Atrial Fibrillation Detected before or after Stroke: Role of Anticoagulation.

BACKGROUND: Atrial fibrillation (AF) known before ischemic stroke (KAF) has been postulated to be an independent category with a recurrence risk higher than that of AF detected after stroke (AFDAS). However, it is unknown whether this risk difference is confounded by pre-existing anticoagulation, which is most common in KAF and also indicates a high ischemic stroke recurrence risk. METHODS: Individual patient data analysis from 5 prospective cohorts of anticoagulated patients following AF-associated ischemic stroke. We compared the primary (ischemic stroke recurrence) and secondary outcome (all-cause death) among patients with AFDAS versus KAF and among anticoagulation-naïve versus previously anticoagulated patients using multivariable Cox, Fine-Gray models, and goodness-of-fit statistics to investigate the relative independent prognostic importance of AF-category and pre-existing anticoagulation. RESULTS: Of 4,357 patients, 1,889 (43%) had AFDAS and 2,468 (57%) had KAF, while 3,105 (71%) were anticoagulation-naïve before stroke and 1,252 (29%) were previously anticoagulated. During 6,071 patient-years of follow-up, we observed 244 recurrent strokes and 661 deaths. Only pre-existing anticoagulation (but not KAF) was independently associated with a higher hazard for stroke recurrence in both Cox and Fine-Gray models. Models incorporating pre-existing anticoagulation showed better fit than those with AF category; adding AF-category did not result in better model fit. Neither pre-existing anticoagulation nor KAF were independently associated with death. CONCLUSION: Our findings challenge the notion that KAF and AFDAS are clinically relevant and distinct prognostic entities. Instead of attributing an independently high stroke recurrence risk to KAF, future research should focus on the causes of stroke despite anticoagulation to develop improved preventive treatments. ANN NEUROL 2023;94:43-54.

Extracellular vesicles from adipose mesenchymal stem cells target inflamed lymph nodes in experimental autoimmune encephalomyelitis.

BACKGROUND AIMS: Adipose mesenchymal stem cells (ASCs) represent a promising therapeutic approach in inflammatory neurological disorders, including multiple sclerosis (MS). Recent lines of evidence indicate that most biological activities of ASCs are mediated by the delivery of soluble factors enclosed in extracellular vesicles (EVs). Indeed, we have previously demonstrated that small EVs derived from ASCs (ASC-EVs) ameliorate experimental autoimmune encephalomyelitis (EAE), a murine model of MS. The precise mechanisms and molecular/cellular target of EVs during EAE are still unknown. METHODS: To investigate the homing of ASC-EVs, we intravenously injected small EVs loaded with ultra-small superparamagnetic iron oxide nanoparticles (USPIO) at disease onset in EAE-induced C57Bl/6J mice. Histochemical analysis and transmission electron microscopy were carried out 48 h after EV treatment. Moreover, to assess the cellular target of EVs, flow cytometry on cells extracted ex vivo from EAE mouse lymph nodes was performed. RESULTS: Histochemical and ultrastructural analysis showed the presence of labeled EVs in lymph nodes but not in lungs and spinal cord of EAE injected mice. Moreover, we identified the cellular target of EVs in EAE lymph nodes by flow cytometry: ASC-EVs were preferentially located in macrophages, with a consistent amount also noted in dendritic cells and CD4+ T lymphocytes. CONCLUSIONS: This represents the first direct evidence of the privileged localization of ASC-EVs in draining lymph nodes of EAE after systemic injection. These data provide prominent information on the distribution, uptake and retention of ASC-EVs, which may help in the development of EV-based therapy in MS.

A Cellular Model of Amyotrophic Lateral Sclerosis to Study the Therapeutic Effects of Extracellular Vesicles from Adipose Mesenchymal Stem Cells on Microglial Activation.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of upper and lower motor neurons (MNs) in the brain and spinal cord, leading to progressive paralysis and death. Increasing evidence indicates that neuroinflammation plays an important role in ALS's pathogenesis and disease progression. Neuroinflammatory responses, primarily driven by activated microglia and astrocytes, and followed by infiltrating peripheral immune cells, contribute to exacerbate/accelerate MN death. In particular, the role of the microglia in ALS remains unclear, partly due to the lack of experimental models that can fully recapitulate the complexity of ALS's pathology. In this study, we developed and characterized a microglial cell line, SIM-A9-expressing human mutant protein Cu+/Zn+ superoxide dismutase_1 (SIM-A9hSOD1(G93A)), as a suitable model in vitro mimicking the microglia activity in ALS. The expression of hSOD1(G93A) in SIM-A9 cells induced a change in their metabolic activity, causing polarization into a pro-inflammatory phenotype and enhancing reactive oxygen species production, which is known to activate cell death processes and apoptosis. Afterward, we used our microglial model as an experimental set-up to investigate the therapeutic action of extracellular vesicles isolated from adipose mesenchymal stem cells (ASC-EVs). ASC-EVs represent a promising therapeutic treatment for ALS due to their neuroprotective and immunomodulatory properties. Here, we demonstrated that treatment with ASC-EVs is able to modulate activated ALS microglia, reducing their metabolic activity and polarizing their phenotype toward an anti-inflammatory one through a mechanism of reduction of reactive oxygen species.

Oral Anticoagulants in the Oldest Old with Recent Stroke and Atrial Fibrillation.

OBJECTIVE: To investigate the safety and effectiveness of direct oral anticoagulants (DOAC) versus vitamin K antagonists (VKA) after recent stroke in patients with atrial fibrillation (AF) aged ≥85 years. METHODS: Individual patient data analysis from seven prospective stroke cohorts. We compared DOAC versus VKA treatment among patients with AF and recent stroke (<3 months) aged ≥85 versus <85 years. Primary outcome was the composite of recurrent stroke, intracranial hemorrhage (ICH) and all-cause death. We used simple, adjusted, and weighted Cox regression to account for confounders. We calculated the net benefit of DOAC versus VKA by balancing stroke reduction against the weighted ICH risk. RESULTS: In total, 5,984 of 6,267 (95.5%) patients were eligible for analysis. Of those, 1,380 (23%) were aged ≥85 years and 3,688 (62%) received a DOAC. During 6,874 patient-years follow-up, the impact of anticoagulant type (DOAC versus VKA) on the hazard for the composite outcome did not differ between patients aged ≥85 (HR≥85y  = 0.65, 95%-CI [0.52, 0.81]) and < 85 years (HR<85y  = 0.79, 95%-CI [0.66, 0.95]) in simple (pinteraction  = 0.129), adjusted (pinteraction  = 0.094) or weighted (pinteraction  = 0.512) models. Analyses on recurrent stroke, ICH and death separately were consistent with the primary analysis, as were sensitivity analyses using age dichotomized at 90 years and as a continuous variable. DOAC had a similar net clinical benefit in patients aged ≥85 (+1.73 to +2.66) and < 85 years (+1.90 to +3.36 events/100 patient-years for ICH-weights 1.5 to 3.1). INTERPRETATION: The favorable profile of DOAC over VKA in patients with AF and recent stroke was maintained in the oldest old. ANN NEUROL 2022;91:78-88.

Application of the "1-2-3-4-day" rule to stroke severity at baseline versus at 24 h to start direct oral anticoagulant for atrial fibrillation within 7 days from symptom onset.

INTRODUCTION: The aim of this study is to compare the "1-2-3-4-day" rule applied to stroke severity at baseline versus at 24 h to start DOAC for AF within 7 days from symptom onset. PATIENTS AND METHODS: We conducted a prospective cohort observational study based on 433 consecutive AF-related stroke patients starting DOAC within 7 days from symptom onset. Four groups were identified according to the timing of DOAC introduction: 2-day, 3-day, 4-day, and 5-7-day. RESULTS: Three models of multivariate ordinal regression including unbalanced variables among four groups (enrolment year, dyslipidemia, known AF, thrombolysis, thrombectomy, hemorrhagic transformation, DOAC type) were used to estimate the association of neurological severity categories (reference: NIHSS > 15) at baseline (Brant test: 0.818), at 24 h (Brant test: 0.997), and radiological severity categories (reference: major infarct) at 24 h (Brant test: 0.902) in the direction of earlier DOAC introduction on days (from 5-7-day to 2-day). Number of deaths was higher in early DOAC group than in late DOAC group according to the "1-2-3-4-day" rule (5.4% versus 1.3%, 6.8% versus 1.1%, and 4.2% versus 1.7% when it was applied to baseline neurological severity, 24-h neurological and radiological severity, respectively), but no significant difference was found and deaths were not caused by early DOAC introduction. Rates of ischemic stroke and intracranial hemorrhage were not different between early and late DOAC groups. CONCLUSIONS: The application of "1-2-3-4-day" rule to start DOAC for AF within 7 days from symptom onset differed when applied to baseline neurological stroke severity versus 24-h neurological and radiological severity, but safety and effecacy are similar.

Current territorial organization for access to revascularization therapies for acute ischemic stroke in the Veneto region (Italy) from 2017 to 2021.

INTRODUCTION: To evaluate the access to treatments with intravenous thrombolysis (IVT) and/or mechanical thrombectomy (MT) in acute ischemic stroke patients admitted to stroke units (SUs) of Veneto region (Italy) according to current "hub-and-spoke" model from 2017 to 2021. PATIENTS AND METHODS: We retrospectively analyzed data on treatments with IVT and/or MT for stroke patients admitted to the 23 SUs (6 Hubs and 17 Spokes) of the 6 macro-areas including 9 local sanitary units (LSUs) and 2 hospitals. RESULTS: We reported 6093 treatments with IVT alone, 1114 with IVT plus MT, and 921 with MT alone. Number of stroke unit (SU) beds/100,000 inhabitants ranges from 2.3 to 2.8, and no difference was found among different macro-areas. Number of treatments/100,000 inhabitants/year ranges from 19 to 34 for IVT alone, from 2 to 7 for IVT plus MT, and from 2 to 5 for MT alone. Number of IVT alone/SU bed/year ranges from 9 to 21 in the Hub and from 6 to 12 in the Spokes. Rate of IVT plus MT in patients directly arrived in the same LSU's Hub ranges from 50 to 81%, likewise the one of MT alone ranges from 49 to 84%. CONCLUSIONS: Treatment target rates of IVT and MT set by Action Plan for Stroke in Europe 2018-2030 has been globally exceeded in the Veneto region. However, the target rate of MT and access revascularization treatments is heterogeneous among different macro-areas. Further efforts should be made to homogenize the current territorial organization.

Extracellular Vesicles from Mesenchymal Stem Cells: Towards Novel Therapeutic Strategies for Neurodegenerative Diseases.

Neurodegenerative diseases are fatal disorders of the central nervous system (CNS) which currently lack effective treatments. The application of mesenchymal stem cells (MSCs) represents a new promising approach for treating these incurable disorders. Growing evidence suggest that the therapeutic effects of MSCs are due to the secretion of neurotrophic molecules through extracellular vesicles. The extracellular vesicles produced by MSCs (MSC-EVs) have valuable innate properties deriving from parental cells and could be exploited as cell-free treatments for many neurological diseases. In particular, thanks to their small size, they are able to overcome biological barriers and reach lesion sites inside the CNS. They have a considerable pharmacokinetic and safety profile, avoiding the critical issues related to the fate of cells following transplantation. This review discusses the therapeutic potential of MSC-EVs in the treatment of neurodegenerative diseases, focusing on the strategies to further enhance their beneficial effects such as tracking methods, bioengineering applications, with particular attention to intranasal delivery as a feasible strategy to deliver MSC-EVs directly to the CNS in an effective and minimally invasive way. Current progresses and limiting issues to the extent of the use of MSC-EVs treatment for human neurodegenerative diseases will be also revised.

Early versus late start of direct oral anticoagulants after acute ischaemic stroke linked to atrial fibrillation: an observational study and individual patient data pooled analysis.

OBJECTIVE: The optimal timing to start direct oral anticoagulants (DOACs) after an acute ischaemic stroke (AIS) related to atrial fibrillation (AF) remains unclear. We aimed to compare early (≤5 days of AIS) versus late (>5 days of AIS) DOAC-start. METHODS: This is an individual patient data pooled analysis of eight prospective European and Japanese cohort studies. We included patients with AIS related to non-valvular AF where a DOAC was started within 30 days. Primary endpoints were 30-day rates of recurrent AIS and ICH. RESULTS: A total of 2550 patients were included. DOACs were started early in 1362 (53%) patients, late in 1188 (47%). During 212 patient-years, 37 patients had a recurrent AIS (1.5%), 16 (43%) before a DOAC was started; 6 patients (0.2%) had an ICH, all after DOAC-start. In the early DOAC-start group, 23 patients (1.7%) suffered from a recurrent AIS, while 2 patients (0.1%) had an ICH. In the late DOAC-start group, 14 patients (1.2%) suffered from a recurrent AIS; 4 patients (0.3%) suffered from ICH. In the propensity score-adjusted comparison of late versus early DOAC-start groups, there was no statistically significant difference in the hazard of recurrent AIS (aHR=1.2, 95% CI 0.5 to 2.9, p=0.69), ICH (aHR=6.0, 95% CI 0.6 to 56.3, p=0.12) or any stroke. CONCLUSIONS: Our results do not corroborate concerns that an early DOAC-start might excessively increase the risk of ICH. The sevenfold higher risk of recurrent AIS than ICH suggests that an early DOAC-start might be reasonable, supporting enrolment into randomised trials comparing an early versus late DOAC-start.

Anti-SARS-CoV-2 T-stem cell memory persists in ocrelizumab-treated MS patients.

BACKGROUND: Development of long-lasting anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) T-cell responses in persons with multiple sclerosis (pwMS) treated with ocrelizumab is questioned. OBJECTIVE: Investigate antiviral T-cell responses after infection with SARS-CoV-2 in ocrelizumab-treated pwMS. Control groups included ocrelizumab-treated pwMS without SARS-CoV-2 infection, and non-MS individuals with and without SARS-CoV-2 infection. METHODS: Peripheral blood mononuclear cells were stimulated with SARS-CoV-2 peptide pools and T-cell reactivity was assessed by ELISPOT for interferon (IFN)-γ detection, and by multiparametric fluorescence-activated cell sorting (FACS) analyses for assessment and characterization of T-cell activation. RESULTS: ELISPOT assay against the spike and the N protein of SARS-CoV-2 displayed specific T-cell reactivity in 28/29 (96%) pwMS treated with ocrelizumab and infected by SARS-CoV-2, similar to infected persons without MS. This reactivity was present 1 year after infection and independent from the time of ocrelizumab infusion. FACS analysis following stimulation with SARS-CoV-2 peptide pools showed the presence of activation-induced markers (AIMs) in both CD4+ and CD8+ T-cell subsets in 96% and 92% of these individuals, respectively. Within naïve AIM+ CD4+ and CD8+ T-cells, we detected T memory stem cells, suggesting the acquisition of long-term memory. CONCLUSIONS: B-cell depletion using ocrelizumab does not impair the development of long-lasting anti-SARS-CoV-2 T-cell responses.

Fabry-Stroke Italian Registry (FSIR): a nationwide, prospective, observational study about incidence and characteristics of Fabry-related stroke in young-adults. Presentation of the study protocol.

BACKGROUND: TIA and stroke, both ischemic and hemorrhagic, may complicate Fabry disease at young-adult age and be the first manifestation that comes to the clinician's attention. No definite indications have yet been elaborated to guide neurologists in Fabry disease diagnostics. In current practice, it is usually sought in case of cryptogenic strokes (while Fabry-related strokes can also occur by classical pathogenic mechanisms) or through screening programs in young cerebrovascular populations. Data on recurrence and secondary prevention of Fabry's stroke are scanty. METHODS: The study had a prospective observational design involving 33 Italian neurological Stroke Units. Considering the incidence of TIA/stroke in the European population aged < 60 years and the frequency of Fabry disease in this category (as foreseen by a pilot study held at the Careggi University-Hospital, Florence), we planned to screen for Fabry disease a total of 1740 < 60-year-old individuals hospitalized for TIA, ischemic, or hemorrhagic stroke. We investigated TIA and stroke pathogenesis through internationally validated scales and we gathered information on possible early signs of Fabry disease among all cerebrovascular patients. Every patient was tested for Fabry disease through dried blood spot analysis. Patients who received Fabry disease diagnosis underwent a 12-month follow-up to monitor stroke recurrence and multi-system progression after the cerebrovascular event. DISCUSSION: The potential implications of this study are as follows: (i) to add information about the yield of systematic screening for Fabry disease in a prospective large cohort of acute cerebrovascular patients; (ii) to deepen knowledge of clinical, pathophysiological, and prognostic characteristics of Fabry-related stroke.

Ischemic Stroke despite Oral Anticoagulant Therapy in Patients with Atrial Fibrillation.

OBJECTIVE: It is not known whether patients with atrial fibrillation (AF) with ischemic stroke despite oral anticoagulant therapy are at increased risk for further recurrent strokes or how ongoing secondary prevention should be managed. METHODS: We conducted an individual patient data pooled analysis of 7 prospective cohort studies that recruited patients with AF and recent cerebral ischemia. We compared patients taking oral anticoagulants (vitamin K antagonists [VKA] or direct oral anticoagulants [DOAC]) prior to index event (OACprior ) with those without prior oral anticoagulation (OACnaive ). We further compared those who changed the type (ie, from VKA or DOAC, vice versa, or DOAC to DOAC) of anticoagulation (OACchanged ) with those who continued the same anticoagulation as secondary prevention (OACunchanged ). Time to recurrent acute ischemic stroke (AIS) was analyzed using multivariate competing risk Fine-Gray models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: We included 5,413 patients (median age = 78 years [interquartile range (IQR) = 71-84 years]; 5,136 [96.7%] had ischemic stroke as the index event, median National Institutes of Health Stroke Scale on admission = 6 [IQR = 2-12]). The median CHA2 DS2 -Vasc score (congestive heart failure, hypertension, age≥ 75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65-74 years, sex category) was 5 (IQR = 4-6) and was similar for OACprior (n = 1,195) and OACnaive (n = 4,119, p = 0.103). During 6,128 patient-years of follow-up, 289 patients had AIS (4.7% per year, 95% CI = 4.2-5.3%). OACprior was associated with an increased risk of AIS (HR = 1.6, 95% CI = 1.2-2.3, p = 0.005). OACchanged (n = 307) was not associated with decreased risk of AIS (HR = 1.2, 95% CI = 0.7-2.1, p = 0.415) compared with OACunchanged (n = 585). INTERPRETATION: Patients with AF who have an ischemic stroke despite previous oral anticoagulation are at a higher risk for recurrent ischemic stroke despite a CHA2 DS2 -Vasc score similar to those without prior oral anticoagulation. Better prevention strategies are needed for this high-risk patient group. ANN NEUROL 2020.

Very early and early neurophysiological abnormalities in Guillain-Barré syndrome: A 4-year retrospective study.

BACKGROUND AND PURPOSE: In its initial stages, Guillain-Barré syndrome (GBS) is difficult to identify, because diagnostic criteria may not always be fulfilled. With this retrospective study, we wanted to identify the most common electrophysiological abnormalities seen on neurophysiological examination of GBS patients and its variants in the early phases. METHODS: We reviewed the clinical records of patients admitted to our Neurology Unit with a confirmed diagnosis of GBS. The study sample was divided in two subgroups according to whether the neurophysiological examination was performed: within 7 days (very early group) or within 7-15 days (early group). H reflex, F waves, and motor and sensory conduction parameters were judged abnormal if they were outside the normal range for at least two nerves. We evaluated neurophysiological findings in Miller-Fisher syndrome (MFS) separately. RESULTS: The study sample comprised 36 patients. In GBS, the most frequent abnormal neurophysiological parameter was the bilateral absence of the H reflex, followed by F wave abnormalities. Motor conduction parameters were altered in less than 50% of patients, and even less common were sensory nerve action potential reduction and the "sural-sparing" pattern. In MFS, H reflex was absent bilaterally in 100% of patients, followed by a predominant peripheral sensory involvement, whereas motor conduction parameters were frequently normal. CONCLUSIONS: Bilateral absence of the H reflex is the most sensitive parameter in early diagnosis of GBS and its variants.

Thrombectomy for ischemic stroke with large vessel occlusion and concomitant subarachnoid hemorrhage.

To report our experience in treating one patient with nontraumatic subarachnoid hemorrhage (SAH) and concurrent acute ischemic stroke (AIS) due to large vessels occlusion (LVO). A man in his 50 s presented with acute right hemiparesis and aphasia. Brain CT showed a SAH in the left central sulcus; CT-angiography revealed a tandem occlusion of the left internal carotid artery and homolateral middle cerebral artery. He underwent an angiographic procedure with successful recanalization. Follow-up CT demonstrated a striatal-lenticular stroke without SAH progression. While the absolute contraindication to IVT during intracranial bleeding remains unquestionable, the potential injury/benefit from MT is still debatable. Such cases constitute a blind spot in the guidelines where physicians face the dilemma of choosing between an acute endovascular treatment with the risks of hemorrhage progression and a conservative treatment with the associated poor clinical outcome. We decided to treat our patient invasively, considering the young age, also given the absence of prognostic factors that generally predict post-procedural reperfusion injury. We believe that, in similar cases, MT should be considered-despite not free of risks and drawbacks-to avoid the detrimental consequences of untreated AIS from LVO.

Factors influencing cognitive performance after 1-year treatment with direct oral anticoagulant in patients with atrial fibrillation and previous ischemic stroke: a pilot study.

Anticoagulant treatment as stroke prevention, particularly direct oral anticoagulant (DOAC), may reduce the risk of dementia in patients with atrial fibrillation (AF). We aimed to assess factors influencing cognitive performance after 1-year treatment with DOAC in patients with AF and previous ischemic stroke. We recruited 33 ischemic stroke patients who were discharged from Verona Stroke Unit with diagnosis of AF and prescription of treatment with DOAC. For each cognitive test, we estimated the effect of T0 (first session) variables on T1 (1-year session) cognitive performance using ordinal logistic regression fitted to a 1 point-shift from 4 to 0 on ESs. The effect of T0 clinical variables was presented as odds ratio (OR) with 95% confidence interval (CI) after adjustment for T0 total score of the corresponding cognitive test. Sustained AF (OR: 4.259, 95% CI 1.071-16.942) and ischemic heart disease (OR: 6.654, 95% CI 1.329-33.300) showed a significant effect on T1 MoCA Test; congestive heart failure on T1 RAVLT Immediate recall (OR: 9.128, 95% CI 1.055-78.995), T1 RAVLT Delayed recall (OR: 7.134, 95% CI 1.214-52.760), and T1 Trail Making Test (Part A) (OR: 16.989, 95% CI 1.765-163.565); sustained AF (OR: 5.055, 95% CI 1.224-20.878) and hyperlipidemia (OR: 4.764, 95% CI 1.175-19.310) on T1 Digit span forward Test; ischemic heart disease (aOR: 8.460, 95% CI 1.364-52.471) on T1 Stroop Color and Word Test (time); Dabigatran use (aOR: 0.084, 95% CI 0.013-0.544) on FAB; age ≥ 75 years (aOR: 0.058, 95% CI 0.006-0.563) and hyperlipidemia (aOR: 5.809, 95% CI 1.059-31.870) on T1 Phonemic word fluency Test; female sex (aOR: 6.105, 95% CI 1.146-32.519), hyperlipidemia (aOR: 21.099, 95% CI 2.773-160.564), total Modified Fazekas Scale score > 1 (aOR: 78.530, 95% CI 3.131-1969.512) on Semantic word fluency Test. Sustained AF, ischemic heart disease, congestive heart failure, hyperlipidemia, and female sex were the factors influencing cognitive performance after 1-year treatment with DOAC in patients with AF and previous ischemic stroke. Modified Fazekas Scale score in the first session was the only radiological variable that had a significant effect on cognitive performance.

Acute revascularization treatments for ischemic stroke in the Stroke Units of Triveneto, northeast Italy: time to treatment and functional outcomes.

It is not known whether the current territorial organization for acute revascularization treatments in ischemic stroke patients guarantees similar time to treatment and functional outcomes among different levels of institutional stroke care. We aimed to assess the impact of time to treatment on functional outcomes in ischemic stroke patients who received intravenous thrombolysis (IVT) alone, bridging (IVT plus thrombectomy), or primary thrombectomy in level 1 and level 2 Stroke Units (SUs) in Triveneto, a geographical macroarea in Northeast of Italy. We conducted an analysis of data prospectively collected from 512 consecutive ischemic stroke patients who received IVT and/or mechanical thrombectomy in 25 SUs from September 17th to December 9th 2018. The favorable outcome measures were mRS score 0-1 and 0-2 at 3 months. The unfavorable outcome measures were mRS score 3-5 and death at 3 months. We estimated separately the possible association of each variable for time to treatment (onset-to-door, door-to-needle, onset-to-needle, door-to-groin puncture, needle-to-groin puncture, and onset-to-groin puncture) with 3-month outcome measures by calculating the odds ratios (ORs) with two-sided 95% confidence intervals (CI) after adjustment for pre-defined variables and variables with a probability value ≤ 0.10 in the univariate analysis for each outcome measure. Distribution of acute revascularization treatments was different between level 1 and level 2 SUs (p < 0.001). Among 182 patients admitted to level 1 SUs (n = 16), treatments were IVT alone in 164 (90.1%), bridging in 12 (6.6%), and primary thrombectomy in 6 (3.3%) patients. Among 330 patients admitted to level 2 SUs (n = 9), treatments were IVT alone in 219 (66.4%), bridging in 74 (22.4%), and primary thrombectomy in 37 (11.2%) patients. Rates of excellent outcome (51.4% vs 45.9%), favorable outcome (60.1% vs 58.7%), unfavorable outcome (33.3% vs 33.8%), and death (9.8% vs 11.3%) at 3 months were similar between level 1 and 2 SUs. No significant association was found between time to IVT alone (onset-to-door, door-to-needle, and onset-to-needle) and functional outcomes. After adjustment, door-to-needle time ≤ 60 min (OR 4.005, 95% CI 1.232-13.016), shorter door-to-groin time (OR 0.991, 95% CI 0.983-0.999), shorter needle-to-groin time (OR 0.986, 95% CI 0.975-0.997), and shorter onset-to-groin time (OR 0.994, 95% CI 0.988-1.000) were associated with mRS 0-1. Shorter door-to-groin time (OR 0.991, 95% CI 0.984-0.998), door-to-groin time ≤ 90 min (OR 12.146, 95% CI 2.193-67.280), shorter needle-to-groin time (OR 0.983, 95% CI 0.972-0.995), and shorter onset-to-groin time (OR 0.993, 95% CI 0.987-0.999) were associated with mRS 0-2. Longer door-to-groin time (OR 1.007, 95% CI 1.001-1.014) and longer needle-to-groin time (OR 1.019, 95% CI 1.005-1.034) were associated with mRS 3-5, while door-to-groin time ≤ 90 min (OR 0.229, 95% CI 0.065-0.808) was inversely associated with mRS 3-5. Longer onset-to-needle time (OR 1.025, 95% CI 1.002-1.048) was associated with death. Times to treatment influenced the 3-month outcomes in patients treated with thrombectomy (bridging or primary). A revision of the current territorial organization for acute stroke treatments in Triveneto is needed to reduce transfer time and to increase the proportion of patients transferred from a level 1 SU to a level 2 SU to perform thrombectomy.

Stroke management during the coronavirus disease 2019 (COVID-19) pandemic: experience from three regions of the north east of Italy (Veneto, Friuli-Venezia-Giulia, Trentino-Alto-Adige).

BACKGROUND: Efficiency of care chain response and hospital reactivity were and are challenged for stroke acute care management during the pandemic period of coronavirus disease 2019 (COVID-19) in North-Eastern Italy (Veneto, Friuli-Venezia-Giulia, Trentino-Alto-Adige), counting 7,193,880 inhabitants (ISTAT), with consequences in acute treatment for patients with ischemic stroke. METHODS: We conducted a retrospective data collection of patients admitted to stroke units eventually treated with thrombolysis and thrombectomy, ranging from January to May 2020 from the beginning to the end of the main first pandemic period of COVID-19 in Italy. The primary endpoint was the number of patients arriving to these stroke units, and secondary endpoints were the number of thrombolysis and/or thrombectomy. Chi-square analysis was used on all patients; furthermore, patients were divided into two cohorts (pre-lockdown and lockdown periods) and the Kruskal-Wallis test was used to test differences on admission and reperfusive therapies. RESULTS: In total, 2536 patients were included in 22 centers. There was a significant decrease of admissions in April compared to January. Furthermore, we observed a significant decrease of thrombectomy during the lockdown period, while thrombolysis rate was unaffected in the same interval across all centers. CONCLUSIONS: Our study confirmed a decrease in admission rate of stroke patients in a large area of northern Italy during the lockdown period, especially during the first dramatic phase. Overall, there was no decrease in thrombolysis rate, confirming an effect of emergency care system for stroke patients. Instead, the significant decrease in thrombectomy rate during lockdown addresses some considerations of local and regional stroke networks during COVID-19 pandemic evolution.

Obesity paradox and stroke: a narrative review.

BACKGROUND: Despite obesity is an established risk factor for stroke, several studies reported a better outcome after stroke in obese and overweight patients. This counterintuitive finding, which was described in the whole spectrum of cardiovascular diseases, is known as obesity paradox. OBJECTIVE: This is a narrative overview on the obesity paradox and stroke. METHODS: We used as sources MEDLINE/PubMed, CINAHL, EMBASE, and Cochrane Library from inception to 2019, and selected papers that discussed the association of obesity with outcome and mortality after stroke. RESULTS: The majority of studies reported lower mortality rates and better functional outcome after stroke in obese and overweight patients compared with normal weight and underweight patients, suggesting the existence of an obesity paradox in stroke. However, available studies are limited by several major methodological concerns including absence of randomized trials, retrospective nature of most studies, assessment of obesity with body mass index (BMI), non-linear relationship between BMI and outcome, short follow-up period, and differences in co-morbid conditions and stroke characteristics. CONCLUSIONS: The existence of an obesity paradox in stroke is still controversial and further higher quality evidence is needed to clarify the relationship between obesity and stroke outcome. LEVEL OF EVIDENCE: Level V, narrative review.

Increased Incidence of Ischemic Cerebrovascular Events in Cardiovascular Patients With Elevated Apolipoprotein CIII.

Background and Purpose- Apo CIII (apolipoprotein CIII), a crucial regulator of lipoprotein metabolism, has been associated with increased activity of coagulation factors and thrombin generation and, in turn, with an increased risk of thromboembolic events in both arterial and venous districts. Thus, we hypothesized that it may affect the risk of acute ischemic cerebrovascular events in cardiovascular patients. Methods- We systematically checked medical records and quantified cerebral ischemic events in a cohort of 950 subjects (median age 65 with interquartile range, 55-79 years; 30.7% females) with or without angiographically defined coronary artery disease (CAD: 774 CAD and 176 CAD-free, respectively). All the subjects, enrolled between May 1999 and December 2006, were prospectively followed until death or July 31, 2018. Assessments of complete plasma lipid and apolipoprotein profiles, including Apo A-I, B, CIII, and E, were available for all subjects at enrollment. Results- After a median follow-up of 130 months (interquartile range, 69-189), 95 subjects (10%) suffered ischemic stroke/transient ischemic attack (TIA) events. Stroke/TIA subjects had higher Apo CIII plasma concentration (11.4; interquartile range: 9.3-14.4 mg/dL) at enrollment than those without stroke/TIA (10.4, interquartile range: 8.7-13.0 mg/dL). Subjects with Apo CIII levels above the median value (10.6 mg/dL) exhibited an ≈2-fold increased risk of stroke/TIA, even after adjustment for potential confounders, including sex, age, CAD diagnosis, hypertension, atrial fibrillation, oral anticoagulant treatment, and all plasma lipid parameters (hazard ratio: 2.23 [95% CI, 1.21-4.13]). This result was confirmed in CAD and CAD-free populations, separately, and even by a propensity score matching method, in which 98 CAD and 98 CAD-free subjects were one-to-one matched for all clinical and laboratory characteristics. Conclusions- These findings suggest that a high Apo CIII plasma concentration may predict an increased risk of ischemic stroke/TIA in cardiovascular patients.

General Anesthesia Versus Conscious Sedation and Local Anesthesia During Thrombectomy for Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: As numerous questions remain about the best anesthetic strategy during thrombectomy, we assessed functional and radiological outcomes in stroke patients treated with thrombectomy in presence of general anesthesia (GA) versus conscious sedation (CS) and local anesthesia (LA). METHODS: We conducted a cohort study on prospectively collected data from 4429 patients enrolled in the Italian Registry of Endovascular Treatment in Acute Stroke. RESULTS: GA was used in 2013 patients, CS in 1285 patients, and LA in 1131 patients. The rates of 3-month modified Rankin Scale score of 0-1 were 32.7%, 33.7%, and 38.1% in the GA, CS, and LA groups: GA versus CS: odds ratios after adjustment for unbalanced variables (adjusted odds ratio [aOR]), 0.811 (95% CI, 0.602-1.091); and GA versus LA: aOR, 0.714 (95% CI, 0.515-0.990). The rates of modified Rankin Scale score of 0-2 were 42.5%, 46.6%, and 52.4% in the GA, CS, and LA groups: GA versus CS: aOR, 0.902 (95% CI, 0.689-1.180); and GA versus LA: aOR, 0.769 (95% CI, 0.566-0.998). The rates of 3-month death were 21.5%, 19.7%, and 14.8% in the GA, CS, and LA groups: GA versus CS: aOR, 0.872 (95% CI, 0.644-1.181); and GA versus LA: aOR, 1.235 (95% CI, 0.844-1.807). The rates of parenchymal hematoma were 9%, 12.6%, and 11.3% in the GA, CS, and LA groups: GA versus CS: aOR, 0.380 (95% CI, 0.262-0.551); and GA versus LA: aOR, 0.532 (95% CI, 0.337-0.838). After model of adjustment for predefined variables (age, sex, thrombolysis, National Institutes of Health Stroke Scale, onset-to-groin time, anterior large vessel occlusion, procedure time, prestroke modified Rankin Scale score of <1, antiplatelet, and anticoagulant), differences were found also between GA versus CS as regards modified Rankin Scale score of 0-2 (aOR, 0.659 [95% CI, 0.538-0.807]) and GA versus LA as regards death (aOR, 1.413 [95% CI, 1.095-1.823]). CONCLUSIONS: GA during thrombectomy was associated with worse 3-month functional outcomes, especially when compared with LA. The inclusion of an LA arm in future randomized clinical trials of anesthesia strategy is recommended.

Direct oral anticoagulants versus vitamin K antagonists after recent ischemic stroke in patients with atrial fibrillation.

OBJECTIVE: We compared outcomes after treatment with direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) and a recent cerebral ischemia. METHODS: We conducted an individual patient data analysis of seven prospective cohort studies. We included patients with AF and a recent cerebral ischemia (<3 months before starting oral anticoagulation) and a minimum follow-up of 3 months. We analyzed the association between type of anticoagulation (DOAC versus VKA) with the composite primary endpoint (recurrent ischemic stroke [AIS], intracerebral hemorrhage [ICH], or mortality) using mixed-effects Cox proportional hazards regression models; we calculated adjusted hazard ratios (HRs) with 95% confidence intervals (95% CIs). RESULTS: We included 4,912 patients (median age, 78 years [interquartile range {IQR}, 71-84]; 2,331 [47.5%] women; median National Institute of Health Stroke Severity Scale at onset, 5 [IQR, 2-12]); 2,256 (45.9%) patients received VKAs and 2,656 (54.1%) DOACs. Median time from index event to starting oral anticoagulation was 5 days (IQR, 2-14) for VKAs and 5 days (IQR, 2-11) for DOACs (p = 0.53). There were 262 acute ischemic strokes (AISs; 4.4%/year), 71 intracranial hemorrrhages (ICHs; 1.2%/year), and 439 deaths (7.4%/year) during the total follow-up of 5,970 patient-years. Compared to VKAs, DOAC treatment was associated with reduced risks of the composite endpoint (HR, 0.82; 95% CI, 0.67-1.00; p = 0.05) and ICH (HR, 0.42; 95% CI, 0.24-0.71; p < 0.01); we found no differences for the risk of recurrent AIS (HR, 0.91; 95% CI, 0.70-1.19; p = 0.5) and mortality (HR, 0.83; 95% CI, 0.68-1.03; p = 0.09). INTERPRETATION: DOAC treatment commenced early after recent cerebral ischemia related to AF was associated with reduced risk of poor clinical outcomes compared to VKA, mainly attributed to lower risks of ICH. ANN NEUROL 2019;85:823-834.