Expansions of a G
C
repeat in the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating adult-onset ...neurodegenerative disorders. Using C9-ALS/FTD patient-derived cells and C9ORF72 BAC transgenic mice, we generated and optimized antisense oligonucleotides (ASOs) that selectively blunt expression of G
C
repeat-containing transcripts and effectively suppress tissue levels of poly(GP) dipeptides. ASOs with reduced phosphorothioate content showed improved tolerability without sacrificing efficacy. In a single patient harboring mutant C9ORF72 with the G
C
repeat expansion, repeated dosing by intrathecal delivery of the optimal ASO was well tolerated, leading to significant reductions in levels of cerebrospinal fluid poly(GP). This report provides insight into the effect of nucleic acid chemistry on toxicity and, to our knowledge, for the first time demonstrates the feasibility of clinical suppression of the C9ORF72 gene. Additional clinical trials will be required to demonstrate safety and efficacy of this therapy in patients with C9ORF72 gene mutations.
Abstract
The introduction of flow diverter technology to the field of neurointervention has revolutionized the treatment of intracranial aneurysms. The therapy approach has shifted from intrasaccular ...aneurysm treatment to exclusion of the aneurysm from the blood circulation with remodeling of the parent artery. Previously, “difficult”-to-treat aneurysms including fusiform and blister aneurysms, but also aneurysms arising from a diseased vessel segment, can now be safely and permanently treated with flow diverters.
A little over a decade ago, after extensive bench testing and refinement of the flow diverter concept, the device was eventually available for clinical use and today it has become a standard treatment for intracranial aneurysms. Currently, United States Food and Drug Administration (FDA)-approved flow diverters are the Pipeline Embolization Device (Medtronic) and the Surpass Streamline Flow Diverter (Stryker).
The devices can either be delivered or deployed via a standard femoral artery approach or a radial artery approach. Other considerations for catheter setup and device deployment strategies depending on aneurysm location or vessel anatomy are described.
•Pathophysiologic review of cerebrovascular disease.•Unmet need is vascular imaging of sufficient resolution for cerebrovascular disease.•Optical coherence tomography designed for the intracranial ...vasculature is reviewed.
Diagnosis of cerebrovascular disease includes vascular neuroimaging techniques such as computed tomography (CT) angiography, magnetic resonance (MR) angiography (with or without use of contrast agents) and catheter digital subtraction angiography (DSA). These techniques provide mostly information about the vessel lumen. Vessel wall imaging with MR seeks to characterize cerebrovascular pathology, but with resolution that is often insufficient for small lesions. Intravascular imaging techniques such as ultrasound and optical coherence tomography (OCT), used for over a decade in the peripheral circulation, is not amendable to routine deployment in the intracranial circulation due to vessel caliber and tortuosity. However, advances in OCT technology including the probe profile, stiffness and unique distal rotation solution, holds the promise for eventual translation of OCT into the clinical arena. As such, it is apropos to review this technology and present the rationale for utilization of OCT in the cerebrovasculature.
Advanced imaging for patient selection in mechanical thrombectomy is not widely available.
To compare the clinical outcomes of patients selected for mechanical thrombectomy by noncontrast computed ...tomography (CT) vs those selected by computed tomography perfusion (CTP) or magnetic resonance imaging (MRI) in the extended time window.
This multinational cohort study included consecutive patients with proximal anterior circulation occlusion stroke presenting within 6 to 24 hours of time last seen well from January 2014 to December 2020. This study was conducted at 15 sites across 5 countries in Europe and North America. The duration of follow-up was 90 days from stroke onset.
Computed tomography with Alberta Stroke Program Early CT Score, CTP, or MRI.
The primary end point was the distribution of modified Rankin Scale (mRS) scores at 90 days (ordinal shift). Secondary outcomes included the rates of 90-day functional independence (mRS scores of 0-2), symptomatic intracranial hemorrhage, and 90-day mortality.
Of 2304 patients screened for eligibility, 1604 patients were included, with a median (IQR) age of 70 (59-80) years; 848 (52.9%) were women. A total of 534 patients were selected to undergo mechanical thrombectomy by CT, 752 by CTP, and 318 by MRI. After adjustment of confounders, there was no difference in 90-day ordinal mRS shift between patients selected by CT vs CTP (adjusted odds ratio aOR, 0.95 95% CI, 0.77-1.17; P = .64) or CT vs MRI (aOR, 0.95 95% CI, 0.8-1.13; P = .55). The rates of 90-day functional independence (mRS scores 0-2 vs 3-6) were similar between patients selected by CT vs CTP (aOR, 0.90 95% CI, 0.7-1.16; P = .42) but lower in patients selected by MRI than CT (aOR, 0.79 95% CI, 0.64-0.98; P = .03). Successful reperfusion was more common in the CT and CTP groups compared with the MRI group (474 88.9% and 670 89.5% vs 250 78.9%; P < .001). No significant differences in symptomatic intracranial hemorrhage (CT, 42 8.1%; CTP, 43 5.8%; MRI, 15 4.7%; P = .11) or 90-day mortality (CT, 125 23.4%; CTP, 159 21.1%; MRI, 62 19.5%; P = .38) were observed.
In patients undergoing proximal anterior circulation mechanical thrombectomy in the extended time window, there were no significant differences in the clinical outcomes of patients selected with noncontrast CT compared with those selected with CTP or MRI. These findings have the potential to widen the indication for treating patients in the extended window using a simpler and more widespread noncontrast CT-only paradigm.
Posterior circulation aneurysms are more likely to rupture than those in the anterior circulation but also pose more of a challenge for endovascular treatment or neurosurgical clipping. Aneurysms ...arising from the posterior cerebral artery are rare; dissecting aneurysms are even rarer. Dissecting posterior cerebral artery aneurysms can be spontaneous or post traumatic. Our case depicts a patient with acute subarachnoid hemorrhage due to a ruptured, dissecting posterior cerebral artery aneurysm who underwent successful endovascular treatment by means of flow diversion.
There is a discrepancy in clinical outcomes and the achieved recanalization rates with stent retrievers in the endovascular treatment of ischemic stroke. It is our hypothesis that procedural release ...of embolic particulate may be one contributor to poor outcomes and is a modifiable risk. The goal of this study is to assess various treatment strategies that reduce the risk of distal emboli.
Mechanical thrombectomy was simulated in a vascular phantom with collateral circulation. Hard fragment-prone clots (HFC) and soft elastic clots (SECs) were used to generate middle cerebral artery (MCA) occlusions that were retrieved by the Solitaire FR devices through (1) an 8 Fr balloon guide catheter (BGC), (2) a 5 Fr distal access catheter at the proximal aspect of the clot in the MCA (Solumbra), or (3) a 6 Fr guide catheter with the tip at the cervical internal carotid artery (guide catheter, GC). Results from mechanical thrombectomy were compared with those from direct aspiration using the Penumbra 5MAX catheter. The primary endpoint was the size distribution of emboli to the distribution of the middle and anterior cerebral arteries.
Solumbra was the most efficient method for reducing HFC fragments (p<0.05) while BGC was the best method for preventing SEC fragmentation (p<0.05). The risk of forming HFC distal emboli (>1000 µm) was significantly increased using GC. A non-statistically significant benefit of direct aspiration was observed in several subgroups of emboli with size 50-1000 µm. However, compared with the stent-retriever mechanical thrombectomy techniques, direct aspiration significantly increased the risk of SEC fragmentation (<50 µm) by at least twofold.
The risk of distal embolization is affected by the catheterization technique and clot mechanics.
To evaluate the impact of proximal flow control on efficacy and safety of mechanical thrombectomy in an in vitro middle cerebral artery occlusion.
Three independent variables, including clot type, ...device (Merci Retriever, Solitaire FR, and Trevo devices), and use of a balloon guide catheter, were used to ascertain the impact of proximal flow control on the size and number of distal emboli generated during thrombectomy. Secondary end points were the recanalization rate and amount of flow restored.
Use of the balloon guide catheter during thrombectomy of the fragile, hard clot significantly reduced the formation of large distal emboli with a diameter >1 mm, regardless of the device used (P<0.01). Applying aspiration via the balloon guide catheter in place of the conventional guide catheter resulted in a significant increase of flow reversal (P<0.0001). Prior to thrombectomy, deployment of the stent-trievers produced immediate flow restoration through the soft and hard clot occlusions, 69.2 ± 27.3 and 45.5 ± 22.8 mL/min, respectively, that was preserved after the balloon inflation because of collateral flow via the posterior communication artery. After deployment but before thrombectomy, no flow was restored when using the Merci Retriever. After thrombectomy, complete flow restoration was achieved in a majority of cases. The Merci Retriever required more thrombectomy attempts to achieve hard clot removal compared with the stent-trievers when the conventional guide catheter was used (1.5 versus 1.1).
The risk of distal embolization was significantly reduced with the use of the balloon guide catheter.
Abstract
Intravascular imaging has emerged as a valuable tool for the treatment of coronary and peripheral artery disease; however, no solution is available for safe and reliable use in the tortuous ...vascular anatomy of the brain. Endovascular treatment of stroke is delivered under image guidance with insufficient resolution to adequately assess underlying arterial pathology and therapeutic devices. High-resolution imaging, enabling surgeons to visualize cerebral arteries' microstructure and micron-level features of neurovascular devices, would have a profound impact in the research, diagnosis, and treatment of cerebrovascular diseases. Here, we present a neurovascular high-frequency optical coherence tomography (HF-OCT) system, including an imaging console and an endoscopic probe designed to rapidly acquire volumetric microscopy data at a resolution approaching 10 microns in tortuous cerebrovascular anatomies. Using a combination of in vitro, ex vivo, and in vivo models, the feasibility of HF-OCT for cerebrovascular imaging was demonstrated.
There is increasing interest in defining stroke lesion volume thresholds to predict poststroke outcome. However, there is a paucity of data on factors that impact the association between critical ...infarct thresholds volume and outcome. We sought to determine whether lesion thresholds best predicting outcome depend on the degree of preexisting white matter hyperintensity (WMH) lesion burden.
Magnetic resonance imaging infarct volumes were quantified in 414 consecutive patients with anterior circulation ischemic strokes evaluated between January 2014 and December 2014. The WMH lesion volume was graded according to the Fazekas scale and dichotomized to absent to mild versus moderate to severe. Receiver operator characteristics curves were calculated to determine the infarct volume threshold best predicting the 90-day outcome. Multivariable logistic regression was used to determine whether the critical lesion thresholds independently predicted a favorable 90-day outcome after adjusting for pertinent confounders.
The infarct volumes thresholds predicting the 90-day outcome for the entire cohort (standard thresholds) were ≤29.5 mL (modified Rankin scale mRS 0-1), ≤29.9 mL (mRS 0-2), and ≤34.1 mL (mRS 0-3). For patients with absent-to-mild WMH lesion burden, WMH-adjusted critical infarct thresholds were significantly greater than the standard infarct thresholds. In the fully adjusted multivariable regression models, the WMH-adjusted infarct thresholds correctly predicted the outcome to a similar degree as the standard thresholds.
In this proof-of-concept study, the WMH lesion burden impacted the critical outcome-predicting infarct thresholds. If confirmed, using a WMH-adjusted infarct threshold could allow defining patients that have a favorable outcome despite having relatively large infarct volumes.
Moyamoya is characterized as a non-atherosclerotic and non-inflammatory vasculopathy that leads to progressive stenosis of the intracranial internal carotid arteries as well as the Circle of Willis. ...While it can be idiopathic (Moyamoya disease) or associated with another condition (Moyamoya syndrome), there is a characteristic ‘puff of smoke’ sign that can be appreciated on cerebral angiography.
•Puff of smoke sign, appreciated on cerebral angiography, is useful in identifying Moyamoya disease (MMD) or syndrome (MMS).•MMD/MMS is a non-atherosclerotic/inflammatory vasculopathy that leads to progressive stenosis of the intracranial arteries.•Most effective management options include direct and/or indirect surgical revascularization interventions.
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