Sex-specific differences in presentations and determinants of outcomes after endovascular thrombectomy for large vessel occlusion stroke

Journal of Neurology - Sex-specific differences in ischemic stroke outcomes are prevalent. We sought to investigate sex differences in the determinants of reperfusion and functional outcomes after...     

Cerebroprotection by angiotensin-(1-7) in endothelin-1-induced ischaemic stroke

Activation of angiotensin-converting enzyme 2 (ACE2), production of angiotensin-(1-7) [Ang-(1-7)] and stimulation of the Ang-(1-7) receptor Mas exert beneficial actions in various peripheral cardiovascular diseases, largely through opposition of the deleterious effects of angiotensin II via its type 1 receptor. Here we considered the possibility that Ang-(1-7) may exert beneficial effects against CNS damage and neurological deficits produced by cerebral ischaemic stroke. We determined the effects of central administration of Ang-(1-7) or pharmacological activation of ACE2 on the cerebral damage and behavioural deficits elicited by endothelin-1 (ET-1)-induced middle cerebral artery occlusion (MCAO), a model of cerebral ischaemia. The results of the present study demonstrated that intracerebroventricular infusion of either Ang-(1-7) or an ACE2 activator, diminazine aceturate (DIZE), prior to and following ET-1-induced MCAO significantly attenuated the cerebral infarct size and neurological deficits measured 72 h after the insult. These beneficial actions of Ang-(1-7) and DIZE were reversed by co-intracerebroventricular administration of the Mas receptor inhibitor, A-779. Neither the Ang-(1-7) nor the DIZE treatments altered the reduction in cerebral blood flow elicited by ET-1. Lastly, intracerebroventricular administration of Ang-(1-7) significantly reduced the increase in inducible nitric oxide synthase mRNA expression within the cerebral infarct that occurs following ET-1-induced MCAO. This is the first demonstration of cerebroprotective properties of the ACE2-Ang-(1-7)-Mas axis during ischaemic stroke, and suggests that the mechanism of the Ang-(1-7) protective action includes blunting of inducible nitric oxide synthase expression.     

CTA Protocols in a Telestroke Network Improve Efficiency for Both Spoke and Hub Hospitals

BACKGROUND AND PURPOSE:Telestroke networks support screening for patients with emergent large-vessel occlusions who are eligible for endovascular thrombectomy. Ideal triage processes within telestroke networks remain uncertain. We characterize the impact of implementing a routine spoke hospital CTA protocol in our integrated telestroke network on transfer and thrombectomy patterns.MATERIALS AND METHODS:A protocol-driven CTA process was introduced at 22 spoke hospitals in November 2017. We retrospectively identified prospectively collected patients who presented to a spoke hospital with National Institutes of Health Stroke Scale scores ≥6 between March 1, 2016 and March 1, 2017 (pre-CTA), and March 1, 2018 and March 1, 2019 (post-CTA). We describe the demographics, CTA utilization, spoke hospital retention rates, emergent large-vessel occlusion identification, and rates of endovascular thrombectomy.RESULTS:There were 167 patients pre-CTA and 207 post-CTA. The rate of CTA at spoke hospitals increased from 15% to 70% (P < .001). Despite increased endovascular thrombectomy screening in the extended window, the overall rates of transfer out of spoke hospitals remained similar (56% versus 54%; P = .83). There was a nonsignificant increase in transfers to our hub hospital for endovascular thrombectomy (26% versus 35%; P = .12), but patients transferred >4.5 hours from last known well increased nearly 5-fold (7% versus 34%; P < .001). The rate of endovascular thrombectomy performed on patients transferred for possible endovascular thrombectomy more than doubled (22% versus 47%; P = .011).CONCLUSIONS:Implementation of CTA at spoke hospitals in our telestroke network was feasible and improved the efficiency of stroke triage. Rates of patients retained at spoke hospitals remained stable despite higher numbers of patients screened. Emergent large-vessel occlusion confirmation at the spoke hospital lead to a more than 2-fold increase in thrombectomy rates among transferred patients at the hub.

Telestroke supports thrombolytic use and screening for patients with emergent large-vessel occlusion (ELVO) across stroke systems of care.^1-3 ELVOs represent a minority of acute stroke presentations but produce most morbidity and mortality in ischemic stroke and are therefore a critical area of focus within stroke care systems.^4-6 For patients with ELVO, the current target of acute stroke therapy is penumbral salvage, which relies on numerous factors, the most important of which is timely reperfusion.^7-9 The powerful therapeutic effect of early reperfusion (<6 hours from last known well [LKW]) through endovascular thrombectomy (EVT) for patients with ELVO is now well established.^10-12 The time window for treatment expanded with the demonstration of benefit of reperfusion in patients between 6 and 24 hours from LKW, a demographic for which previously no therapeutic intervention was available.^13-14 Selection for thrombectomy in both early and late treatment windows required identification of ELVO by noninvasive imaging in all recent trials.The expansion of treatment with EVT up to 24 hours from LKW has dramatically increased the pool of patients to screen. Current telestroke care system approaches require the emergent transfer of patients from spoke hospitals (SHs), which lack the ability to perform thrombectomy, to hub hospitals, which are thrombectomy capable. Ideal triage processes within telestroke networks remain uncertain and may vary based on geographic region. Here we describe the effects of the implementation of a routine SH CTA protocol within our integrated telestroke network on SH retention rates and hub hospital thrombectomy rates.     

Intramuscular injection of α-synuclein induces CNS α-synuclein pathology and a rapid-onset motor phenotype in transgenic mice

It has been hypothesized that α-synuclein (αS) misfolding may begin in peripheral nerves and spread to the central nervous system (CNS), leading to Parkinson disease and related disorders. Although recent data suggest that αS pathology can spread within the mouse brain, there is no direct evidence for spread of disease from a peripheral site. In the present study, we show that hind limb intramuscular (IM) injection of αS can induce pathology in the CNS in the human Ala53Thr (M83) and wild-type (M20) αS transgenic (Tg) mouse models. Within 2–3 mo after IM injection in αS homozygous M83 Tg mice and 3–4 mo for hemizygous M83 Tg mice, these animals developed a rapid, synchronized, and predictable induction of widespread CNS αS inclusion pathology, accompanied by astrogliosis, microgliosis, and debilitating motor impairments. In M20 Tg mice, starting at 4 mo after IM injection, we observed αS inclusion pathology in the spinal cord, but motor function remained intact. Transection of the sciatic nerve in the M83 Tg mice significantly delayed the appearance of CNS pathology and motor symptoms, demonstrating the involvement of retrograde transport in inducing αS CNS inclusion pathology. Outside of scrapie-mediated prion disease, to our knowledge, this findiing is the first evidence that an entire neurodegenerative proteinopathy associated with a robust, lethal motor phenotype can be initiated by peripheral inoculation with a pathogenic protein. Furthermore, this facile, synchronized rapid-onset model of α-synucleinopathy will be highly valuable in testing disease-modifying therapies and dissecting the mechanism(s) that drive αS-induced neurodegeneration.Synucleinopathies are a group of diseases defined by the presence of amyloidogenic α-synuclein (αS) inclusions that can occur in neurons and glia of the central nervous system (CNS) (1–4). In Parkinson disease (PD), a causative role for αS has been established via the discovery of mutations in the αS gene SNCA resulting in autosomal-dominant PD (4–11). Although αS inclusions (e.g., Lewy bodies) are the hallmark pathology of PD, how they contribute to disease pathogenesis remains controversial (1, 3, 4, 12).Postmortem studies have suggested that αS pathology may spread following neuroanatomical tracts (13–15) and between cells (16–18). αS pathology has also been found in the peripheral nervous system (PNS): for example, in the enteric and pelvic plexus (19, 20). And it has been suggested that αS pathology might originate in the nerves of the PNS and spread to the CNS (14). Experimentally, it has been reported that intracerebral injections of preformed amyloidogenic αS fibrils in nontransgenic (nTg) and αS transgenic (Tg) mice induce the formation of intracellular αS inclusions that appear to progress from the site of injection (21–26). Collectively, these studies support the notion that αS inclusion pathology may propagate via a prion-like conformational self-templating mechanism (27, 28). A caveat of the direct intracerebral injection of αS is that this CNS invasive surgical procedure directly alters brain homeostasis that could influence or facilitate the formation of brain pathologies, especially because incidents such as traumatic brain injury can promote the formation of αS pathology (29). Here, we report that the intramuscular (IM) injection of fibrillar (fib) αS in M83 Tg mice expressing human Ala53Thr (A53T) αS can result in the rapid and synchronized development of hind limb motor weakness and robust widespread CNS αS pathology. Additionally, similar injection into M20 Tg mice expressing human wild-type αS, which do not intrinsically develop pathology, leads to the induction of CNS αS pathology as early as 4 mo postinjection.     

Treatment Approaches to Lacunar Stroke

Lacunar strokes are appropriately named for their ability to cavitate and form ponds or “little lakes” (Latin: lacune -ae meaning pond or pit is a diminutive form of lacus meaning lake). They account for a substantial proportion of both symptomatic and asymptomatic ischemic strokes. In recent years, there have been several advances in the management of large vessel occlusions. New therapies such as non-vitamin K antagonist oral anticoagulants and left atrial appendage closure have recently been developed to improve stroke prevention in atrial fibrillation; however, the treatment of small vessel disease-related strokes lags frustratingly behind. Since Fisher characterized the lacunar syndromes and associated infarcts in the late 1960s, there have been no therapies specifically targeting lacunar stroke. Unfortunately, many therapeutic agents used for the treatment of ischemic stroke in general offer only a modest benefit in reducing recurrent stroke while adding to the risk of intracerebral hemorrhage and systemic bleeding. Escalation of antithrombotic treatments beyond standard single antiplatelet agents has not been effective in long-term lacunar stroke prevention efforts, unequivocally increasing intracerebral hemorrhage risk without providing a significant benefit. In this review, we critically review the available treatments for lacunar stroke based on evidence from clinical trials. For several of the major drugs, we summarize the adverse effects in the context of this unique patient population. We also discuss the role of neuroprotective therapies and neural repair strategies as they may relate to recovery from lacunar stroke.