Autistic-like behaviour and changes in thalamic cell numbers a rat model of valproic acid-induced autism; A behavioural and stereological study.

The contribution of the thalamus to the development and behavioural changes in autism spectrum disorders (ASD), a neurodevelopmental syndrome, remains unclear. The aim of this study was to determine the changes in thalamic volume and cell number in the valproic acid (VPA)-induced ASD model using stereological methods and to clarify the relationship between thalamus and ASD-like behaviour. Ten pregnant rats were administered a single dose (600 mg/kg) of VPA intraperitoneally on G12.5 (VPA group), while five pregnant rats were injected with 5 ml saline (control group). Behavioural tests were performed to determine appropriate subjects and ASD-like behaviours. At P55, the brains of the subjects were removed. The sagittal sections were stained with cresyl violet and toluidine blue. The thalamic and hemispheric volumes with their ratios, the total number of thalamic cells, neurons and non-neuronal cells were calculated using stereological methods. Data were compared using a t-test and a Pearson correlation analysis was performed to examine the relationship between behaviour and stereological outcomes. VPA-treated rats had lower sociability and sociability indexes. There was no difference in social novelty preference and anxiety. The VPA group had larger hemispheric volume, lower thalamic volume, and fewer neurons. The highest percentage decrease was in non-neuronal cells. There was a moderate positive correlation between the number of non-neuronal cells and sociability, thalamic volume and the number of neurons as well as the time spent in the light box. The correlation between behaviour and stereological data suggests that the thalamus is associated with ASD-like behaviour.

Tolerability and Safety of Large-Volume Hyaluronidase-Facilitated Subcutaneous Immunoglobulin 10% Administered with or without Dose Ramp-Up: A Phase 1 Study in Healthy Participants.

PURPOSE: Facilitated subcutaneous immunoglobulin (fSCIG; immune globulin infusion 10% [human] with recombinant human hyaluronidase [rHuPH20]) permits high-volume subcutaneous immunoglobulin (SCIG) infusion, shorter infusion times and reduced dosing frequency relative to conventional SCIG. It is initiated by gradually increasing infusion volumes over time (dose ramp-up) to achieve target dose level (TDL). Whether ramp-up strategies have tolerability or safety advantages over direct initiation at full TDL has not been evaluated clinically. METHODS: This phase 1 open-label study assessed tolerability and safety of fSCIG 10% with accelerated or no ramp-up compared with conventional ramp-up in healthy adults (NCT04578535). Participants were assigned to one of the three ramp-up arms to achieve TDLs of 0.4 or 1.0 g/kg/infusion. The primary endpoint was the proportion of infusions completed without interruption or infusion rate reduction owing to treatment-emergent adverse events (TEAEs). Safety was assessed as a secondary endpoint. RESULTS: Of 51 participants enrolled, 50 (98.0%) tolerated all fSCIG 10% infusions initiated (n = 174). Infusion rate was reduced in one participant owing to headache in the 0.4 g/kg/infusion conventional ramp-up arm. Study discontinuations were higher in the no ramp-up arm (70%) versus the conventional (0%) and accelerated (22%) arms at the 1.0 g/kg/infusion TDL. Safety outcomes did not substantially differ between treatment arms. CONCLUSION: The favorable tolerability and safety profiles of fSCIG 10% in healthy participants support initiating treatment with fSCIG 10% with accelerated ramp-up at TDLs up to 1.0 g/kg. Data support no ramp-up at TDLs close to 0.4 g/kg but additional data are needed for higher doses.

Statin Therapy for Secondary Prevention in Ischemic Stroke Patients With Cerebral Microbleeds.

BACKGROUND AND OBJECTIVES: The association between statin use and the risk of intracranial hemorrhage (ICrH) following ischemic stroke (IS) or transient ischemic attack (TIA) in patients with cerebral microbleeds (CMBs) remains uncertain. This study investigated the risk of recurrent IS and ICrH in patients receiving statins based on the presence of CMBs. METHODS: We conducted a pooled analysis of individual patient data from the Microbleeds International Collaborative Network, comprising 32 hospital-based prospective studies fulfilling the following criteria: adult patients with IS or TIA, availability of appropriate baseline MRI for CMB quantification and distribution, registration of statin use after the index stroke, and collection of stroke event data during a follow-up period of ≥3 months. The primary endpoint was the occurrence of recurrent symptomatic stroke (IS or ICrH), while secondary endpoints included IS alone or ICrH alone. We calculated incidence rates and performed Cox regression analyses adjusting for age, sex, hypertension, atrial fibrillation, previous stroke, and use of antiplatelet or anticoagulant drugs to explore the association between statin use and stroke events during follow-up in patients with CMBs. RESULTS: In total, 16,373 patients were included (mean age 70.5 ± 12.8 years; 42.5% female). Among them, 10,812 received statins at discharge, and 4,668 had 1 or more CMBs. The median follow-up duration was 1.34 years (interquartile range: 0.32-2.44). In patients with CMBs, statin users were compared with nonusers. Compared with nonusers, statin therapy was associated with a reduced risk of any stroke (incidence rate [IR] 53 vs 79 per 1,000 patient-years, adjusted hazard ratio [aHR] 0.68 [95% CI 0.56-0.84]), a reduced risk of IS (IR 39 vs 65 per 1,000 patient-years, aHR 0.65 [95% CI 0.51-0.82]), and no association with the risk of ICrH (IR 11 vs 16 per 1,000 patient-years, aHR 0.73 [95% CI 0.46-1.15]). The results in aHR remained consistent when considering anatomical distribution and high burden (≥5) of CMBs. DISCUSSION: These observational data suggest that secondary stroke prevention with statins in patients with IS or TIA and CMBs is associated with a lower risk of any stroke or IS without an increased risk of ICrH. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with IS or TIA and CMBs, statins lower the risk of any stroke or IS without increasing the risk of ICrH.

Stroke-Related Visceral Alterations: A Voxel-Based Neuroanatomic Localization Study.

OBJECTIVE: Functional and morphologic changes in extracranial organs can occur after acute brain injury. The neuroanatomic correlates of such changes are not fully known. Herein, we tested the hypothesis that brain infarcts are associated with cardiac and systemic abnormalities (CSAs) in a regionally specific manner. METHODS: We generated voxelwise p value maps of brain infarcts for poststroke plasma cardiac troponin T (cTnT) elevation, QTc prolongation, in-hospital infection, and acute stress hyperglycemia (ASH) in 1,208 acute ischemic stroke patients prospectively recruited into the Heart-Brain Interactions Study. We examined the relationship between infarct location and CSAs using a permutation-based approach and identified clusters of contiguous voxels associated with p < 0.05. RESULTS: cTnT elevation not attributable to a known cardiac reason was detected in 5.5%, QTc prolongation in the absence of a known provoker in 21.2%, ASH in 33.9%, and poststroke infection in 13.6%. We identified significant, spatially segregated voxel clusters for each CSA. The clusters for troponin elevation and QTc prolongation mapped to the right hemisphere. There were 3 clusters for ASH, the largest of which was in the left hemisphere. We found 2 clusters for poststroke infection, one associated with pneumonia in the left and one with urinary tract infection in the right hemisphere. The relationship between infarct location and CSAs persisted after adjusting for infarct volume. INTERPRETATION: Our results show that there are discrete regions of brain infarcts associated with CSAs. This information could be used to bootstrap toward new markers for better differentiation between neurogenic and non-neurogenic mechanisms of poststroke CSAs. ANN NEUROL 2023;94:1155-1163.

Hyaluronidase-facilitated subcutaneous immunoglobulin 10% as maintenance therapy for chronic inflammatory demyelinating polyradiculoneuropathy: The ADVANCE-CIDP 1 randomized controlled trial.

BACKGROUND AND AIMS: ADVANCE-CIDP 1 evaluated facilitated subcutaneous immunoglobulin (fSCIG; human immunoglobulin G 10% with recombinant human hyaluronidase) efficacy and safety in preventing chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) relapse. METHODS: ADVANCE-CIDP 1 was a phase 3, double-blind, placebo-controlled trial conducted at 54 sites in 21 countries. Eligible adults had definite or probable CIDP and adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability scores of 0-7 (inclusive), and received stable intravenous immunoglobulin (IVIG) for ≥12 weeks before screening. After stopping IVIG, patients were randomized 1:1 to fSCIG 10% or placebo for 6 months or until relapse/discontinuation. fSCIG 10% was administered at the same dose (or matching placebo volume) and interval as pre-randomization IVIG. The primary outcome was patient proportion experiencing CIDP relapse (≥1-point increase in adjusted INCAT score from pre-subcutaneous treatment baseline) in the modified intention-to-treat population. Secondary outcomes included time to relapse and safety endpoints. RESULTS: Overall, 132 patients (mean age 54.4 years, 56.1% male) received fSCIG 10% (n = 62) or placebo (n = 70). CIDP relapse was reduced with fSCIG 10% versus placebo (n = 6 [9.7%; 95% confidence interval 4.5%, 19.6%] vs n = 22 [31.4%; 21.8%, 43.0%], respectively; absolute difference: -21.8% [-34.5%, -7.9%], p = .0045). Relapse probability was higher with placebo versus fSCIG 10% over time (p = .002). Adverse events (AEs) were more frequent with fSCIG 10% (79.0% of patients) than placebo (57.1%), but severe (1.6% vs 8.6%) and serious AEs (3.2% vs 7.1%) were less common. INTERPRETATION: fSCIG 10% more effectively prevented CIDP relapse than placebo, supporting its potential use as maintenance CIDP treatment.

Intravenous Immunoglobulin Initiation in Patients with Chronic Inflammatory Demyelinating Polyradiculoneuropathy: A US Claims-based Cohort Study.

INTRODUCTION: Intravenous immunoglobulin (IVIG) is recommended as first-line therapy for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), an immune-mediated neuropathy. The clinical profile of patients with CIDP newly initiating IVIG is poorly characterized. This claims-based cohort study describes characteristics of US patients with CIDP initiating IVIG treatment. METHODS: Adult immunoglobulin (IG)-naïve patients with CIDP diagnosed between 2008 and 2018 and a subgroup of patients subsequently initiating IVIG were identified in the Merative MarketScan Research Databases. Demographics, clinical characteristics, and diagnostic procedures were described for patients initiating IVIG. RESULTS: Of 32,090 patients with CIDP identified, 3975 (mean age 57 years) subsequently initiated IVIG. In the 6 months prior to IVIG initiation, diagnoses of comorbidities including neuropathy (75%), hypertension (62%), and diabetes (33%) were frequent, as were CIDP features/symptoms/markers of functional status including chronic pain (80%), difficulty walking (30%), and weakness (30%). CIDP-related laboratory/diagnostic procedures were performed in approximately 20- > 40% of patients in the 3 months prior to IVIG initiation (63.7% underwent electrodiagnostic/nerve conduction testing in the 6 months prior to IVIG initiation). Patient characteristics by initial IVIG product differed only in IVIG initiation year, US geographic region, and insurance type. Comorbidities, CIDP severity or functional status markers, and other clinical variables were generally well balanced across initial IVIG product groups. CONCLUSION: A heavy burden of symptoms, comorbidities, and diagnostic testing exists in patients with CIDP initiating IVIG. Characteristics of patients with CIDP initiating different IVIG products are well balanced, suggesting an absence of clinical or demographic determinants underlying IVIG selection.

Intravenous immunoglobulin, also called IVIG, involves giving antibodies through a drip into a vein. IVIG is recommended as one of the first treatments that patients receive if they have chronic inflammatory demyelinating polyradiculoneuropathy, also called CIDP, which is a rare disease that causes the body's immune system to attack its nerves. Our study described the characteristics of patients with CIDP who received IVIG in the USA. Information was collected from a large health insurance database and included records of patients aged ≥ 18 years who were diagnosed with CIDP between 2008 and 2018. Overall, 3975 patients with CIDP who received IVIG were included in the study. In the 6 months before starting IVIG, patients frequently had diagnoses of other diseases in addition to their CIDP; these included neuropathy (75% of patients), hypertension (62%), and diabetes (33%). CIDP features and symptoms that affected patients' daily lives were also frequently reported in these 6 months, including long-lasting pain (80%), difficulty walking (30%), and weakness (30%). In the 3 months before starting IVIG treatment, 20% to > 40% of patients underwent diagnostic procedures related to their CIDP. Different IVIG products were used similarly, but the year of IVIG initiation, geographic region, and insurance type all differed by IVIG product. In conclusion, patients with CIDP who receive IVIG experience a heavy burden caused by their symptoms, other diseases, and CIDP-related procedures. Patient characteristics were generally similar between patients receiving different IVIG products, suggesting that no specific characteristics are factored in when doctors select an IVIG product.

Intravenous Immunoglobulin Treatment Patterns and Outcomes in Patients with Chronic Inflammatory Demyelinating Polyradiculoneuropathy: A US Claims Database Analysis.

INTRODUCTION: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare progressive or relapsing inflammatory disease. Intravenous immunoglobulin (IVIG) is recommended as a first-line therapy. The aim of this study was to describe real-world treatment patterns and outcomes of patients with CIDP in the Define initiating IVIG treatment. METHODS: This cohort study used health insurance claims data from the Merative MarketScan Research Databases (2008-2018). Adult patients (≥ 18 years old) with CIDP without prior immunoglobulin treatment were identified using International Statistical Classification of Diseases and Related Health Problems (ICD) codes, and patients subsequently initiating IVIG were included in the analysis. Real-world IVIG treatment patterns and treatment and safety outcomes (assessed via ICD codes) were described. RESULTS: In total, 3975 patients (median age 58 years) with CIDP who initiated IVIG were identified. After the initial IVIG loading period, patients received IVIG at a median dosing interval of 21 days (quartile [Q]1, Q3: 7, 28), and continued treatment for a median of 129 days (Q1, Q3: 85, 271). After the 2-year follow-up period, 55% of patients had discontinued all IVIG treatment; more than one-half of these discontinuations occurred within 4 months. Diagnoses of impaired functional status were evident in more than 30% of patients at baseline, but at lower rates during follow-up. Rates of new-onset safety outcomes after IVIG treatment were low. CONCLUSION: This real-world analysis of IVIG treatment patterns and treatment and safety outcomes of patients with CIDP who initiated IVIG highlights the unmet need for improved long-term management. Further research is needed to evaluate the use of functional status measures as endpoints for immunoglobulin treatment effectiveness.

Chronic inflammatory demyelinating polyradiculoneuropathy, also called CIDP, is a rare disease that causes the body's immune system to attack its nerves. Treatments for CIDP include antibodies, which are also called immunoglobulins. Immunoglobulins may be given intravenously, meaning they are administered into a vein. Intravenous immunoglobulin, also called IVIG, is recommended as one of the first treatments that patients with CIDP receive in their therapy and involves giving antibodies through a drip into a vein. This study aimed to gather information on the day-to-day use of IVIG by patients with CIDP. Information from 2008 to 2018 was collected from a large health insurance database in the USA. Information was taken from the records of patients aged 18 years or older who had received IVIG during the information collection period. In total, records from 3975 patients with an average age of 58 years were included in the study. On average, patients received IVIG every 21 days for 129 days. By 2 years, 55% of patients had stopped receiving IVIG; most of those patients had stopped within 4 months of first receiving the treatment. In the 6 months before receiving IVIG, over 30% of patients experienced limitations owing to their CIDP that affected their daily lives, although this percentage became smaller once patients started to receive IVIG. In addition, a low number of patients experienced side effects because of their IVIG treatment. This study highlights that improved long-term care for patients with CIDP is needed. Further research into ways of measuring the impact of CIDP on patients' daily lives is required, which may help doctors to work out how effective IVIG is at treating CIDP.

Adverse effects of maternal retinyl palmitate, a vitamin A compound, on the fetal liver.

Background: Consuming high doses of vitamin A during pregnancy may lead to malformations in the offspring. Some reports state that low doses that do not cause macroscopic abnormalities may result in mental and behavioral disorders. However, there are few studies on the microscopic effects of these doses on the organism. Objective: The aim was to investigate the effects of early prenatal exposure to different doses of oral vitamin A on the fetal liver. Materials and methods: Twenty-five pregnant rats, divided into five groups, received oral vitamin A at doses of 10,000, 50,000, 100,000, and 200,000 IU/kg between days 10 and 12 of gestation. The fetuses were collected on day 19 of gestation, their livers were dissected, and histology, apoptosis, and proliferation were examined by hematoxylin-eosin, TUNEL assay, and Ki67 immunolabeling using stereological methods. Results: Vitamin A decreased fetal liver volume, the number of Ki67-positive cells per unit volume, and the total number of hepatocytes at all doses except 10,000 IU/kg (p<0.001). Consequently, apoptosis was significantly higher in the groups receiving 100,000 and 200,000 IU/kg vitamin A (p<0.001). Conclusion: Our study shows that vitamin A administered during gestation days 10-12 has a suppressive effect on the developing rat liver when the dose exceeds 10,000 IU/kg, probably due to increased apoptosis and suppressed cell division.

Assessment of safety and feasibility of non-invasive vagus nerve stimulation for treatment of acute stroke.

BACKGROUND: Non-invasive vagus nerve stimulation (nVNS) using a hand-held stimulator placed on the neck is an FDA-approved treatment for primary headache disorders. The safety of nVNS is unknown in stroke patients. OBJECTIVE: To assess the safety and feasibility of nVNS for the acute treatment of stroke. METHODS: TR-VENUS (clinicaltrials.gov identifier NCT03733431) was a randomized, sham-controlled, open-label, multicenter trial conducted in patients with acute ischemic stroke (IS) or intracerebral hemorrhage (ICH). Patients were randomly assigned to standard-dose nVNS, high-dose nVNS, or sham stimulation. The primary endpoint was a composite safety outcome defined as bradycardia or reduction in mean arterial blood pressure during treatment or progression of neurological or death within 24 h of treatment. The feasibility endpoints were the proportion of eligible subjects receiving nVNS within 6 h of symptom onset and the proportion completing all pre-specified treatment doses. Efficacy assessments included infarct growth from baseline to 24 h after treatment. RESULTS: Sixty-nine patients (61 IS, 8 ICH) completed the study. The composite safety outcome was achieved in 32.0% in sham and 47.7% in nVNS group (p = 0.203). Treatment was initiated in all but two randomized patients. All dosed subjects received 100% of prespecified stimulations. A non-significant reduction in infarct growth was observed in the high-dose nVNS group (184.2% in sham vs. 63.3% in high-dose nVNS; p = 0.109). CONCLUSIONS: The results of this study suggest that nVNS may be safe and feasible in the setting of acute stroke. These findings support further development of nVNS as a potential treatment for acute ischemic stroke.

Association of Socioeconomic Status and Infarct Volume With Functional Outcome in Patients With Ischemic Stroke.

Importance: Long-term disability after stroke is associated with socioeconomic status (SES). However, the reasons for such disparities in outcomes remain unclear. Objective: To assess whether lower SES is associated with larger admission infarct volume and whether initial infarct volume accounts for the association between SES and long-term disability. Design, Setting, and Participants: This cohort study was conducted in a prospective, consecutive population (n = 1256) presenting with acute ischemic stroke who underwent magnetic resonance imaging (MRI) within 24 hours of admission. Patients were recruited in Massachusetts General Hospital, Boston, from May 31, 2009, to December 31, 2011. Data were analyzed from May 1, 2019, until June 30, 2020. Main Outcomes and Measures: Initial stroke severity (within 24 hours of presentation) was determined using clinical (National Institutes of Health Stroke Scale [NIHSS]) and imaging (infarct volume by diffusion-weighted MRI) measures. Stroke etiologic subtypes were determined using the Causative Classification of Ischemic Stroke algorithm. Long-term stroke disability was measured using the modified Rankin Scale. Socioeconomic status was estimated using zip code-derived median household income and census block group-derived area deprivation index (ADI). Regression and mediation analyses were performed. Results: A total of 1098 patients had imaging and SES data available (mean [SD] age, 68.1 [15.7] years; 607 men [55.3%]). Income was inversely associated with initial infarct volume (standardized ß, -0.074 [95% CI, -0.127 to -0.020]; P = .007), initial NIHSS (standardized ß, -0.113 [95% CI, -0.171 to -0.054]; P < .001), and long-term disability (standardized ß, -0.092 [95% CI, -0.149 to -0.035]; P = .001), which remained significant after multivariable adjustments. Initial stroke severity accounted for 64% of the association between SES and long-term disability (standardized ß, -0.063 [95% CI, -0.095 to -0.029]; P < .05). Findings were similar when SES was alternatively assessed using ADI. Conclusions and Relevance: The findings of this cohort study suggest that lower SES is associated with larger infarct volumes on presentation. These SES-associated differences in initial stroke severity accounted for most of the subsequent disparities in long-term disability in this study. These findings shift the culpability for SES-associated disparities in poststroke disability from poststroke factors to those that precede presentation.

Stroke Care during the COVID-19 Pandemic: International Expert Panel Review.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has placed a tremendous strain on healthcare services. This study, prepared by a large international panel of stroke experts, assesses the rapidly growing research and personal experience with COVID-19 stroke and offers recommendations for stroke management in this challenging new setting: modifications needed for prehospital emergency rescue and hyperacute care; inpatient intensive or stroke units; posthospitalization rehabilitation; follow-up including at-risk family and community; and multispecialty departmental developments in the allied professions. SUMMARY: The severe acute respiratory syndrome coronavirus 2 uses spike proteins binding to tissue angiotensin-converting enzyme (ACE)-2 receptors, most often through the respiratory system by virus inhalation and thence to other susceptible organ systems, leading to COVID-19. Clinicians facing the many etiologies for stroke have been sobered by the unusual incidence of combined etiologies and presentations, prominent among them are vasculitis, cardiomyopathy, hypercoagulable state, and endothelial dysfunction. International standards of acute stroke management remain in force, but COVID-19 adds the burdens of personal protections for the patient, rescue, and hospital staff and for some even into the postdischarge phase. For pending COVID-19 determination and also for those shown to be COVID-19 affected, strict infection control is needed at all times to reduce spread of infection and to protect healthcare staff, using the wealth of well-described methods. For COVID-19 patients with stroke, thrombolysis and thrombectomy should be continued, and the usual early management of hypertension applies, save that recent work suggests continuing ACE inhibitors and ARBs. Prothrombotic states, some acute and severe, encourage prophylactic LMWH unless bleeding risk is high. COVID-19-related cardiomyopathy adds risk of cardioembolic stroke, where heparin or warfarin may be preferable, with experience accumulating with DOACs. As ever, arteritis can prove a difficult diagnosis, especially if not obvious on the acute angiogram done for clot extraction. This field is under rapid development and may generate management recommendations which are as yet unsettled, even undiscovered. Beyond the acute management phase, COVID-19-related stroke also forces rehabilitation services to use protective precautions. As with all stroke patients, health workers should be aware of symptoms of depression, anxiety, insomnia, and/or distress developing in their patients and caregivers. Postdischarge outpatient care currently includes continued secondary prevention measures. Although hoping a COVID-19 stroke patient can be considered cured of the virus, those concerned for contact safety can take comfort in the increasing use of telemedicine, which is itself a growing source of patient-physician contacts. Many online resources are available to patients and physicians. Like prior challenges, stroke care teams will also overcome this one. Key Messages: Evidence-based stroke management should continue to be provided throughout the patient care journey, while strict infection control measures are enforced.

Effect of Intensive Versus Standard Blood Pressure Control on Stroke Subtypes.

[Figure: see text].

White matter hyperintensity determines ischemic stroke severity in symptomatic carotid artery stenosis.

INTRODUCTION: The aim of this study is to investigate the influence of white matter hyperintensity (WMH) on stroke severity and prognosis in patients with symptomatic carotid artery stenosis. METHODS: Patients with symptomatic carotid artery stenosis were retrieved from the Samsung Medical Center stroke registry from January 2011 to December 2016. Stroke severity was categorized into three levels according to National Institutes of Health Stroke Scale (NIHSS): transient ischemic attack (TIA) or transient symptoms with infarction (TSI), mild stroke, and moderate to severe stroke. WMH volume was measured with medical image processing and visualization. The clinical outcome was assessed using the modified Rankin scale on the 90th day from which the latest onset of the neurological symptom. Logistic regression was used to predict stroke severity, and ordinal regression was used to compare the clinical outcome. RESULTS: Among 158 patients, the numbers of patients with TIA or TSI, mild stroke, and moderate to severe stroke were 48 (30.4%), 59 (37.3%), and 51 (32.3%), respectively. The larger WMH volume was associated with moderate to severe strokes (TIA/TSI vs. moderate to severe strokes, odds ratio (OR) 2.318, 95% confidence interval (CI) 1.194-4.502, p = 0.007; mild vs. moderate to severe strokes, OR 1.972, 95% CI 1.118-3.479, p = 0.013). Patients with larger volume of WMH showed poorer clinical outcome (cutoff value: 9.71 cm3, OR 2.099, 95% CI 1.030-4.311, p = 0.042). CONCLUSION: Our study showed that larger WMH volume is associated with more severe stroke and poorer prognosis in patients with symptomatic carotid artery stenosis.

Left atrial cross-sectional area is a novel measure of atrial shape associated with cardioembolic strokes.

OBJECTIVE: Cardioembolic (CE) stroke carries significant morbidity and mortality. Left atrial (LA) size has been associated with CE risk. We hypothesised that differential LA remodelling impacts on pathophysiological mechanism of major CE strokes. METHODS: A cohort of consecutive patients hospitalised with ischaemic stroke, classified into CE versus non-CE strokes using the Causative Classification System for Ischaemic Stroke were enrolled. LA shape and remodelling was characterised by assessing differences in maximal LA cross-sectional area (LA-CSA) in a cohort of 40 prospectively recruited patients with ischaemic stroke using three-dimensional (3D) echocardiography. Flow velocity profiles were measured in spherical versus ellipsoidal in vitro models to determine if LA shape influences flow dynamics. Two-dimensional (2D) LA-CSA was subsequently derived from standard echocardiographic views and compared with 3D LA-CSA. RESULTS: A total of 1023 patients with ischaemic stroke were included, 230 (22.5%) of them were classified as major CE. The mean age was 68±16 years, and 464 (45%) were women. The 2D calculated LA-CSA correlated strongly with the LA-CSA measured by 3D in both end-systole and end-diastole. In vitro flow models showed shape-related differences in mid-level flow velocity profiles. Increased LA-CSA was associated with major CE stroke (adjusted relative risk 1.10, 95% CI 1.04 to 1.16; p<0.001), independent of age, gender, atrial fibrillation, left ventricular ejection fraction and CHA2DS2-VASc score. Specifically, the inclusion of LA-CSA in a model with traditional risk factors for CE stroke resulted in significant improvement in model performance with the net reclassification improvement of 0.346 (95% CI 0.189 to 0.501; p=0.00001) and the integrated discrimination improvement of 0.013 (95% CI 0.003 to 0.024; p=0.0119). CONCLUSIONS: LA-CSA is a marker of adverse LA shape associated with CE stroke, reflecting importance of differential LA remodelling, not simply LA size, in the mechanism of CE risk.

Cerebral Small Vessel Diseases and Sleep Related Strokes.

BACKGROUND AND PURPOSE: Sleep related Stroke (SRS) is common and has been associated with cerebral small vessel diseases (SVD) in ischemic strokes (ISs). We tested the hypothesis that SRS is associated with SVD in both ischemic and hemorrhagic stroke. METHODS: Prospectively collected data from patients consecutively enrolled after intracerebral hemorrhage (ICH) related to SVD or after IS were analyzed. Symptom onset was recorded as SRS versus awake. Each ICH was grouped according to lobar and deep locations. The IS cohort was etiologically characterized based on the Causative Classification of Stroke system. Frequencies of SRS within and between ICH and IS cohorts as well as its associations (etiology, risk factors) were analyzed. RESULTS: We analyzed 1812 IS (mean age 67.9 years ± 15.9 years, 46.4% female) and 1038 ICH patients (mean age 72.5 years ± 13.0 years, 45.4% female). SRS was significantly more common among SVD-related ICH patients (n = 276, 26.6%) when compared to all IS (n = 363, 20.0%, P < .001) and in both, small artery occlusion (SAO) related IS and lobar ICH within the respective IS and ICH cohorts (16.3% SRS versus 9.1% awake for SAO within all IS, P < .001; and 57.1% SRS versus 47.7% awake for lobar bleeds within all ICH, P = .008). These associations remained significant after controlling for age, sex and risk factors. CONCLUSIONS: SRS was associated with SVD. The SAO etiology and cerebral amyloid angiopathy related lobar ICH suggest that the presence of SVD can interact with sleep or arousal related hemodynamic changes to cause ischemic and hemorrhagic stroke.

Subtype Specificity of Genetic Loci Associated With Stroke in 16 664 Cases and 32 792 Controls.

BACKGROUND: Genome-wide association studies have identified multiple loci associated with stroke. However, the specific stroke subtypes affected, and whether loci influence both ischemic and hemorrhagic stroke, remains unknown. For loci associated with stroke, we aimed to infer the combination of stroke subtypes likely to be affected, and in doing so assess the extent to which such loci have homogeneous effects across stroke subtypes. METHODS: We performed Bayesian multinomial regression in 16 664 stroke cases and 32 792 controls of European ancestry to determine the most likely combination of stroke subtypes affected for loci with published genome-wide stroke associations, using model selection. Cases were subtyped under 2 commonly used stroke classification systems, TOAST (Trial of Org 10172 Acute Stroke Treatment) and causative classification of stroke. All individuals had genotypes imputed to the Haplotype Reference Consortium 1.1 Panel. RESULTS: Sixteen loci were considered for analysis. Seven loci influenced both hemorrhagic and ischemic stroke, 3 of which influenced ischemic and hemorrhagic subtypes under both TOAST and causative classification of stroke. Under causative classification of stroke, 4 loci influenced both small vessel stroke and intracerebral hemorrhage. An EDNRA locus demonstrated opposing effects on ischemic and hemorrhagic stroke. No loci were predicted to influence all stroke subtypes in the same direction, and only one locus (12q24) was predicted to influence all ischemic stroke subtypes. CONCLUSIONS: Heterogeneity in the influence of stroke-associated loci on stroke subtypes is pervasive, reflecting differing causal pathways. However, overlap exists between hemorrhagic and ischemic stroke, which may reflect shared pathobiology predisposing to small vessel arteriopathy. Stroke is a complex, heterogeneous disorder requiring tailored analytic strategies to decipher genetic mechanisms.

Publisher Correction: Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Reduced Ischemic Lesion Growth with Heparin in Acute Ischemic Stroke.

OBJECTIVE: The role of heparin in acute ischemic stroke is controversial. We investigated the effect of heparin on ischemic lesion growth. METHODS: Data were analyzed on nonthrombolyzed ischemic stroke patients in whom diffusion-weighted imaging (DWI)/perfusion-weighted imaging (PWI) MRI was performed less than 12 hours of last known well and showed a PWI-DWI lesion mismatch, and who underwent follow-up neuroimaging at least 4 days after admission. Lesion growth was assessed by (1) absolute lesion growth and (2) percentage mismatch lost (PML). Univariate and multivariate regression analysis, and propensity score matching, were used to determine the effects of heparin on ischemic lesion growth. RESULTS: Of the 113 patients meeting study criteria, 59 received heparin within 24 hours. Heparin use was associated with ∼5-fold reductions in PML (3.5% versus 19.2%, P = .002) and absolute lesion growth (4.7 versus 20.5 mL, P = .009). In multivariate regression models, heparin independently predicted reduced PML (P = .04) and absolute lesion growth (P = .04) in the entire cohort, and in multiple subgroups (patients with and without proximal artery occlusion; DWI volume greater than 5 mL; cardio-embolic mechanism; DEFUSE-3 target mismatch). In propensity score matching analysis where patients were matched by admission NIHSS, DWI volume and proximal artery occlusion, heparin remained an independent predictor of PML (P = .048) and tended to predict absolute lesion growth (P = .06). Heparin treatment did not predict functional outcome at discharge or 90 days. CONCLUSION: Early heparin treatment in acute ischemic stroke patients with PWI-DWI mismatch attenuates ischemic lesion growth. Clinical trials with careful patient selection are warranted to investigate the potential ischemic protective effects of heparin.

Vasoactive Intestinal Peptide Decreases ß-Amyloid Accumulation and Prevents Brain Atrophy in the 5xFAD Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by extracellular deposits of fibrillary ß-amyloid (Aß) plaques in the brain that initiate an inflammatory process resulting in neurodegeneration. The neuronal loss associated with AD results in gross atrophy of affected regions causing a progressive loss of cognitive ability and memory function, ultimately leading to dementia. Growing evidence suggests that vasoactive intestinal peptide (VIP) could be beneficial for various neurodegenerative diseases, including AD. The study investigated the effects of VIP on 5xFAD, a transgenic mouse model of AD. Toward this aim, we used 20 5xFAD mice in two groups (n = 10 each), VIP-treated (25 ng/kg i.p. injection, three times per week) and saline-treated (the drug's vehicle) following the same administration regimen. Treatment started at 1 month of age and ended 2 months later. After 2 months of treatment, the mice were euthanized, their brains dissected out, and immunohistochemically stained for Aß40 and Aß42 on serial sections. Then, plaque analysis and stereological morphometric analysis were performed in different brain regions. Chronic VIP administration in 5xFAD mice significantly decreased the levels of Aß40 and Aß42 plaques in the subiculum compared to the saline treated 5xFAD mice. VIP treatment also significantly decreased Aß40 and Aß42 plaques in cortical areas and significantly increased the hippocampus/cerebrum and corpus callosum/cerebrum ratio but not the cerebral cortex/cerebrum ratio. In summary, we found that chronic administration of VIP significantly decreased Aß plaques and preserved against atrophy for related brain regions in 5xFAD AD mice.