NEWS FROM THE WORLD-Rivaroxaban vs Warfarin Sodium in the Ultra-Early Period After Atrial Fibrillation–Related Mild Ischemic Stroke A Randomized Clinical Trial

Abstract

Importance  In atrial fibrillation (AF)–related acute ischemic stroke, the optimal oral anticoagulation strategy remains unclear.

Objective  To test whether rivaroxaban or warfarin sodium is safer and more effective for preventing early recurrent stroke in patients with AF-related acute ischemic stroke.

Design, Setting, and Participants  A randomized, multicenter, open-label, blinded end point evaluation, comparative phase 2 trial was conducted from April 28, 2014, to December 7, 2015, at 14 academic medical centers in South Korea among patients with mild AF-related stroke within the previous 5 days who were deemed suitable for early anticoagulation. Analysis was performed on a modified intent-to-treat basis.

Interventions  Participants were randomized 1:1 to receive rivaroxaban, 10 mg/d for 5 days followed by 15 or 20 mg/d, or warfarin with a target international normalized ratio of 2.0-3.0, for 4 weeks.

Main Outcomes and Measures  The primary end point was the composite of new ischemic lesion or new intracranial hemorrhage seen on results of magnetic resonance imaging at 4 weeks. Primary analysis was performed in patients who received at least 1 dose of study medications and completed follow-up magnetic resonance imaging. Key secondary end points were individual components of the primary end point and hospitalization length.

Results  Of 195 patients randomized, 183 individuals (76 women and 107 men; mean [SD] age, 70.4 [10.4] years) completed magnetic resonance imaging follow-up and were included in the primary end point analysis. The rivaroxaban group (n = 95) and warfarin group (n = 88) showed no differences in the primary end point (47 [49.5%] vs 48 [54.5%]; relative risk, 0.91; 95% CI, 0.69-1.20; P = .49) or its individual components (new ischemic lesion: 28 [29.5%] vs 31 of 87 [35.6%]; relative risk, 0.83; 95% CI, 0.54-1.26; P = .38; new intracranial hemorrhage: 30 [31.6%] vs 25 of 87 [28.7%]; relative risk, 1.10; 95% CI, 0.70-1.71; P = .68). Each group had 1 clinical ischemic stroke, and all new intracranial hemorrhages were asymptomatic hemorrhagic transformations. Hospitalization length was reduced with rivaroxaban compared with warfarin (median, 4.0 days [interquartile range, 2.0-6.0 days] vs 6.0 days [interquartile range, 4.0-8.0]; P < .001).

Conclusions and Relevance  In mild AF-related acute ischemic stroke, rivaroxaban and warfarin had comparable safety and efficacy.

JAMA Neurology 2017

NEWS FROM THE WORLD -Utility of Combining a Simulation-Based Method With a Lecture-Based Method for Fundoscopy Training in Neurology Residency

Abstract

Importance  Fundoscopic examination is an essential component of the neurologic examination. Competence in its performance is mandated as a required clinical skill for neurology residents by the American Council of Graduate Medical Education. Government and private insurance agencies require its performance and documentation for moderate- and high-level neurologic evaluations. Traditionally, assessment and teaching of this key clinical examination technique have been difficult in neurology residency training.

Objective  To evaluate the utility of a simulation-based method and the traditional lecture-based method for assessment and teaching of fundoscopy to neurology residents.

Design, Setting, and Participants  This study was a prospective, single-blinded, education research study of 48 neurology residents recruited from July 1, 2015, through June 30, 2016, at a large neurology residency training program. Participants were equally divided into control and intervention groups after stratification by training year. Baseline and postintervention assessments were performed using questionnaire, survey, and fundoscopy simulators.

Interventions  After baseline assessment, both groups initially received lecture-based training, which covered fundamental knowledge on the components of fundoscopy and key neurologic findings observed on fundoscopic examination. The intervention group additionally received simulation-based training, which consisted of an instructor-led, hands-on workshop that covered practical skills of performing fundoscopic examination and identifying neurologically relevant findings on another fundoscopy simulator.

Main Outcomes and Measures  The primary outcome measures were the postintervention changes in fundoscopy knowledge, skills, and total scores.

Results  A total of 30 men and 18 women were equally distributed between the 2 groups. The intervention group had significantly higher mean (SD) increases in skills (2.5 [2.3] vs 0.8 [1.8], P = .01) and total (9.3 [4.3] vs 5.3 [5.8], P = .02) scores compared with the control group. Knowledge scores (6.8 [3.3] vs 4.5 [4.9], P = .11) increased nonsignificantly in both groups.

Conclusions and Relevance  This study supports the use of a simulation-based method as a supplementary tool to the lecture-based method in the assessment and teaching of fundoscopic examination in neurology residency.

JAMA Neurology 2017

NEWS FROM THE WORLD- Genetic variants influencing elevated myeloperoxidase levels increase risk of stroke

Abstract

Primary intracerebral haemorrhage and lacunar ischaemic stroke are acute manifestations of progressive cerebral microvascular disease. Current paradigms suggest atherosclerosis is a chronic, dynamic, inflammatory condition precipitated in response to endothelial injury from various environmental challenges. Myeloperoxidase plays a central role in initiation and progression of vascular inflammation, but prior studies linking myeloperoxidase with stroke risk have been inconclusive. We hypothesized that genetic determinants of myeloperoxidase levels influence the development of vascular instability, leading to increased primary intracerebral haemorrhage and lacunar stroke risk. We used a discovery cohort of 1409 primary intracerebral haemorrhage cases and 1624 controls from three studies, an extension cohort of 12 577 ischaemic stroke cases and 25 643 controls from NINDS-SiGN, and a validation cohort of 10 307 ischaemic stroke cases and 29 326 controls from METASTROKE Consortium with genome-wide genotyping to test this hypothesis. A genetic risk score reflecting elevated myeloperoxidase levels was constructed from 15 common single nucleotide polymorphisms identified from prior genome-wide studies of circulating myeloperoxidase levels (P < 5 × 10−6). This genetic risk score was used as the independent variable in multivariable regression models for association with primary intracerebral haemorrhage and ischaemic stroke subtypes. We used fixed effects meta-analyses to pool estimates across studies. We also used Cox regression models in a prospective cohort of 174 primary intracerebral haemorrhage survivors for association with intracerebral haemorrhage recurrence. We present effects of myeloperoxidase elevating single nucleotide polymorphisms on stroke risk per risk allele, corresponding to a one allele increase in the myeloperoxidase increasing genetic risk score. Genetic determinants of elevated circulating myeloperoxidase levels were associated with both primary intracerebral haemorrhage risk (odds ratio, 1.07, P = 0.04) and recurrent intracerebral haemorrhage risk (hazards ratio, 1.45, P = 0.006). In analysis of ischaemic stroke subtypes, the myeloperoxidase increasing genetic risk score was strongly associated with lacunar subtype only (odds ratio, 1.05, P = 0.0012). These results, demonstrating that common genetic variants that increase myeloperoxidase levels increase risk of primary intracerebral haemorrhage and lacunar stroke, directly implicate the myeloperoxidase pathway in the pathogenesis of cerebral small vessel disease. Because genetic variants are not influenced by environmental exposures, these results provide new support for a causal rather than bystander role for myeloperoxidase in the progression of cerebrovascular disease. Furthermore, these results support a rationale for chronic inflammation as a potential modifiable stroke risk mechanism, and suggest that immune-targeted therapies could be useful for treatment and prevention of cerebrovascular disease.

Brain 2017

NEWS FROM THE WORLD- Rates of hippocampal atrophy and presence of post-mortem TDP-43 in patients with Alzheimer's disease: a longitudinal retrospective study

Summary

Background

Post-mortem studies have not identified an association between β-amyloid or tau and rates of hippocampal atrophy in patients with Alzheimer's disease. TAR DNA binding protein 43 (TDP-43) is another protein linked to Alzheimer's disease. We aimed to investigate whether hippocampal TDP-43 is associated with increased rates of hippocampal atrophy.

Methods

In this longitudinal retrospective study, we analysed post-mortem brain tissue of all individuals with an Alzheimer's disease spectrum pathological diagnosis who had antemortem head MRI scans between Jan 1, 1999, and Dec 31, 2012, and who had been recruited into the Mayo Clinic Alzheimer's Disease Research Center, Mayo Clinic Alzheimer's Disease Patient Registry, or the Mayo Clinic Study of Aging. We did TDP-43 immunohistochemistry and classified individuals as follows: no TDP-43 in the amygdala or hippocampus; TDP-43 restricted to the amygdala; and TDP-43 spreading into the hippocampus. Each individual was also assigned a neurofibrillary tangle stage (B1–B3), relating to the likelihood of having Alzheimer's disease. We used longitudinal FreeSurfer software and tensor-based morphometry with symmetric normalisation to calculate hippocampal volume on all serial MRI scans and used linear mixed-effects regression models to estimate associations between TDP-43 and rate of hippocampal atrophy and to assess the trajectory of TDP-43-associated atrophy.

Findings

We identified 298 individuals meeting the inclusion criteria, with 816 usable MRI scans (spanning 1·0–11·2 years of the disease) available for analysis. 141 individuals showed no TDP-43 in the amygdala or hippocampus, 33 had TDP-43 restricted to the amygdala, and 124 had TDP-43 in the hippocampus. Among individuals with a high likelihood of having Alzheimer's disease (neurofibrillary tangle stage B3; n=205), those with hippocampal TDP-43 had faster rates of hippocampal atrophy (n=103, annual volume change −4·39%, 95% CI −4·82 to −3·95; p<0·0001) than did those with amygdala-only TDP-43 (n=20, −3·29%, −4·11 to −2·46; p<0·0001; difference −1·10%, 95% CI −2·02 to −0·19; p=0·02) and those without TDP-43 (n=82, −3·11%, −3·54 to −2·68; p<0·0001; difference −1·28%, −1·88 to −0·67; p<0·0001). Among individuals with an intermediate likelihood of having Alzheimer's disease (neurofibrillary tangle stage B2; n=56), those with hippocampal TDP-43 had faster rates of hippocampal atrophy (n=17, annual volume change −4·05%, 95% CI −5·09 to −2·99; p<0·0001) than did those with amygdala-only TDP-43 (n=6, −1·78%, −3·04 to −0·55; p=0·004; difference −2·27%, 95% CI −3·79 to −0·67; p=0·006) and those without TDP-43 (n=33, −1·63%, −2·43 to −0·83; p=0·0002; difference −2·43%, −3·66 to −1·18; p=0·0002). Hippocampal TDP-43 was not associated with the rate of hippocampal atrophy in individuals with a low likelihood of having Alzheimer's disease (neurofibrillary tangle stage B1; n=37). The trajectory analysis suggested that increased rates of TDP-43-associated hippocampal atrophy might occur at least 10 years before death. Results were similar for FreeSurfer and tensor-based morphometry.

Interpretation

TDP-43 should be considered as a potential factor related to increased rates of hippocampal atrophy in patients with Alzheimer's disease. Given the importance of hippocampal atrophy in Alzheimer's disease, it is imperative that techniques are developed for detection of TDP-43 in vivo.

Neurology 2017

NEWS FROM THE WORLD- Reversibility of the effects of natalizumab on peripheral immune cell dynamics in MS patients

ABSTRACT

Objective: To characterize the reversibility of natalizumab-mediated changes in pharmacokinetics/pharmacodynamics in patients with multiple sclerosis (MS) following therapy interruption.

Methods: Pharmacokinetic/pharmacodynamic data were collected in the Safety and Efficacy of Natalizumab in the Treatment of Multiple Sclerosis (AFFIRM) (every 12 weeks for 116 weeks) and Randomized Treatment Interruption of Natalizumab (RESTORE) (every 4 weeks for 28 weeks) studies. Serum natalizumab and soluble vascular cell adhesion molecule–1 (sVCAM-1) were measured using immunoassays. Lymphocyte subsets, α4-integrin expression/saturation, and vascular cell adhesion molecule–1 (VCAM-1) binding were assessed using flow cytometry.

Results: Blood lymphocyte counts (cells/L) in natalizumab-treated patients increased from 2.1 × 10⁹ to 3.5 × 10⁹. Starting 8 weeks post last natalizumab dose, lymphocyte counts became significantly lower in patients interrupting treatment than in those continuing treatment (3.1 × 10⁹ vs 3.5 × 10⁹; p = 0.031), plateauing at prenatalizumab levels from week 16 onward. All measured cell subpopulation, α4-integrin expression/saturation, and sVCAM changes demonstrated similar reversibility. Lymphocyte counts remained within the normal range. Ex vivo VCAM-1 binding to lymphocytes increased until ≈16 weeks after the last natalizumab dose, then plateaued, suggesting reversibility of immune cell functionality. The temporal appearance of gadolinium-enhancing lesions was consistent with pharmacodynamic marker reversal.

Conclusions: Natalizumab's effects on peripheral immune cells and pharmacodynamic markers were reversible, with changes starting 8 weeks post last natalizumab dose; levels returned to those observed/expected in untreated patients ≈16 weeks post last dose. This reversibility differentiates natalizumab from MS treatments that require longer reconstitution times. Characterization of the time course of natalizumab's biological effects may help clinicians make treatment sequencing decisions.

Classification of evidence: This study provides Class III evidence that the pharmacodynamic markers of natalizumab are reversed ≈16 weeks after stopping natalizumab.

Neurology 2017

NEWS FROM THE WORLD- Functional impairments for outcomes in a randomized trial of unruptured brain AVMs

ABSTRACT

Objective: To investigate the effects of medical vs interventional management on functional outcome in A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA).

Methods: We used the initial results of a nonblinded, randomized, controlled, parallel-group trial involving adults ≥18 years of age with an unruptured brain arteriovenous malformation (AVM) to compare the effects of medical management (MM) with or without interventional therapy (IT) on functional impairment, defined by a primary outcome of death or symptomatic stroke causing modified Rankin Scale (mRS) score ≥2. ARUBA closed recruitment on April 15, 2013.

Results: After a median of 33.3 months of follow-up (interquartile range 16.3–49.8 months), of the 223 enrolled in the trial, those in the MM arm were less likely to experience primary outcomes with an mRS score ≥2 than those who underwent IT. The results applied for both those as randomized (MM n = 109 vs IT n = 114) (hazard ratio [HR] 0.25, 95% confidence interval [CI] 0.11–0.57, p = 0.001) and as treated (MM n = 125 vs IT n = 98) (HR 0.10, 95% CI 0.04–0.28, p < 0.001). Functional impairment for the outcomes showed no significant difference by Spetzler-Martin grade for MM but was more frequent with increasing grades for IT (p < 0.001).

Conclusion: Death or stroke with functional impairment in ARUBA after a median follow-up of 33 months was significantly lower for those in the MM arm both as randomized and as treated compared with those with IT. Functional severity of outcomes was lower in the MM arm, regardless of Spetzler-Martin grades.

Neurology 2017

NEWS FROM THE WORLD- Analysis of blood-based gene expression in idiopathic Parkinson disease

ABSTRACT

Objective: To examine whether gene expression analysis of a large-scale Parkinson disease (PD) patient cohort produces a robust blood-based PD gene signature compared to previous studies that have used relatively small cohorts (≤220 samples).

Methods: Whole-blood gene expression profiles were collected from a total of 523 individuals. After preprocessing, the data contained 486 gene profiles (n = 205 PD, n = 233 controls, n = 48 other neurodegenerative diseases) that were partitioned into training, validation, and independent test cohorts to identify and validate a gene signature. Batch-effect reduction and cross-validation were performed to ensure signature reliability. Finally, functional and pathway enrichment analyses were applied to the signature to identify PD-associated gene networks.

Results: A gene signature of 100 probes that mapped to 87 genes, corresponding to 64 upregulated and 23 downregulated genes differentiating between patients with idiopathic PD and controls, was identified with the training cohort and successfully replicated in both an independent validation cohort (area under the curve [AUC] = 0.79, p = 7.13E–6) and a subsequent independent test cohort (AUC = 0.74, p = 4.2E–4). Network analysis of the signature revealed gene enrichment in pathways, including metabolism, oxidation, and ubiquitination/proteasomal activity, and misregulation of mitochondria-localized genes, including downregulation of COX4I1, ATP5A1, and VDAC3.

Conclusions: We present a large-scale study of PD gene expression profiling. This work identifies a reliable blood-based PD signature and highlights the importance of large-scale patient cohorts in developing potential PD biomarkers.

Neurology 2017