Hypoperfusion index ratio and pretreatment with intravenous thrombolysis are independent predictors of good functional outcome in acute ischemic stroke patients with large vessel occlusion treated with acute reperfusion therapies.

INTRODUCTION: We aimed to investigate the performance of several neuroimaging markers provided by perfusion imaging of Acute Ischemic Stroke (AIS) patients with large vessel occlusion (LVO) in order to predict clinical outcomes following reperfusion treatments. METHODS: We prospectively evaluated consecutive AIS patients with LVO who were treated with reperfusion therapies, during a six-year period. In order to compare patients with good (mRS scores 0-2) and poor (mRS scores 3-6) functional outcomes, data regarding clinical characteristics, the Alberta Stroke Programme Early Computed Tomography Score (ASPECTS) based on unenhanced computed tomography (CT), CT angiography collateral status and perfusion parameters including ischemic core, hypoperfusion volume, mismatch volume between core and penumbra, Tmax > 10 s volume, CBV index and the Hypoperfusion Index Ratio (HIR) were assessed. RESULTS: A total of 84 acute stroke patients with LVO who met all the inclusion criteria were enrolled. In multivariable logistic regression models increasing age (odds ratio [OR]: 0.93; 95%CI: 0.88-0.96, p = 0.001), lower admission National Institute of Health Stroke Scale (NIHSS)-score (OR: 0.88; 95%CI: 0.80-0.95, p = 0.004), pretreatment with intravenous thrombolysis (OR: 3.83; 95%CI: 1.29-12.49, p = 0.019) and HIR (OR:0.36; 95%CI: 0.10-0.95, p = 0.042) were independent predictors of good functional outcome at 3 months. The initial univariable associations between HIR and higher likelihood for symptomatic intracranial hemorrhage (sICH) and parenchymal hematoma type 2 (PH2) were attenuated in multivariable analyses failing to reach statistical significance. DISCUSSION: Our pilot observational study of unselected AIS patients with LVO treated with reperfusion therapies demonstrated that pre-treatment low HIR in perfusion imaging and IVT were associated with better functional outcomes.

Overview of systematic reviews comparing endovascular to best medical treatment for large-vessel occlusion acute ischaemic stroke: an umbrella review.

Background: The literature on endovascular treatment (EVT) for large-vessel occlusion (LVO) acute ischaemic stroke (AIS) has been rapidly increasing after the publication of positive randomized-controlled clinical trials (RCTs) and a plethora of systematic reviews (SRs) showing benefit compared to best medical therapy (BMT) for LVO. Objectives: An overview of SRs (umbrella review) and meta-analysis of primary RCTs were performed to summarize the literature and present efficacy and safety of EVT. Design and methods: MEDLINE via Pubmed, Embase and Epistemonikos databases were searched from January 2015 until 15 October 2023. All SRs of RCTs comparing EVT to BMT were included. Quality was assessed using Risk of Bias in Systematic Reviews scores and the RoB 2 Cochrane Collaboration tool, as appropriate. GRADE approach was used to evaluate the strength of evidence. Data were presented according to the Preferred Reporting Items for Overviews of Reviews statement. The primary outcome was 3-month good functional outcome [modified Rankin scale (mRS) score 0-2]. Results: Three eligible SRs and 4 additional RCTs were included in the overview, comprising a total of 24 RCTs, corresponding to 5968 AIS patients with LVO (3044 randomized to EVT versus 2924 patients randomized to BMT). High-quality evidence shows that EVT is associated with an increased likelihood of good functional outcome [risk ratio (RR) 1.78 (95% confidence interval (CI): 1.54-2.06); 166 more per 1000 patients], independent ambulation [mRS-scores 0-3; RR 1.50 (95% CI: 1.37-1.64); 174 more per 1000 patients], excellent functional outcome [mRS-scores 0-1; RR 1.90 (95% CI: 1.62-2.22); 118 more per 1000 patients] at 3 months. EVT was associated with reduced 3-month mortality [RR 0.81 (95% CI: 0.74-0.88); 61 less per 1000 patients] despite an increase in symptomatic intracranial haemorrhage [sICH; RR 1.65 (95% CI: 1.23-2.21); 22 more per 1000 patients]. Conclusion: In patients with AIS due to LVO in the anterior or posterior circulation, within 24 h from symptom onset, EVT improves functional outcomes and increases the chance of survival despite increased sICH risk. Registration: PROSPERO Registration Number CRD42023461138.

Update of Anticoagulation Use in Cardioembolic Stroke With a Special Reference to Endovascular Treatment.

Cardioembolic stroke is a major cause of morbidity, with a high risk of recurrence, and anticoagulation represents the mainstay of secondary stroke prevention in most patients. The implementation of endovascular treatment in routine clinical practice complicates the decision to initiate anticoagulation, especially in patients with early hemorrhagic transformation who are considered at higher risk of hematoma expansion. Late hemorrhagic transformation in the days and weeks following stroke remains a potentially serious complication for which we still do not have any established clinical or radiological prediction tools. The optimal time to initiate therapy is challenging to define since delaying effective secondary prevention treatment exposes patients to the risk of recurrent embolism. Consequently, there is clinical equipoise to define and individualize the optimal timepoint to initiate anticoagulation combining the lowest risk of hemorrhagic transformation and ischemic recurrence in cardioembolic stroke patients. In this narrative review, we will highlight and critically outline recent observational and randomized relevant evidence in different subtypes of cardioembolic stroke with a special focus on anticoagulation initiation following endovascular treatment. We will refer mainly to the commonest cause of cardioembolism, non-valvular atrial fibrillation, and examine the possible risk and benefit of anticoagulation before, during, and shortly after the acute phase of stroke. Other indications of anticoagulation after ischemic stroke will be briefly discussed. We provide a synthesis of available data to help clinicians individualize the timing of initiation of oral anticoagulation based on the presence and extent of hemorrhagic transformation as well as stroke severity.

Clinical Characteristics, Neuroimaging Markers, and Outcomes in Patients with Cerebral Amyloid Angiopathy: A Prospective Cohort Study.

Background and purpose: Sporadic cerebral amyloid angiopathy (CAA) is a small vessel disease, resulting from progressive amyloid-ß deposition in the media/adventitia of cortical and leptomeningeal arterioles. We sought to assess the prevalence of baseline characteristics, clinical and radiological findings, as well as outcomes among patients with CAA, in the largest study to date conducted in Greece. Methods: Sixty-eight patients fulfilling the Boston Criteria v1.5 for probable/possible CAA were enrolled and followed for at least twelve months. Magnetic Resonance Imaging was used to assess specific neuroimaging markers. Data regarding cerebrospinal fluid biomarker profile and Apolipoprotein-E genotype were collected. Multiple logistic regression analyses were performed to identify predictors of clinical phenotypes. Cox-proportional hazard regression models were used to calculate associations with the risk of recurrent intracerebral hemorrhage (ICH). Results: Focal neurological deficits (75%), cognitive decline (57%), and transient focal neurological episodes (TFNEs; 21%) were the most common clinical manifestations. Hemorrhagic lesions, including lobar cerebral microbleeds (CMBs; 93%), cortical superficial siderosis (cSS; 48%), and lobar ICH (43%) were the most prevalent neuroimaging findings. cSS was independently associated with the likelihood of TFNEs at presentation (OR: 4.504, 95%CI:1.258-19.088), while multiple (>10) lobar CMBs were independently associated with cognitive decline at presentation (OR:5.418, 95%CI:1.316-28.497). cSS emerged as the only risk factor of recurrent ICH (HR:4.238, 95%CI:1.509-11.900) during a median follow-up of 20 months. Conclusions: cSS was independently associated with TFNEs at presentation and ICH recurrence at follow-up, while a higher burden of lobar CMBs with cognitive decline at baseline. These findings highlight the prognostic value of neuroimaging markers, which may influence clinical decision-making.

Medical Management Versus Endovascular Treatment for Large-Vessel Occlusion Anterior Circulation Stroke With Low NIHSS.

BACKGROUND: Endovascular treatment (EVT) for acute ischemic stroke (AIS) patients presenting with National Institutes of Health Stroke Scale score of 0 to 5 is common in clinical practice but has not yet been proven safe and effective. Our objective is to assess whether EVT on top of best medical treatment (BMT) in AIS patients with large-vessel occlusion of the anterior circulation presenting with mild symptoms is beneficial compared with BMT. METHODS: We searched MEDLINE, SCOPUS, and reference lists of retrieved articles published until December 28, 2022. A systematic literature search was conducted to identify clinical trials or observational cohort studies evaluating patients with AIS due to anterior circulation large-vessel occlusion and admission National Institutes of Health Stroke Scale score ≤5 treated with EVT versus BMT alone. The primary outcome was excellent functional outcome (modified Rankin Scale score 0-1) at 3 months. The protocol had been registered before data collection (PROSPERO). RESULTS: Eleven observational eligible studies were included in the meta-analysis, comprising a total of 2019 AIS patients with National Institutes of Health Stroke Scale score ≤5 treated with EVT versus 3171 patients treated with BMT. EVT was not associated with excellent functional outcome (risk ratio, 1.10 [95% CI, 0.93-1.31]). When stratified for different study design (per-protocol versus intention-to-treat), there were no significant subgroup differences. EVT was not associated with good functional outcome (modified Rankin Scale score 0-2; risk ratio, 1.01 [95% CI, 0.89-1.16]) or reduced disability at 3 months (common odds ratio, 0.92 [95% CI, 0.60-1.41]). Symptomatic intracranial hemorrhage was more common in the patients receiving EVT (risk ratio, 3.53 [95% CI, 2.35-5.31]). No correlation was found between EVT and mortality at 3 months (risk ratio, 1.34 [95% CI, 0.83-2.18]). The same overall associations were confirmed in the sensitivity analysis of studies that performed propensity score matching. CONCLUSIONS: EVT appears equivalent to BMT for patients with anterior circulation large-vessel occlusion AIS with low baseline National Institutes of Health Stroke Scale, despite the increased risk for symptomatic intracranial hemorrhage. REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42022334417.

Endovascular treatment for large-core ischaemic stroke: a meta-analysis of randomised controlled clinical trials.

BACKGROUND AND PURPOSE: Current guidelines recommend endovascular treatment (EVT) for acute ischaemic stroke (AIS), due to large-vessel occlusion and an Alberta Stroke Program Early CT Score (ASPECTS) of ≥6. High-quality evidence resulting from randomised controlled clinical trials (RCTs) regarding EVT among large-core AIS has recently become available, justifying an updated meta-analysis aiming to evaluate efficacy and safety of EVT in this clinical setting. METHODS: We conducted a systematic review and meta-analysis including all available RCTs that compared EVT in addition to best medical treatment (BMT) versus BMT alone for large-core AIS (defined by ASPECTS 2-5 or volumetric methods). The primary outcome was reduced disability at 3 months (≥1-point reduction across all Modified Rankin Scale (mRS) grades). Secondary outcomes included independent ambulation at 3 months (mRS score 0-3), good functional outcome at 3 months (mRS score 0-2), excellent functional outcome at 3 months (mRS score 0-1), symptomatic intracranial haemorrhage (sICH) and any intracranial haemorrhage (ICH) and mortality at 3 months. The random-effects model was used. RESULTS: Four RCTs were included comprising a total of 662 patients treated with EVT vs 649 patients treated with BMT. Compared with BMT, EVT was significantly associated with reduced disability (common OR 1.70, 95% CI 1.39 to 2.07; I2=0%), independent ambulation (risk ratio (RR) 1.69, 95% CI 1.33 to 2.14; I2=39%) and good functional outcome (RR 2.33, 95% CI 1.76 to 3.10; I2=0%), but not with excellent functional outcome (RR 1.46, 95% CI 0.91 to 2.33; I2=39%) at 3 months. Although rates of sICH (RR 1.98, 95% CI 1.07 to 3.68; I2=0%) and any ICH (RR 2.13, 95% CI 1.70 to 2.66; I2=37%) were higher in the EVT group, 3-month mortality (RR 0.98, 95% CI 0.83 to 1.15; I2=0%) did not differ between the two groups. CONCLUSION: EVT appears to be effective and safe and may be considered for the treatment of large-core AIS, as assessed by ASPECTS of 2-5 or volumetric methods. PROSPERO REGISTRATION NUMBER: CRD42022334417.

Endovascular Treatment for Acute Basilar Artery Occlusion: A Fragility Index Meta-Analysis.

INTRODUCTION: High-quality evidence regarding the use of endovascular treatment (EVT) in patients with acute basilar artery occlusion (BAO) has been provided by recently completed randomized controlled clinical trials (RCTs). METHODS: We conducted a systematic review and meta-analysis including all available RCTs that investigated efficacy and safety of EVT in addition to best medical treatment (BMT) versus BMT alone for BAO. The random-effects model was used, while the fragility index (FI) was calculated for dichotomous outcomes of interest. RESULTS: Four RCTs were included comprising a total of 988 patients with acute BAO (mean age: 65.6 years, 70% men, median NIHSS: 24, 39% pretreatment with intravenous thrombolysis). EVT was related to higher likelihood of good functional outcome (RR: 1.54; 95% CI: 1.16-2.05; I2 = 60%), functional independence (RR: 1.83; 95% CI: 1.08-3.08; I2 = 79%) and reduced disability at 3 months (adjusted common OR: 1.96; 95% CI: 1.26-3.05; I2 = 59%) compared to BMT alone. Despite that EVT was associated with a higher risk for symptomatic intracranial hemorrhage (RR: 7.78; 95% CI: 2.36-25.61; I2 = 0%) and any intracranial hemorrhage (RR: 2.85; 95% CI: 1.50-5.44; I2 = 16%), mortality at 3 months was lower among patients that received EVT plus BMT versus BMT alone (RR: 0.76; 95% CI: 0.65-0.89; I2 = 0%). However, sufficient robustness was not evident in any of the reported associations (FI < 10) including the overall effect regarding the primary outcome. The former associations were predominantly driven by RCTs with recruitment limited in China. CONCLUSIONS: EVT combined with BMT is associated with a higher likelihood of achieving good functional outcomes and a lower risk of death at 3 months compared to BMT alone, despite the higher risk of sICH. An individual-patient data meta-analysis is warranted to uncover and adjust for potential sources of heterogeneity and to provide further insight.

Quality metrics in the management of acute stroke in Greece during the first 5 years of Registry of Stroke Care Quality (RES-Q) implementation.

Introduction: Establishment of a prospective stroke registry may promote the documentation and improvement of acute stroke care. We present the status of stroke management in Greece using the Registry of Stroke Care Quality (RES-Q) dataset. Methods: Consecutive patients with acute stroke were prospectively registered in RES-Q registry by contributing sites in Greece during the years 2017-2021. Demographic and baseline characteristics, acute management, and clinical outcomes at discharge were recorded. Stroke quality metrics, with a specific interest in the association between acute reperfusion therapies and functional recovery in ischemic stroke patients are presented. Results: A total of 3590 acute stroke patients were treated in 20 Greek sites (61% men, median age 64 years; median baseline NIHSS 4; 74% ischemic stroke). Acute reperfusion therapies were administered in almost 20% of acute ischemic stroke patients, with a door to needle and door to groin puncture times of 40 and 64 min, respectively. After adjustment for contributing sites, the rates of acute reperfusion therapies were higher during the time epoch 2020-2021 compared to 2017-2019 (adjusted OR 1.31; 95% CI 1.04-1.64; p < 0.022; Cochran-Mantel-Haenszel test). After propensity-score-matching, acute reperfusion therapies administration was independently associated with higher odds of reduced disability (one point reduction across all mRS scores) at hospital discharge (common OR 1.93; 95% CI 1.45-2.58; p < 0.001). Conclusions: Implementation and maintenance of a nationwide stroke registry in Greece may guide the stroke management planning, so that prompt patient transportation, acute reperfusion therapies, and stroke unit hospitalization become more widely accessible, improving the functional outcomes of stroke patients.

Bilateral dural arteriovenous fistula diagnosed with neurovascular ultrasonography.

BACKGROUND: Intracranial dural arteriovenous fistulas (dAVFs) are pathological anastomoses between meningeal arteries and dural venous sinuses or cortical veins. Diagnosis of dAVFs can be challenging due to their broad range of clinical manifestations and the lack of specificity in their symptoms. We present a rare case of a patient with bilateral dAVFs, who was referred to our department for carotid doppler ultrasonography/transcranial color Doppler. CASE REPORT: A 67-year-old man was referred by his treating physician for neurovascular ultrasonography due to vision impairment associated with papilledema of both eyes. On ultrasound examination both external carotid arteries showed a "pseudo-internalization" pattern with high end-diastolic velocities and reduced resistance indices. Subsequent magnetic resonance and digital subtraction angiography revealed dAVF of both transverse sinuses, with occipital and medial meningeal arteries as feeders. CONCLUSIONS: Neurovascular sonography may serve as a screening and follow-up tool when a DAVF in the transverse sinus/sigmoid sinus is suspected.

Endovascular treatment for anterior circulation large-vessel occlusion ischemic stroke with low ASPECTS: a systematic review and meta-analysis.

Background: Endovascular treatment (EVT) for acute ischemic stroke (AIS) patients presenting with Alberta Stroke Program Early CT Score (ASPECTS) 0-5 has not yet proven safe and effective by clinical trials. Objectives: The aim of the study was to assess whether EVT in AIS patients presenting with low ASPECTS is beneficial. Design: Systematic review and meta-analysis of available studies in accordance with the PRISMA statement. Data sources and Methods: We have searched MEDLINE, the Cochrane Central Register of Controlled Trials, and reference lists of articles published until 28 May 2022 with the aim to calculate (1) modified Rankin scale (mRS) score 0-3 at 3 months, (2) mRS score 0-2 at 3 months, (3) symptomatic intracranial hemorrhage (sICH), and (3) mortality at 3 months. Results: Overall, 24 eligible studies were included in the meta-analysis, comprising a total of 2539 AIS patients with ASPECTS 0-5 treated with EVT. The pooled proportion of EVT-treated patients achieving mRS 0-3 at 3 months was calculated at 38.4%. The pooled proportion of EVT-treated patients achieving mRS 0-2 at 3 months was 25.7%. Regarding safety outcomes, sICH occurred in 12.8% of patients. The 3-month pooled mortality was 30%. In pairwise meta-analysis, patients treated with EVT had a higher likelihood of achieving mRS 0-3 at 3 months compared with patients treated with best medical therapy (BMT, OR: 2.41). sICH occurred more frequently in EVT-treated patients compared with the BMT-treated patients (OR: 2.30). Mortality at 3 months was not different between the two treatment groups (OR: 0.71). Conclusion: EVT may be beneficial for AIS patients with low baseline ASPECTS despite an increased risk for sICH. Further data from randomized-controlled clinical trials are needed to elucidate the role of EVT in this subgroup of AIS patients. Registration: The protocol has been registered in the International Prospective Register of Ongoing Systematic Reviews PROSPERO; Registration Number: CRD42022334417.

Cerebral Amyloid Angiopathy-Related Inflammation: A Single-Center Experience and a Literature Review.

Background: Limited data exist regarding the prevalence of clinical, neuroimaging, and genetic markers among patients diagnosed with Cerebral Amyloid Angiopathy−related inflammation (CAA-ri). We sought to determine these characteristics in patients diagnosed in our center and to summarize available literature published either as single-case reports or small case series (<5 patients). Methods: We reported our single-center experience of patients diagnosed with CAA-ri according to international criteria during a seven-year period (2015−2022), and we abstracted data from 90 previously published cases. Results: Seven patients (43% women, mean age 70 ± 13 years) were diagnosed with CAA-ri in our center. The most common symptom at presentation was focal neurological dysfunction (71%), and the most prevalent radiological finding was the presence of T2/FLAIR white matter hyperintensities (100%). All patients were treated with corticosteroids and had a favorable functional outcome. Among 90 previously published CAA-ri cases (51% women, mean age 70 ± 9 years), focal neurological dysfunction was the most common symptom (76%), followed by a cognitive decline (46%) and headache (34%). The most prevalent neuroimaging findings were cerebral microbleeds (85%), asymmetric T2/FLAIR white matter hyperintensities (81%), and gadolinium-enhancing T1-lesions (37%). Genetic testing for the Apolipoprotein-E gene was available in 27 cases; 59% carried the APOE ε4/ε4 genotype. The majority of the published CAA-ri cases (78%) received corticosteroid monotherapy, while 17 patients (19%) were treated with additional immunosuppressive treatment. Favorable functional outcome following treatment was documented in 70% of patients. Conclusion: Improving the vigilance of clinicians regarding the early recognition and accurate diagnosis of CAA-ri is crucial for swift therapy initiation, which may result in improved functional outcomes.

Diagnosis and treatment of acute isolated proximal internal carotid artery occlusions: a narrative review.

The clinical manifestations of proximal (extracranial) internal carotid artery occlusions (pICAOs) may range from asymptomatic to acute, large, and devastating ischemic strokes. The etiology and pathophysiology of the occlusion, intracranial collateral status and patient's premorbid status are among the factors determining the clinical presentation and outcome of pICAOs. Rapid and accurate diagnosis is crucial and may be assisted by the combination of carotid and transcranial duplex sonography, or a computed tomography/magnetic resonance angiography (CTA/MRA). It should be noted that with either imaging modalities, the discrimination of a pseudo-occlusion of the extracranial internal carotid artery (ICA) from a true pICAO may not be straightforward. In the absence of randomized data, the management of acute, symptomatic pICAOs remains individualized and relies largely on expert opinion. Administration of intravenous thrombolysis is reasonable and probably beneficial in the settings of acute ischemic stroke with early presentation. Unfortunately, rates of recanalization are rather low and acute interventional reperfusion therapies emerge as a potentially powerful therapeutic option for patients with persistent and severe symptoms. However, none of the pivotal clinical trials on mechanical thrombectomy for acute ischemic stroke randomized patients with isolated extracranial large vessel occlusions. On the contrary, several lines of evidence from non-randomized studies have shown that acute carotid endarterectomy, or endovascular thrombectomy/stenting of the ICA are feasible and safe, and pοtentially beneficial. The heterogeneity in the pathophysiology and clinical presentation of acute pICAOs renders patient selection for an acute interventional treatment a complicated decision-making process. The present narrative review will outline the pathophysiology, clinical presentation, diagnostic challenges, and possible treatment options for pICAOs.

HSV-Encephalitis Resembling Acute Cerebral Infarction in a Patient With Atrial Fibrillation: Beware of Stroke Mimics.

INTRODUCTION: Herpes simplex virus-1 (HSV-1) encephalitis, the most common and potentially life-threatening type of encephalitis, may rarely present as a stroke mimic. Prompt diagnosis is of paramount importance for the timely initiation of antiviral treatment and to avert intravenous thrombolysis. CASE REPORT: A 60-year-old man with a history of lone paroxysmal atrial fibrillation without prior antithrombotic treatment was admitted due to mild gait unsteadiness and intermittent dysarthria of acute onset. On admission, the patient was afebrile, whereas neurological examination revealed only a mild pronator drift on the left. Brain magnetic resonance imaging (MRI) showed an extensive right temporo-occipital and thalamic lesion with restricted diffusion and 3 small-sized hemorrhagic foci. Brain MR-angiography did not show large vessel stenosis or occlusion. On the basis of careful observation and the depiction of several imaging discrepancies, such as early vasogenic edema and hemorrhagic transformation, as well as uncus involvement, but also the lack of significant neurological deficits despite the size of the brain lesion we suspected viral encephalitis which was confirmed by the detection of HSV-1 DNA in the cerebrospinal fluid. CONCLUSION: HSV-encephalitis might occasionally result in the development of unilateral brain MRI lesions with extensive cytotoxic edema, resembling an acute ischemic stroke. Therefore, HSV-encephalitis must be considered in the differential diagnosis of acute ischemic stroke with atypical presentation. The presence of a significant dissociation between the brain MRI lesion volume and the neurological deficits, as well as certain brain MRI imaging discrepancies might serve as "red flags" to extend the diagnostic workup.

Hereditary cerebral amyloid angiopathy mimicking CADASIL syndrome.

BACKGROUND: Small vessel disease (SVD), and most specifically hereditary forms like CADASIL and cerebral amyloid angiopathy (hCAA), are conditions of increasing clinical importance. We report a rare case of hCAA in a Greek family that presented with a CADASIL clinical and neuroimaging phenotype. METHODS: A 65-year-old man was admitted with recurrent transient episodes of right leg numbness. The patient's medical history started at the age of 50 years with depression and behavioral disorders. His family history was positive for stroke (father), dementia (father and brother), migraine (daughter) and depression (father and daughter). RESULTS: Neurological examination disclosed anomic aphasia with severely impaired cognitive status, and brisk reflexes. Brain computed tomography and magnetic resonance imaging showed CADASIL-like leukoencephalopathy (hyperintense lesions in bilateral temporopolar area, external capsule, thalami, centrum semiovale and superior frontal regions) with occipital calcifications and cerebral microbleeds. Screen for variants in NOTCH3 gene was negative. Exome sequencing revealed a novel pathogenic mutation for hCAA. CONCLUSIONS: We report a novel amyloid precursor protein mutation which results in a CADASIL-like clinical phenotype (progressive cognitive and motor decline, stroke, migraine and behavioral disorders) and CADASIL-leukoencephalopathy coupled with occipital calcifications. Earlier recognition and swift hCAA diagnosis may prompt rational preventive and potential disease-modifying interventions.

Emerging agents for the treatment and prevention of stroke: progress in clinical trials.

INTRODUCTION: Recent years have witnessed unprecedented progress in stroke care, but unmet needs persist regarding the efficacy of acute treatment and secondary prevention. Novel approaches are being tested to enhance the efficacy of thrombolysis or provide neuroprotection in non-thrombolized patients. AREAS COVERED: The current review highlights pharmaceutical agents under evaluation in clinical trials concerning the acute, subacute, and chronic phase post-stroke. We examine the evidence in favor of tenecteplase as an alternative thrombolytic drug to alteplase, nerinetide as a promising neuroprotective agent, and glibenclamide for reducing edema in malignant hemispheric infarction. We discuss the use of ticagrelor and the promising novel category of factor XI inhibitors in the subacute phase after stroke. We offer our insights on combined rivaroxaban and antiplatelet therapy, PCSK-9 inhibitors, and other non-statin hypolipidemic agents, as well as novel antidiabetic agents that have been shown to reduce cardiovascular events in the long-term. EXPERT OPINION: Current approaches in stroke treatment and stroke prevention have already transformed stroke care from a linear one-for-all treatment paradigm to a more individualized approach that targets specific patient subgroups with novel pharmaceutical agents. This tendency enriches the therapeutic armamentarium with novel agents developed for specific stroke subgroups. ABBREVIATIONS: IVT: intravenous thrombolysis; RCTs: randomized-controlled clinical trials; TNK: Tenecteplase; COVID-19: Coronavirus 2019 Disease; EXTEND-IA TNK: The Tenecteplase versus Alteplase Before Endovascular Therapy for Ischemic Stroke trial; AIS: acute ischemic stroke; NNT: number needed to treat; MT: mechanical thrombectomy; sICH: symptomatic intracranial hemorrhage; mRS: modified Rankin Scale; AHA/ASA: American Heart Association/American Stroke Association; ESO: European Stroke Organization; NA-1: Nerinetide; ENACT: Evaluating Neuroprotection in Aneurysm Coiling Therapy; CTA: CT angiography; TIA: transient ischemic attack; CHANCE: Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events; LOF: loss-of-function; PRINCE: Platelet Reactivity in Acute Nondisabling Cerebrovascular Events; THALES: Acute Stroke or Transient Ischemic Attack Treated with Ticagrelor and ASA [acetylsalicylic acid] for Prevention of Stroke and Death; CHANCE-2: Clopidogrel With Aspirin in High-risk Patients With Acute Non-disabling Cerebrovascular Events II; FXI: Factor XI; PACIFIC-STROKE: Program of Anticoagulation via Inhibition of FXIa by the Oral Compound BAY 2433334-NonCardioembolic Stroke study; COMPASS: Cardiovascular Outcomes for People Using Anticoagulation Strategies; CANTOS-ICAD: Combination Antithrombotic Treatment for Prevention of Recurrent Ischemic Stroke in Intracranial Atherosclerotic Disease; SAMMPRIS: Stenting and Aggressive Medical Therapy for Preventing Recurrent Stroke in Intracranial Stenosis; WASID: Warfarin-Aspirin Symptomatic Intracranial Disease; SPARCL: Stroke Prevention by Aggressive Reduction in Cholesterol Levels; LDL-C: low-density lipoprotein cholesterol; TST: Treat Stroke to Target; IMPROVE-IT: Improved Reduction of Outcomes: Vytorin Efficacy International Trial; PCSK9: proprotein convertase subtilisin-kexin type 9; FOURIER: Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk; CLEAR: Cholesterol Lowering via Bempedoic acid, an ACL-inhibiting Regimen; REDUCE-IT: Reduction of Cardiovascular Events With EPA Intervention Trial; STRENGTH: Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridemia; ACCORD: Action to Control Cardiovascular Risk in Diabetes; ADVANCE: Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; VADT: Veterans Affairs Diabetes Trial; GLP-1R: Glucagon-like peptide-1 receptor; SGLT2: sodium-glucose cotransporter 2; CONVINCE: COlchicine for preventioN of Vascular Inflammation in Non-CardioEmbolic stroke; PROBE: Prospective Randomized Open-label Blinded Endpoint assessment.

Advanced Neuroimaging Preceding Intravenous Thrombolysis in Acute Ischemic Stroke Patients Is Safe and Effective.

Advanced neuroimaging is one of the most important means that we have in the attempt to overcome time constraints and expand the use of intravenous thrombolysis (IVT). We assessed whether, and how, the prior use of advanced neuroimaging (AN), and more specifically CT/MR perfusion post-processed with RAPID software, regardless of time from symptoms onset, affected the outcomes of acute ischemic stroke (AIS) patients who received IVT. Methods. We retrospectively evaluated consecutive AIS patients who received intravenous thrombolysis monotherapy (without endovascular reperfusion) during a six-year period. The study population was divided into two groups according to the neuroimaging protocol used prior to IVT administration in AIS patients (AN+ vs. AN-). Safety outcomes included any intracranial hemorrhage (ICH) and 3-month mortality. Effectiveness outcomes included door-to-needle time, neurological status (NIHSS-score) on discharge, and functional status at three months assessed by the modified Rankin Scale (mRS). Results. The rate of IVT monotherapy increased from ten patients per year (n = 29) in the AN- to fifteen patients per year (n = 47) in the AN+ group. Although the onset-to-treatment time was longer in the AN+ cohort, the two groups did not differ in door-to-needle time, discharge NIHSS-score, symptomatic ICH, any ICH, 3-month favorable functional outcome (mRS-scores of 0-1), 3-month functional independence (mRS-scores of 0-2), distribution of 3-month mRS-scores, or 3-month mortality. Conclusion. Our pilot observational study showed that the incorporation of advanced neuroimaging in the acute stroke chain pathway in AIS patients increases the yield of IVT administration without affecting the effectiveness and safety of the treatment.

Acute reperfusion therapies for acute ischemic stroke patients with unknown time of symptom onset or in extended time windows: an individualized approach.

Recent randomized controlled clinical trials (RCTs) have revolutionized acute ischemic stroke care by extending the use of intravenous thrombolysis and endovascular reperfusion therapies in time windows that have been originally considered futile or even unsafe. Both systemic and endovascular reperfusion therapies have been shown to improve outcome in patients with wake-up strokes or symptom onset beyond 4.5 h for intravenous thrombolysis and beyond 6 h for endovascular treatment; however, they require advanced neuroimaging to select stroke patients safely. Experts have proposed simpler imaging algorithms but high-quality data on safety and efficacy are currently missing. RCTs used diverse imaging and clinical inclusion criteria for patient selection during the dawn of this novel stroke treatment paradigm. After taking into consideration the dismal prognosis of nonrecanalized ischemic stroke patients and the substantial clinical benefit of reperfusion therapies in selected late presenters, we propose rescue reperfusion therapies for acute ischemic stroke patients not fulfilling all clinical and imaging inclusion criteria as an option in a subgroup of patients with clinical and radiological profiles suggesting low risk for complications, notably hemorrhagic transformation as well as local or remote parenchymal hemorrhage. Incorporating new data to treatment algorithms may seem perplexing to stroke physicians, since treatment and imaging capabilities of each stroke center may dictate diverse treatment pathways. This narrative review will summarize current data that will assist clinicians in the selection of those late presenters that will most likely benefit from acute reperfusion therapies. Different treatment algorithms are provided according to available neuroimaging and endovascular treatment capabilities.

Expanding indications for endovascular thrombectomy-how to leave no patient behind.

Endovascular thrombectomy (EVT) has become standard of care for large vessel occlusion strokes but current guidelines exclude a large proportion of patients from this highly effective treatment. This review therefore focuses on expanding indications for EVT in several borderline indications such as patients in the extended time window, patients with extensive signs of infarction on admission imaging, elderly patients and patients with pre-existing deficits. It also discusses the current knowledge on intravenous thrombolysis as an adjunct to EVT and EVT as primary therapy for distal vessel occlusions, for tandem occlusions, for basilar artery occlusions and in pediatric patients. We provide clear recommendations based on current guidelines and further literature.