaplan-Meier method yields 2.6-fold higher estimates for the EDSS, 2.9-fold higher estimates for the T25FW, and 5.1-fold higher estimates for the NHPT compared to a more conservative presentation of the same data.
Our analyses raise concerns about using the EDSS as the standard disability outcome in RRMS trials and suggest that the T25FW may be a more useful measure. These findings are relevant for the design and critical appraisal of RCTs.
We used clinically acquired 3-dimensional (3D) T1-weighted and 3D fluid-attenuated inversion recovery MRI of 148 patients (median age 23 years [range 2–55 years]; 47% female) with histologically verified FCD at 9 centers to train a deep convolutional neural network (CNN) classifier. Images were initially deemed MRI-negative in 51% of patients, in whom intracranial EEG determined the focus. For risk stratification, the CNN incorporated bayesian uncertainty estimation as a measure of confidence. To evaluate performance, detection maps were compared to expert FCD manual labels. Sensitivity was tested in an independent cohort of 23 cases with FCD (13 ± 10 years). Applying the algorithm to 42 healthy controls and 89 controls with temporal lobe epilepsy disease tested specificity.
Overall sensitivity was 93% (137 of 148 FCD detected) using a leave-one-site-out cross-validation, with an average of 6 false positives per patient. Sensitivity in MRI-negative FCD was 85%. In 73% of patients, the FCD was among the clusters with the highest confidence; in half, it ranked the highest. Sensitivity in the independent cohort was 83% (19 of 23; average of 5 false positives per patient). Specificity was 89% in healthy and disease controls.
This first multicenter-validated deep learning detection algorithm yields the highest sensitivity to date in MRI-negative FCD. By pairing predictions with risk stratification, this classifier may assist clinicians in adjusting hypotheses relative to other tests, increasing diagnostic confidence. Moreover, generalizability across age and MRI hardware makes this approach ideal for presurgical evaluation of MRI-negative epilepsy.
This study provides Class III evidence that deep learning on multimodal MRI accurately identifies FCD in patients with epilepsy initially diagnosed as MRI negative.
MRI未能显示30%至50%的颞叶癫痫(TLE)手术患者的海马病理。为了解决这一临床挑战，我们开发了一种基于mri的自动分类器，可侧移TLE中隐蔽的海马组织病理。< / p > < /秒> We trained a surface-based linear discriminant classifier that uses T1-weighted (morphology) and T2-weighted and fluid-attenuated inversion recovery (FLAIR)/T1 (intensity) features. The classifier was trained on 60 patients with TLE (mean age 35.6 years, 58% female) with histologically verified hippocampal sclerosis (HS). Images were deemed to be MRI negative in 42% of cases on the basis of neuroradiologic reading (40% based on hippocampal volumetry). The predictive model automatically labeled patients as having left or right TLE. Lateralization accuracy was compared to electroclinical data, including side of surgery. Accuracy of the classifier was further assessed in 2 independent TLE cohorts with similar demographics and electroclinical characteristics (n = 57, 58% MRI negative). The overall lateralization accuracy was 93% (95% confidence interval 92%–94%), regardless of HS visibility. In MRI-negative TLE, the combination of T2 and FLAIR/T1 intensities provided the highest accuracy in both the training (84%, area under the curve [AUC] 0.95 ± 0.02) and validation (cohort 1 90%, AUC 0.99; cohort 2 76%, AUC 0.94) cohorts. This prediction model for TLE lateralization operates on readily available conventional MRI contrasts and offers gain in accuracy over visual radiologic assessment. The combined contribution of decreased T1- and increased T2-weighted intensities makes the synthetic FLAIR/T1 contrast particularly effective in MRI-negative HS, setting the basis for broad clinical translation. This study provides Class II evidence that in people with TLE and MRI-negative HS, an automated MRI-based classifier accurately determines the side of pathology.
Compared with controls, GM atrophy on VBM was greater and more diffuse in genetic FTD, followed by sporadic FTD and genetic MND cases, whereas patients with sporadic MND (sMND) showed focal motor cortical atrophy. Patients carrying C9orf72 and GRN mutations showed the most widespread cortical volume loss, in contrast with GM sparing in SOD1 and TARDBP. Globally, patients with gFTLD showed greater atrophy of parietal cortices and thalami compared with sFTLD. In volumetric analysis, patients with gFTLD showed volume loss compared with sFTLD in the caudate nuclei and thalami, in particular comparing C9-MND with sMND cases. In the cerebellum, patients with gFTLD showed greater atrophy of the right lobule VIIb than sFTLD. Thalamic volumes of patients with gFTLD with a C9orf72 mutation showed an inverse correlation with Frontal Behavioral Inventory scores.
Measures of deep GM and cerebellar structural involvement may be useful markers of gFTLD, particularly C9orf72-related disorders, regardless of the clinical presentation within the FTLD spectrum.
Data were obtained from the Gothenburg H70 Birth Cohort Studies, in which individuals are invited based on birthdate. This study has a cross-sectional design and includes individuals born in 1944 who underwent structural brain MRI in 2014 to 2017. AF diagnoses were based on self-report, ECG, and register data. Symptomatic stroke was based on self-report, proxy interviews, and register data. Brain infarcts and CMBs were assessed by a radiologist. WMH volumes were measured on fluid-attenuated inversion recovery images with the Lesion Segmentation Tool. Multivariable logistic regression was used to study the association between AF and infarcts/CMBs, and multivariable linear regression was used to study the association between AF and WMHs.
A total of 776 individuals were included, and 65 (8.4%) had AF. AF was associated with symptomatic stroke (odds ratio [OR] 4.5, 95% confidence interval [CI] 2.1–9.5) and MRI findings of large infarcts (OR 5.0, 95% CI 1.5–15.9), lacunes (OR 2.7, 95% CI 1.2–5.6), and silent brain infarcts (OR 3.5; 95% CI 1.6–7.4). Among those with symptomatic stroke, individuals with AF had larger WMH volumes (0.0137 mL/total intracranial volume [TIV], 95% CI 0.0074–0.0252) compared to those without AF (0.0043 mL/TIV, 95% CI 0.0029–0.0064). There was no association between AF and WMH volumes among those without symptomatic stroke. In addition, AF was associated to CMBs in the frontal lobe.
AF was associated with a broad range of cerebrovascular pathologies. Further research is needed to establish whether cerebrovascular MRI markers can be added to current treatment guidelines to further personalize anticoagulant treatment in patients with AF and to further characterize the pathogenetic processes underlying the associations between AF and cerebrovascular diseases, as well as dementia.
睡眠障碍常与偏头痛相关。然而，关于偏头痛患者睡眠的客观和主观测量的研究还很少。这项荟萃分析旨在确定成人、儿童患者和健康对照组在使用匹兹堡睡眠质量指数(PSQI)测量的主观睡眠质量和使用多导睡眠图(PSG)测量的客观睡眠结构方面是否存在差异。
对5个数据库(Embase、MEDLINE、Global Health、APA PsycINFO和APA psycararticles，最后一次搜索是在2020年12月17日)进行了系统搜索，以找到测量偏头痛患者PSG或PSQI的病例对照研究。孕妇和患有其他头痛疾病的人被排除在外。效应大小(Hedges g)被纳入随机效应模型meta分析。研究质量采用纽卡斯尔渥太华量表评价，发表偏倚采用Egger回归检验。< / p > < /秒> Thirty-two studies were eligible, of which 21 measured PSQI or Migraine Disability Assessment Test in adults, 6 measured PSG in adults, and 5 measured PSG in children. The overall mean study quality score was 5/9; this did not moderate any of the results and there was no risk of publication bias. Overall, adults with migraine had higher PSQI scores than healthy controls (g = 0.75, p < 0.001, 95% confidence interval [CI] 0.54–0.96). This effect was larger in those with a chronic rather than episodic condition (g = 1.03, p < 0.001, 95% CI 0.37–1.01; g = 0.63, p < 0.001, 95% CI 0.38–0.88, respectively). For polysomnographic studies, adults and children with migraine displayed a lower percentage of rapid eye movement sleep (g = –0.22, p = 0.017, 95% CI –0.41 to –0.04; g = –0.71, p = 0.025, 95% CI –1.34 to –0.10, respectively) than controls. Pediatric patients displayed less total sleep time (g = –1.37, p = 0.039, 95% CI –2.66 to –0.10), more wake (g = 0.52, p < 0.001, 95% CI 0.08–0.79), and shorter sleep onset latency (g = –0.37, p < 0.001, 95% CI –0.54 to –0.21) than controls. People with migraine have significantly poorer subjective sleep quality and altered sleep architecture compared to healthy individuals. Further longitudinal empirical studies are required to enhance our understanding of this relationship.
一位73岁女性，有6个月的间歇性口齿不清、流口水和误吸病史。初步评估显示右半边舌萎缩(图1)，伴同侧肌束和无力。残余神经检查无明显变化。MRI证实右侧舌下神经麻痹(HNP)继发于舌下管脑膜瘤，影像学表现典型(图2)。