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Importance: Some patients have poor outcomes despite small infarcts after endovascular therapy (EVT), while others with large infarcts do well. Understanding why these discrepancies occur may help to optimize EVT outcomes., Objective: To validate exploratory findings from the Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times (ESCAPE) trial regarding pretreatment, treatment-related, and posttreatment factors associated with discrepancies between follow-up infarct volume (FIV) and 90-day functional outcome., Design, Setting, and Participants: This cohort study is a post hoc analysis of the Safety and Efficacy of Nerinetide in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE-NA1) trial, a double-blind, randomized, placebo-controlled, international, multicenter trial conducted from March 2017 to August 2019. Patients who participated in ESCAPE-NA1 and had available 90-day modified Rankin Scale (mRS) scores and 24-hour to 48-hour posttreatment follow-up parenchymal imaging were included., Exposures: Small FIV (volume ≤25th percentile) and large FIV (volume ≥75th percentile) on 24-hour computed tomography/magnetic resonance imaging. Baseline factors, outcomes, treatments, and poststroke serious adverse events (SAEs) were compared between discrepant cases (ie, patients with 90-day mRS score ≥3 despite small FIV or those with mRS scores ≤2 despite large FIV) and nondiscrepant cases., Main Outcomes and Measures: Area under the curve (AUC) and goodness of fit of prespecified logistic models, including pretreatment (eg, age, cancer, vascular risk factors) and treatment-related and posttreatment (eg, SAEs) factors, were compared with stepwise regression-derived models for ability to identify small FIV with higher mRS score and large FIV with lower mRS score., Results: Among 1091 patients (median [IQR] age, 70.8 [60.8-79.8] years; 549 [49.7%] women; median [IQR] FIV, 24.9 mL [6.6-92.2 mL]), 42 of 287 patients (14.6%) with FIV of 7 mL or less (ie, ≤25th percentile) had an mRS score of at least 3; 65 of 275 patients (23.6%) with FIV of 92 mL or greater (ie, ≥75th percentile) had an mRS score of 2 or less. Prespecified models of pretreatment factors (ie, age, cancer, vascular risk factors) associated with low FIV and higher mRS score performed similarly to models selected by stepwise regression (AUC, 0.92 [95% CI, 0.89-0.95] vs 0.93 [95% CI, 0.90-0.95]; P = .42). SAEs, specifically infarct in new territory, recurrent stroke, pneumonia, and congestive heart failure, were associated with low FIV and higher mRS scores; stepwise models also identified 24-hour hemoglobin as treatment-related/posttreatment factor (AUC, 0.92 [95% CI, 0.90-0.95] vs 0.94 [95% CI, 0.91-0.96]; P = .14). Younger age was associated with high FIV and lower mRS score; stepwise models identified absence of diabetes and higher baseline hemoglobin as additional pretreatment factors (AUC, 0.76 [95% CI, 0.70-0.82] vs 0.77 [95% CI, 0.71-0.83]; P = .82). Absence of SAEs, especially stroke progression, symptomatic intracerebral hemorrhage, and pneumonia, was associated with high FIV and lower mRS score2; stepwise models also identified 24-hour hemoglobin level, glucose, and diastolic blood pressure as posttreatment factors associated with discrepant cases (AUC, 0.80 [95% CI, 0.74-0.87] vs 0.79 [95% CI, 0.72-0.86]; P = .92)., Conclusions and Relevance: In this study, discrepancies between functional outcome and post-EVT infarct volume were associated with differences in pretreatment factors, such as age and comorbidities, and posttreatment complications related to index stroke evolution, secondary prevention, and quality of stroke unit care. Besides preventing such complications, optimization of blood pressure, glucose levels, and hemoglobin levels are potentially modifiable factors meriting further study.

Background: The DAWN and DEFUSE-3 trials showed the benefit of endovascular treatment (EVT) in acute ischemic stroke patients presenting beyond 6 hours from last known well (LKW) and selected by perfusion imaging criteria. The ESCAPE NA1-trial selected patients based on non-contrast CT (NCCT) Alberta Stroke Program Early CT Score (ASPECTS) and multiphase CT angiography (CTA) collateral status. This study compares baseline characteristics, workflow, and outcomes in the EVT arms of DAWN and DEFUSE-3 with late-window patients from the EVT-only arm of ESCAPE-NA1., Methods: Aggregate data on baseline characteristics, workflow, reperfusion quality, final infarct volume, and clinical outcomes (modified Rankin Score [mRS] at 90 days) in subjects enrolled in the DAWN and DEFUSE-3 EVT arms were compared with similar data from the ESCAPE-NA1 control arm (EVT-only arm) presenting beyond 6 hours from LKW using descriptive statistics., Results: Baseline characteristics among late-window patients in the ESCAPE NA1 trial were similar to those in the DAWN and DEFUSE-3 EVT arms. Median time from LKW-to-puncture in subjects enrolled in the ESCAPE NA1 trial was 9 hrs (IQR: 7.5-11 hours) when compared with DAWN (n=107; 12.8 hours, IQR: 10.6-16.7 hours) and DEFUSE-3 (n=92; 11.5 hours, IQR: 9.2-12.8 hours). Median post-treatment infarct-volume was largest in the ESCAPE NA1-patients (47 mL [IQR: 19-146] vs median 8 mL [IQR: 0-48] in the DAWN group and 35 mL [IQR: 18-82] in DEFUSE-3), while % mRS 0-2 at 90 days were similar across the three trials (ESCAPE NA1: 50/111 [45%], DAWN: 52/107 [49%], DEFUSE-3: 41/92 [45%])., Conclusion: Patients enrolled beyond 6 hours from LKW in the ESCAPE-NA1 trial based on NCCT-ASPECTS and mCTA had similar clinical outcomes when compared with patients selected by perfusion imaging in the DAWN and DEFUSE-3 trials., Competing Interests: Competing interests: BM holds a patent on systems of triage in acute stroke and stock ownership in Circle Neurovascular Inc. MG is a consultant for Medtronic, Stryker, Microvention, GE Healthcare, and Mentice. MH reports grants from CIHR during the conduct of the study, grants from Medtronic, and grants from NoNO Inc. outside the submitted work. In addition, he has a patent to US Patent office Number: 62/086,077 issued and licensed, and Director, Board of Circle Neurovascular, Director, Board of the Canadian Neuroscience Federation, and Director, Board of the Canadian Stroke Consortium., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, is a neuroprotectant that is effective in preclinical stroke models of ischaemia-reperfusion. In this trial, we assessed the efficacy and safety of nerinetide in human ischaemia-reperfusion that occurs with rapid endovascular thrombectomy in patients who had an acute ischaemic stroke., Methods: For this multicentre, double-blind, randomised, placebo-controlled study done in 48 acute care hospitals in eight countries, we enrolled patients with acute ischaemic stroke due to large vessel occlusion within a 12 h treatment window. Eligible patients were aged 18 years or older with a disabling ischaemic stroke at the time of randomisation, had been functioning independently in the community before the stroke, had an Alberta Stroke Program Early CT Score (ASPECTS) greater than 4, and vascular imaging showing moderate-to-good collateral filling, as determined by multiphase CT angiography. Patients were randomly assigned (1:1) to receive intravenous nerinetide in a single dose of 2·6 mg/kg, up to a maximum dose of 270 mg, on the basis of estimated or actual weight (if known) or saline placebo by use of a real-time, dynamic, internet-based, stratified randomised minimisation procedure. Patients were stratified by intravenous alteplase treatment and declared endovascular device choice. All trial personnel and patients were masked to sequence and treatment allocation. All patients underwent endovascular thrombectomy and received alteplase in usual care when indicated. The primary outcome was a favourable functional outcome 90 days after randomisation, defined as a modified Rankin Scale (mRS) score of 0-2. Secondary outcomes were measures of neurological disability, functional independence in activities of daily living, excellent functional outcome (mRS 0-1), and mortality. The analysis was done in the intention-to-treat population and adjusted for age, sex, baseline National Institutes of Health Stroke Scale score, ASPECTS, occlusion location, site, alteplase use, and declared first device. The safety population included all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, NCT02930018., Findings: Between March 1, 2017, and Aug 12, 2019, 1105 patients were randomly assigned to receive nerinetide (n=549) or placebo (n=556). 337 (61·4%) of 549 patients with nerinetide and 329 (59·2%) of 556 with placebo achieved an mRS score of 0-2 at 90 days (adjusted risk ratio 1·04, 95% CI 0·96-1·14; p=0·35). Secondary outcomes were similar between groups. We observed evidence of treatment effect modification resulting in inhibition of treatment effect in patients receiving alteplase. Serious adverse events occurred equally between groups., Interpretation: Nerinetide did not improve the proportion of patients achieving good clinical outcomes after endovascular thrombectomy compared with patients receiving placebo., Funding: Canadian Institutes for Health Research, Alberta Innovates, and NoNO., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background and Purpose: The impact of increased aneurysm packing density on angiographic outcomes has not been studied in a randomized trial. We sought to determine the potential for larger caliber coils to achieve higher packing densities and to improve the angiographic results of embolization of intracranial aneurysms at 1 year., Materials and Methods: Does Embolization with Larger Coils Lead to Better Treatment of Aneurysms (DELTA) was an investigator-initiated multicenter prospective, parallel, randomized, controlled clinical trial. Patients had 4- to 12-mm unruptured aneurysms. Treatment allocation to either 15- (experimental) or 10-caliber coils (control group) was randomized 1:1 using a Web-based platform. The primary efficacy outcome was a major recurrence or a residual aneurysm at follow-up angiography at 12 ± 2 months adjudicated by an independent core lab blinded to the treatment allocation. Secondary outcomes included indices of treatment success and standard safety outcomes. Recruitment of 564 patients was judged necessary to show a decrease in poor outcomes from 33% to 20% with 15-caliber coils., Results: Funding was interrupted and the trial was stopped after 210 patients were recruited between November 2013 and June 2017. On an intent-to-treat analysis, the primary outcome was reached in 37 patients allocated to 15-caliber coils and 36 patients allocated to 10-caliber coils (OR = 0.931; 95% CI, 0.528-1.644; P  = .885). Safety and other clinical outcomes were similar. The 15-caliber coil group had a higher mean packing density (37.0% versus 26.9%, P  = .0001). Packing density had no effect on the primary outcome when adjusted for initial angiographic results (OR = 1.001; 95% CI, 0.981-1.022; P  = .879)., Conclusions: Coiling of aneurysms randomized to 15-caliber coils achieved higher packing densities compared with 10-caliber coils, but this had no impact on the angiographic outcomes at 1 year, which were primarily driven by aneurysm size and initial angiographic results., (© 2020 by American Journal of Neuroradiology.)

Objective: To determine the time to complications during and after elective endovascular intracranial aneurysm coiling., Methods: A retrospective chart review of patients undergoing elective endovascular aneurysm coiling between March 2006 and October 2013 in one large Eastern Canadian Neurointerventional Service was performed. Data regarding the incidence, time and type of complication related to the endovascular coiling procedure and clinical outcome at last follow-up were collected. Patient, aneurysm and operation factors were analyzed to determine any factors associated with complication occurrence., Results: Of the 150 patient procedures analyzed, 16% experienced a coiling-related complication, although none resulted in death. 6.7% of patients experienced an intraoperative complication, of which thromboembolism was the most common type. The majority of the complications were detected in the first 6 hours after reversal of anesthesia, and a small proportion the next morning prior to discharge. Only 3.3% of patients had persistent neurological deficit after the procedure on last follow-up. Duration of the operation demonstrated a strong association with the occurrence of procedure-related complications., Conclusion: This study demonstrates that coiling-related complications of elective endovascular coiling tend to occur either intraoperatively or are detected shortly after reversal of anesthesia. Further investigation with a larger cohort may help to guide important preoperative communication with patients and identify a select group of patients who may not necessarily require prolonged admission to hospital for observation., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Thrombolytic therapy with intravenous recombinant tissue plasminogen activator is well established as a beneficial treatment for patients presenting with acute ischemic stroke (AIS). The odds of a favorable clinical outcome (living independently) increase as the time between stroke onset and treatment with IV thrombolysis decreases. However, many patients present with a large clot burden that seldom responds to systemic fibrinolysis. Alternative options include new and emerging endovascular therapies that have recently proven effectiveness at restoring cerebral blood flow to the ischemic brain parenchyma. This review article will briefly outline some of the key evidence for intravenous thrombolysis as well as endovascular therapy for AIS., (© 2015 International Society on Thrombosis and Haemostasis.)

Metabolic myopathies are inborn errors of metabolism that result in impaired energy production due to defects in glycogen, lipid, mitochondrial, and possibly adenine nucleotide metabolism. Fatty acid oxidation defects (FAOD), glycogen storage disease, and mitochondrial myopathies represent the 3 main groups of disorders, and some consider myoadenylate deaminase (AMPD1 deficiency) to be a metabolic myopathy. Clinically, a variety of neuromuscular presentations are seen at different ages of life. Newborns and infants commonly present with hypotonia and multisystem involvement (liver and brain), whereas onset later in life usually presents with exercise intolerance with or without progressive muscle weakness and myoglobinuria. In general, the glycogen storage diseases result in high-intensity exercise intolerance, whereas the FAODs and the mitochondrial myopathies manifest predominately during endurance-type activity or under fasted or other metabolically stressful conditions. The clinical examination is often normal, and testing requires various combinations of exercise stress testing, serum creatine kinase activity and lactate concentration determination, urine organic acids, muscle biopsy, neuroimaging, and specific genetic testing for the diagnosis of a specific metabolic myopathy. Prenatal screening is available in many countries for several of the FAODs through liquid chromatography-tandem mass spectrometry. Early identification of these conditions with lifestyle measures, nutritional intervention, and cofactor treatment is important to prevent or delay the onset of muscle weakness and to avoid potential life-threatening complications such as rhabdomyolysis with resultant renal failure or hepatic failure. This article will review the key clinical features, diagnostic tests, and treatment recommendations for the more common metabolic myopathies, with an emphasis on mitochondrial myopathies.

The ascending projections to the lateral lemniscal nuclei and the inferior colliculus were investigated in the albino rat by using Fluoro-Gold, either alone or in combination with other retrograde tract tracers. Injections were made into the central nucleus of the inferior colliculus (ICC), the dorsal nucleus of the lateral lemniscus (DNLL), the intermediate nucleus of the lateral lemniscus (INLL), or the ventral nucleus of the lateral lemniscus (VNLL). The ICC receives both ipsilateral and contralateral projections from the DNLL and the lateral superior olive, major ipsilateral projections from the INLL, VNLL, medial superior olive, and superior paraolivary nucleus, and major contralateral projections from both dorsal and ventral cochlear nucleus. The DNLL receives a similar pattern of projections from the auditory lower brainstem nuclei. The INLL, in contrast, receives its major projections from the ipsilateral VNLL, lateral superior olive, medial superior olive, superior paraolivary nucleus, and medial nucleus of the trapezoid body, but does not receive a heavy projection from the contralateral lateral superior olive. It receives a major contralateral projection from the ventral cochlear nucleus, but a much lighter projection from the contralateral dorsal cochlear nucleus. The VNLL receives projections from the ipsilateral medial nucleus of the trapezoid body and the contralateral ventral cochlear nucleus, but does not receive projections from the medial or lateral superior olives, the superior paraolivary nucleus, or the dorsal cochlear nucleus. Thus, the three primary subdivisions of the rat's lateral lemniscus can be distinguished from each other on the basis of their distinctive projection patterns., (2008 Wiley-Liss, Inc.)

Adenoviral-mediated transfer of ciliary neurotrophic factor (CNTF) to the retina rescued retinal ganglion cells (RGCs) from axotomy-induced apoptosis, presumably via activation of the high affinity CNTF receptor alpha (CNTFRalpha) expressed on RGCs. CNTF can also activate astrocytes, via its low affinity leukemia inhibitory receptor beta expressed on mature astrocytes, suggesting that CNTF may also protect injured neurons indirectly by modulating glia. Adenoviral-mediated overexpression of CNTF in normal and axotomized rat retinas was examined to determine if it could increase the expression of several glial markers previously demonstrated to have a neuroprotective function in the injured brain and retina. Using Western blotting, the expression of glial fibrillary acid protein (GFAP), glutamate/aspartate transporter-1 (GLAST-1), glutamine synthetase (GS), and connexin 43 (Cx43) was examined 7 days after intravitreal injections of Ad.CNTF or control Ad.LacZ. Compared to controls, intravitreal injection of Ad.CNTF led to significant changes in the expression of CNTFRalpha, pSTAT(3), GFAP, GLAST, GS, and Cx43 in normal and axotomized retinas. Taken together, these results suggest that the neuroprotective effects of CNTF may result from a shift of retinal glia cells to a more neuroprotective phenotype. Moreover, the modulation of astrocytes may buffer high concentrations of glutamate that have been shown to contribute to the death of RGCs after optic nerve transection.

Ciliary neurotrophic factor (CNTF) has recently been demonstrated to be one of the most promising neurotrophic factors to improve both the survival and regeneration of injured retinal ganglion cells (RGCs). In the present study, we used optic nerve transection as an in vivo model to evaluate the effectiveness of a self-inactivating, replication-deficient lentiviral-mediated transfer of human ciliary neurotrophic factor (SIN-PGK-CNTF) on the survival of axotomized adult rat RGCs. Counts of dextran-fluorescein isothiocyanate conjugated (D-FITC)-retrogradely labeled RGCs revealed that the percentage of RGCs was drastically reduced (<90% cell death) 21 days after optic nerve transection. Retinal sections stained with X-gal revealed that intravitreal injection of the control LacZ-expressing lentiviral vector (LV-LacZ) resulted in the transduction of RGCs and retinal pigment epithelium (RPE) cells. A single intravitreal injection of LV-CNTF at the time of axotomy significantly enhanced RGC survival at 14 and 21 days postaxotomy compared to controls. These results demonstrate for the first time that rapid and prolonged delivery of CNTF using lentiviral-mediated gene transfer to the retina is an effective treatment for rescuing axotomized RGCs for an extended period of time. These results suggest that early and continuous administration of CNTF could serve as a potential treatment for retinal disorders involving optic neuropathy and RGC injury such as in glaucoma.

Catecholamine regulated protein 40 (CRP40) has been shown to be expressed in the central nervous system (CNS) of several mammalian species where it may function in a similar manner to members of the heat shock protein (HSP) family. Immunohistochemical and immunoblotting techniques were utilized to investigate whether CRP40 is expressed in normal rat retinas. In addition, changes in CRP40 expression were studied following optic nerve transection. The immunohistochemical results showed that CRP40 is expressed in the normal rat retina. The protein was found to be highly expressed in the ganglion cell layer (GCL), the inner nuclear layer (INL) and the outer plexiform layer (OPL). In addition, a low level of CRP40 was found in the inner plexiform layer (IPL), and in the inner segment layer (ISL). No expression was found in the outer nuclear layer (ONL) of normal rat retina. The immunoblotting results show that CRP40 expression decreased in a time-dependent fashion after the optic nerve transection. This decrease indicates that the expression of CRP40 is dependent on the neuron's normal physiological state and that it plays an important function in physiological and pathological conditions in the retina.

Binaural evoked responses were recorded with glass micropipettes from the central nucleus of the rat's inferior colliculus (ICC) before and after transection of the commissure of Probst (CP) with a microsurgical knife. The peak-to-peak amplitude of the averaged evoked response was measured for binaural clicks with interaural time differences (ITDs) between -1.0 and +30.0 ms (positive values reflecting ipsilateral-leading-contralateral click pairs). Before transection, the amplitude of the evoked response decreased as the ITD was shifted in favor of larger ipsilateral lead times. After transection of the CP, acoustic stimulation of the ipsilateral ear was much less effective in reducing evoked response amplitude. Responses to both short (+/-1.0 ms) and long (1.0-30.0 ms) ITD intervals were affected. After recordings were made, both anterograde and retrograde tract tracing methods were used to verify that the CP was completely transected and that all crossed projections from the dorsal nucleus of the lateral lemniscus (DNLL) to ICC were destroyed. The surgery completely eliminated the retrograde transport of fluorogold from the ICC to the opposite DNLL and blocked the anterograde transport of biotinylated dextran to contralateral DNLL and ICC. The physiological consequences of CP transection are attributed to the complete destruction of decussating, inhibitory (GABAergic) efferent projections from the DNLL.

The ability of rats to localize sounds in space was determined before and after kainic acid lesions of the superior olivary complex (SOC). Animals were tested with a 45-ms noise burst delivered from loudspeakers on the right or left of midline. Anatomical data showed that the lesions destroyed neurons in SOC while preserving fibers of passage in the trapezoid body and other decussating pathways of the auditory brainstem. Animals with either unilateral or bilateral SOC lesions were impaired in their ability to localize a single noise burst postoperatively. Deficits were also found after unilateral lesions restricted primarily to the lateral superior olive. SOC lesions resulted in an elevation in minimum audible angles for sound localization.