Patent foramen ovale (PFO) is frequently identified in young patients with cryptogenic ischaemic stroke. Potential stroke mechanisms include paradoxical embolism from a venous clot which traverses the PFO, in situ clot formation within the PFO, and atrial arrhythmias due to electrical signalling disruption. The purpose of this guideline is to provide recommendations for diagnosing, treating, and long-term managing patients with ischaemic stroke and PFO. Conversely, Transient Ischaemic Attack (TIA) was not considered an index event in this context because only one RCT involved TIA patients. However, this subgroup analysis showed no significant differences between TIA and stroke outcomes. The working group identified questions and outcomes, graded evidence, and developed recommendations following the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach and the European Stroke Organisation (ESO) standard operating procedure for guideline development. This document underwent peer-review by independent experts and members of the ESO Guideline Board and Executive Committee. The working group acknowledges the current evidentiary gap in delineating an unequivocal diagnostic algorithm for the detection of PFO. Although transoesophageal echocardiography is conventionally held as the most accurate diagnostic tool for PFO identification, its status as the ‘gold standard’ remains unsubstantiated by rigorously validated evidence. We found high-quality evidence to recommend PFO closure plus antiplatelet therapy in selected patients aged 18–60 years in whom no other evident cause of stroke is found but a PFO (i.e. PFO-associated stroke). The PASCAL classification system can be used to select such candidates for PFO closure. Patients with both a large right-to-left shunt and an atrial septal aneurysm benefit most from PFO closure. There is insufficient evidence to make an evidence-based recommendation on PFO closure in patients older than 60 and younger than 18 years. We found low quality evidence to suggest against PFO closure in patients with unlikely PFO-related stroke according to the PASCAL classification, except in specific scenarios (Expert Consensus). We suggest against long-term anticoagulation in patients with PFO-associated stroke unless anticoagulation is indicated for other medical reasons. Regarding the long-term AF monitoring after PFO closure, the working group concluded that there remains significant uncertainty regarding the risks and benefits associated with the use of long-term cardiac monitoring, such as implantable loop recorders. This document provides additional guidance, in the form of evidence-based recommendations or expert consensus statements, on diagnostic methods for PFO detection, and medical management after PFO closure. Graphical abstract

With the constant failure of the clinical trials continuous exploration of a therapeutic target against Alzheimer's disease (AD) is the utmost need. Numerous studies have supported the hypothesis that central insulin resistance plays a significant role in AD. Serine phosphorylation of Insulin Receptor Substarte-1 (IRS-1) has been found to be a contributing factor in neuronal insulin resistance. Astaxanthin (ASX) is xanthophyll carotenoid which has previously demonstrated significant antidiabetic and neuroprotective actions. In the present study, AD was induced by i.c.v administration of Amyloid-β (1-42) peptides in Wistar rats. After 7 days of recovery, rats were treated with 0.5 mg/kg and 1 mg/kg of ASX orally for 28 days. Behavioral analysis was done in the last week of our experimental study. On the 36th day, rats were sacrificed and their hippocampus were separated from the whole brain, then homogenized and stored for biochemical estimations. ASX significantly and dose-dependently reversed the cognitive and memory impairment, assessed by Morris water maze test and Novel object Recognition test, Aβ (1-42) peptides infused Wistar rats. ASX also significantly attenuated soluble Aβ (1-42) level, IRS-S307 activity, GSK-3β activity, TNF-α level, AChE level, nitrite level and oxidative stress in the hippocampus. Histopathological evaluation, done through H&E and Congo red staining, also demonstrated neuroprotective and anti-amyloidogenic effects of ASX in hippocampus. Our study concludes preventive action of Astaxanthin against hippocampal insulin resistance and Alzheimer's disease complications, supporting potential role of hippocampal insulin resistance targeting against AD.

A quarter of ischaemic strokes are lacunar subtype, typically neurologically mild, usually resulting from intrinsic cerebral small vessel pathology, with risk factor profiles and outcome rates differing from other stroke subtypes. This European Stroke Organisation (ESO) guideline provides evidence-based recommendations to assist with clinical decisions about management of lacunar ischaemic stroke to prevent adverse clinical outcomes. The guideline was developed according to ESO standard operating procedures and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. We addressed acute treatment (including progressive lacunar stroke) and secondary prevention in lacunar ischaemic stroke, and prioritised the interventions of thrombolysis, antiplatelet drugs, blood pressure lowering, lipid lowering, lifestyle, and other interventions and their potential effects on the clinical outcomes recurrent stroke, dependency, major adverse cardiovascular events, death, cognitive decline, mobility, gait, or mood disorders. We systematically reviewed the literature, assessed the evidence and where feasible formulated evidence-based recommendations, and expert concensus statements. We found little direct evidence, mostly of low quality. We recommend that patients with suspected acute lacunar ischaemic stroke receive intravenous alteplase, antiplatelet drugs and avoid blood pressure lowering according to current acute ischaemic stroke guidelines. For secondary prevention, we recommend single antiplatelet treatment long-term, blood pressure control, and lipid lowering according to current guidelines. We recommend smoking cessation, regular exercise, other healthy lifestyle modifications, and avoid obesity for general health benefits. We cannot make any recommendation concerning progressive stroke or other drugs. Large randomised controlled trials with clinically important endpoints, including cognitive endpoints, are a priority for lacunar ischaemic stroke.

The aim of the present European Stroke Organisation (ESO) guideline is to provide evidence-based recommendations on the acute management of patients with basilar artery occlusion (BAO). These guidelines were prepared following the Standard Operational Procedure of the ESO and according to the GRADE methodology. Although BAO accounts for only 1%–2% of all strokes, it has very poor natural outcome. We identified 10 relevant clinical situations and formulated the corresponding Population Intervention Comparator Outcomes (PICO) questions, based on which a systematic literature search and review was performed. The working group consisted of 10 voting members (five representing ESO and five ESMINT) and three non-voting junior members. The certainty of evidence was generally very low. In many PICOs, available data were scarce or lacking, hence, we provided expert consensus statements. First, we compared intravenous thrombolysis (IVT) to no IVT, but specific BAO-related data do not exist. Yet, historically, IVT was standard of care for BAO patients who were also included (albeit in small numbers) in IVT trials. Non-randomised studies of IVT-only cohorts showed high proportion of favourable outcomes. Expert Consensus suggests using IVT up to 24 h unless otherwise contraindicated. We further suggest IVT plus endovascular treatment (EVT) over direct EVT. EVT on top of best medical treatment (BMT) was compared to BMT alone within 6 and 6–24 h from last seen well. In both time windows, we observed a different effect of treatment depending on (a) the region where the patients were treated (Europe vs. Asia), (b) on the proportion of IVT in the BMT arm, and (c) on the initial stroke severity. In case of high proportion of IVT in the BMT group and in patients with NIHSS below 10, EVT plus BMT was not found better than BMT alone. Based on very low certainty of evidence, we suggest EVT + BMT over BMT alone (i.e. based on results of patients with at least 10 NIHSS points and a low proportion of IVT in BMT). For patients with an NIHSS below 10, we found no evidence to recommend EVT over BMT. In fact, BMT was non-significantly better and safer than EVT. Furthermore, we found a stronger treatment effect of EVT + BMT over BMT alone in proximal and middle locations of BAO compared to distal location. While recommendations for patients without extensive early ischaemic changes in the posterior fossa can, in general, follow those of other PICOs, we formulated an Expert Consensus Statement suggesting against reperfusion therapy in those with extensive bilateral and/or brainstem ischaemic changes. Another Expert Consensus suggests reperfusion therapy regardless of collateral scores. Based on limited evidence, we suggest direct aspiration over stent retriever as the first-line strategy of mechanical thrombectomy. As an Expert Consensus, we suggest rescue percutaneous transluminal angioplasty and/or stenting after a failed EVT procedure. Finally, based on very low certainty of evidence, we suggest add-on antithrombotic treatment during EVT or within 24 h after EVT in patients with no concomitant IVT and in whom EVT was complicated (defined as failed or imminent re-occlusion, or need for additional stenting or angioplasty).

Mucormycosis, a secondary fungal infection, gained much attention in the ongoing COVID-19 pandemic. This deadly infection has a high all-cause mortality rate and imposes a significant economic, epidemiological, and humanistic burden on the patients and healthcare system. Evidence from the published epidemiological studies showed the varying prevalence of COVID-19-associated mucormycosis (CAM). This study aims to compute the pooled prevalence of CAM and other associated clinical outcomes. MEDLINE, Embase, Cochrane COVID-19 Study Register, and WHO COVID-19 databases were scanned to retrieve the relevant articles until August 2021. All studies reporting the prevalence of mucormycosis among COVID-19 patients were eligible for inclusion. Two investigators independently screened the articles against the selection criteria, extracted the data, and performed the quality assessment using the JBI tool. The pooled prevalence of CAM was the primary outcome, and the pooled prevalence of diabetes, steroid exposure, and the mortality rate were the secondary outcomes of interest. Comprehensive Meta-Analysis software version 2 was used for performing the meta-analysis. This meta-analysis comprised six studies with a pooled sample size of 52,916 COVID-19 patients with a mean age of 62.12 ± 9.69 years. The mean duration of mucormycosis onset was 14.59 ± 6.88 days after the COVID-19 diagnosis. The pooled prevalence of CAM (seven cases per 1000 patients) was 50 times higher than the highest recorded background of mucormycosis (0.14 cases per 1000 patients). A high mortality rate was found among CAM patients with a pooled prevalence rate of 29.6% (95% CI: 17.2–45.9%). Optimal glycemic control and the judicious use of steroids should be the approach for tackling rising CAM cases.