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Posterior circulation ischaemic stroke diagnosis and management.
This narrative review provides an overview of the posterior circulation and the clinical features of common posterior circulation stroke (PCS) syndromes in the posterior arterial territories and how to distinguish them from mimics. We outline the hyperacute management of patients with suspected PCS with emphasis on how to identify those who are likely to benefit from intervention based on imaging findings. Finally, we review advances in treatment options, including developments in endovascular thrombectomy (EVT) and intravenous thrombolysis (IVT), and the principles of medical management and indications for neurosurgery. Observational and randomised clinical trial data have been equivocal regarding EVT in PCS, but more recent studies strongly support its efficacy. There have been concomitant advances in imaging of posterior stroke to guide optimal patient selection for thrombectomy. Recent evidence suggests that clinicians should have a heightened suspicion of posterior circulation events with the resultant implementation of timely, evidence-based management.
A Systematic Review and Meta-Analysis of Randomized Controlled Trials of Endovascular Thrombectomy Compared with Best Medical Treatment for Acute Ischemic Stroke
Background Acute ischemic strokes involving occlusion of large vessels usually recanalize poorly following treatment with intravenous thrombolysis. Recent studies have shown higher recanalization and higher good outcome rates with endovascular therapy compared with best medical management alone. A systematic review and meta-analysis investigating the benefits of all randomized controlled trials of endovascular thrombectomy where at least 25% of patients were treated with a thrombectomy device for the treatment of acute ischemic stroke compared with best medical treatment have yet to be performed. Aim To perform a systematic review and a meta-analysis evaluating the effectiveness of endovascular thrombectomy compared with best medical care for treatment of acute ischemic stroke. Summary of review Our search identified 437 publications, from which eight studies (totaling 2423 patients) matched the inclusion criteria. Overall, endovascular thrombectomy was associated with improved functional outcomes (modified Rankin Scale 0–2) [odds ratio 1·56 (1·32–1·85), P < 0·00001]. There was a tendency toward decreased mortality [odds ratio 0·84 (0·67–1·05), P = 0·12], and symptomatic intracerebral hemorrhage was not increased [odds ratio 1·03 (0·71–1·49), P = 0·88] compared with best medical management alone. The odds ratio for a favorable functional outcome increased to 2·23 (1·77–2·81, P < 0·00001) when newer generation thrombectomy devices were used in greater than 50% of the cases in each trial. Conclusions There is clear evidence for improvement in functional independence with endovascular thrombectomy compared with standard medical care, suggesting that endovascular thrombectomy should be considered the standard effective treatment alongside thombolysis in eligible patients.
Endogenous Neuroprotection: Hamartin Modulates an Austere Approach to Staying Alive in a Recession
Tuberous sclerosis complex 1 (hamartin) is an effective endogenous neuroprotectant. Understanding the endogenous mechanism for neuroprotection mediated by hamartin may afford a novel approach to effective treatment of neurological diseases such as stroke, neurodegenerative diseases, and epilepsy, with possible applications to nonneurological conditions.
Growth Differentiation Factor-11 Causes Neurotoxicity During Ischemia in vitro.
Age-related neuronal dysfunction can be overcome by circulating factors present in young blood. Growth differentiation factor-11 (GDF-11), a systemic factor that declines with age, can reverse age-related dysfunction in brain, heart and skeletal muscle. Given that age increases susceptibility to stroke, we hypothesized that GDF-11 may be directly protective to neurons following ischemia. Primary cortical neurons were isolated from E18 Wistar rat embryos and cultured for 7-10 days. Neurons were deprived of oxygen and glucose (OGD) to simulate ischemia. Neuronal death was assessed by lactate dehydrogenase, propidium iodide or CellTox™ green cytotoxicity assays. 40 ng/mL GDF-11 administration during 2 h OGD significantly increased neuronal death following 24 h recovery. However, GDF-11 pre-treatment did not affect neuronal death during 2 h OGD. GDF-11 treatment during the 24 h recovery period after 2 h OGD also did not alter death. Real-time monitoring for 24 h revealed that by 2 h OGD, GDF-11 treatment had increased neuronal death which remained raised at 24 h. Co-treatment of 1 μM SB431542 (ALK4/5/7 receptor inhibitor) with GDF-11 prevented GDF-11 neurotoxicity after 2 h OGD and 24 h OGD. Transforming growth factor beta (TGFβ) did not increase neuronal death to the same extent as GDF-11 following OGD. GDF-11 neurotoxicity was also exhibited following neuronal exposure to hydrogen peroxide. These results reveal for the first time that GDF-11 is neurotoxic to primary neurons in the acute phase of simulated stroke through primarily ALK4 receptor signaling.
Suppression of the inflammatory response by diphenyleneiodonium after transient focal cerebral ischemia
AbstractDiphenyleneiodonium (DPI), a NADPH oxidase inhibitor, reduces production of reactive oxygen species (ROS) and confers neuroprotection to focal cerebral ischemia. Our objective was to investigate whether the neuroprotective action of DPI extends to averting the immune response. DPI‐induced gene changes were analyzed by microarray analysis from rat brains subjected to 90 min of middle cerebral artery occlusion, treated with NaCl (ischemia), dimethylsulfoxide (DMSO), or DMSO and DPI (DPI), and reperfused for 48 h. The genomic expression profile was compared between groups using ingenuity pathway analysis at the pathway and network level. DPI selectively up‐regulated 23 genes and down‐regulated 75 genes more than twofold compared with both DMSO and ischemia. It significantly suppressed inducible nitric oxide synthase signaling and increased the expression of methionine adenosyltransferasesynthetase 2A and adenosylmethionine decarboxylase 1 genes, which are involved in increasing the production of the antioxidant glutathione. The most significantly affected gene network comprised genes implicated in the inflammatory response with an expression change indicating an overall suppression. Both integrin‐ and interleukin‐17A‐signaling pathways were also significantly associated and suppressed. In conclusion, the neuroprotective effects of DPI are mediated not only by suppressing ischemia‐triggered oxidative stress but also by limiting leukocyte migration and infiltration.
Reality of evidence-based practice in palliative care.
There has been a paradigm shift in medicine away from tradition, anecdote and theoretical reasoning from the basic sciences towards evidence-based medicine (EBM). In palliative care however, statistically significant benefits may be marginal and may not be related to clinical meaningfulness. The typical treatment vs. placebo comparison necessitated by 'gold standard' randomised controlled trials (RCTs) is not necessarily applicable. The complex multimorbidity of end of life care involves considerations of the patient's physical, psychological, social and spiritual needs. In addition, the field of palliative care covers a heterogeneous group of chronic and incurable diseases no longer limited to cancer. Adequate sample sizes can be difficult to achieve, reducing the power of studies and high attrition rates can result in inadequate follow up periods. This review uses examples of the management of cancer-related fatigue and death rattle (noisy breathing) to demonstrate the current state of EBM in palliative care. The future of EBM in palliative care needs to be as diverse as the patients who ultimately derive benefit. Non-RCT methodologies of equivalent quality, validity and size conducted by collaborative research networks using a 'mixed methods approach' are likely to pose the correct clinical questions and derive evidence-based yet clinically relevant outcomes.
The role of the endoplasmic reticulum stress response following cerebral ischemia
Background Cornu ammonis 3 (CA3) hippocampal neurons are resistant to global ischemia, whereas cornu ammonis (CA1) 1 neurons are vulnerable. Hamartin expression in CA3 neurons mediates this endogenous resistance via productive autophagy. Neurons lacking hamartin demonstrate exacerbated endoplasmic reticulum stress and increased cell death. We investigated endoplasmic reticulum stress responses in CA1 and CA3 regions following global cerebral ischemia, and whether pharmacological modulation of endoplasmic reticulum stress or autophagy altered neuronal viability . Methods In vivo: male Wistar rats underwent sham or 10 min of transient global cerebral ischemia. CA1 and CA3 areas were microdissected and endoplasmic reticulum stress protein expression quantified at 3 h and 12 h of reperfusion. In vitro: primary neuronal cultures (E18 Wistar rat embryos) were exposed to 2 h of oxygen and glucose deprivation or normoxia in the presence of an endoplasmic reticulum stress inducer (thapsigargin or tunicamycin), an endoplasmic reticulum stress inhibitor (salubrinal or 4-phenylbutyric acid), an autophagy inducer ([4′-(N-diethylamino) butyl]-2-chlorophenoxazine (10-NCP)) or autophagy inhibitor (3-methyladenine). Results In vivo, decreased endoplasmic reticulum stress protein expression (phospho-eIF2α and ATF4) was observed at 3 h of reperfusion in CA3 neurons following ischemia, and increased in CA1 neurons at 12 h of reperfusion. In vitro, endoplasmic reticulum stress inducers and high doses of the endoplasmic reticulum stress inhibitors also increased cell death. Both induction and inhibition of autophagy also increased cell death. Conclusion Endoplasmic reticulum stress is associated with neuronal cell death following ischemia. Neither reduction of endoplasmic reticulum stress nor induction of autophagy demonstrated neuroprotection in vitro, highlighting their complex role in neuronal biology following ischemia.
The transient intraluminal filament middle cerebral artery occlusion model as a model of endovascular thrombectomy in stroke
The clinical relevance of the transient intraluminal filament model of middle cerebral artery occlusion (tMCAO) has been questioned due to distinct cerebral blood flow profiles upon reperfusion between tMCAO (abrupt reperfusion) and alteplase treatment (gradual reperfusion), resulting in differing pathophysiologies. Positive results from recent endovascular thrombectomy trials, where the occluding clot is mechanically removed, could revolutionize stroke treatment. The rapid cerebral blood flow restoration in both tMCAO and endovascular thrombectomy provides clinical relevance for this pre-clinical model. Any future clinical trials of neuroprotective agents as adjuncts to endovascular thrombectomy should consider tMCAO as the model of choice to determine pre-clinical efficacy.
A Systematic Review and Meta-analysis of Randomized Controlled Trials of Endovascular Thrombectomy Compared to Best Medical Treatment for Acute Ischemic Stroke
Background Acute ischemic strokes involving occlusion of large vessels usually recanalize poorly following treatment with intravenous thrombolysis. Recent studies have shown higher recanalization and higher good outcome rates with endovascular therapy compared to best medical management alone. A systematic review and meta-analysis investigating the benefits of all randomized controlled trials (RCTs) of endovascular thrombectomy where at least 25% of patients were treated with a thrombectomy device for the treatment of acute ischemic stroke compared to intravenous thrombolysis has yet to be performed. Aims To perform a systematic review and a meta-analysis evaluating the effectiveness of endovascular thrombectomy compared with best medical care for treatment of acute ischemic stroke. Summary of review Our search identified 437 publications, from which 8 studies (totaling 2,423 patients) matched the inclusion criteria. Overall, endovascular thrombectomy was associated with improved functional outcomes (mRS 0-2) (odds ratio (OR) 1.56 (1.32-1.85), p< 0.00001). There was a tendency towards decreased mortality (OR 0.84 (0.67-1.05), p=0.12) and symptomatic intracerebral hemorrhage was not increased (OR 1.03 (0.71-1.49), p=0.88) compared to best medical management alone. The OR for a favorable functional outcome increased to 2.23 (1.77-2.81, p<0.00001) when newer generation thrombectomy devices were used in greater than 50% of the cases in each trial. Conclusions There is clear evidence for improvement in functional independence with endovascular thrombectomy compared to standard medical care suggesting that endovascular thrombectomy should be considered the standard effective treatment alongside thombolysis in eligible patients.
Rapamycin in ischemic stroke: Old drug, new tricks?
The significant morbidity that accompanies stroke makes it one of the world's most devastating neurological disorders. Currently, proven effective therapies have been limited to thrombolysis and thrombectomy. The window for the administration of these therapies is narrow, hampered by the necessity of rapidly imaging patients. A therapy that could extend this window by protecting neurons may improve outcome. Endogenous neuroprotection has been shown to be, in part, due to changes in mTOR signalling pathways and the instigation of productive autophagy. Inducing this effect pharmacologically could improve clinical outcomes. One such therapy already in use in transplant medicine is the mTOR inhibitor rapamycin. Recent evidence suggests that rapamycin is neuroprotective, not only via neuronal autophagy but also through its broader effects on other cells of the neurovascular unit. This review highlights the potential use of rapamycin as a multimodal therapy, acting on the blood–brain barrier, cerebral blood flow and inflammation, as well as directly on neurons. There is significant potential in applying this old drug in new ways to improve functional outcomes for patients after stroke.
Comment on Di Giosaffatte et al. A Novel Hypothesis on Choroideremia-Manifesting Female Carriers: Could CHM In-Frame Variants Exert a Dominant Negative Effect? A Case Report. Genes 2022, 13, 1268.
The recent publication of Di Giosaffatte et al. [...].