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Background: Previous cohort studies have suggested an association between cerebral small vessel disease (cSVD) and "unexplained dizziness". The causality of this link remains uncertain, but it would be of significant clinical importance, considering the substantial number of patients presenting with unexplained dizziness is large. We aimed to investigate the causal effect of cSVD-related phenotypes on unexplained dizziness using a Mendelian randomization approach., Methods: Genetic instruments for each cSVD-related phenotype - white matter hyperintensity (WMH) volume, lacunar stroke (LS), perivascular spaces (PVS), and cerebral microbleeds (CMBs) - as well as unexplained dizziness were identified through large-scale genome-wide association studies. We conducted 2-sample Mendelian randomization analyses. The random-effects inverse-variance weighted (IVW) method was chosen for the primary analysis. For sensitivity analyses, we employed the weighted-median, MR-Egger, MR pleiotropy residual sum and outlier (MR-PRESSO), and leave-one-out analysis methods were implemented for the sensitivity analyses., Results: We successfully identified a significant causal effect of WMH volume on unexplained dizziness (odds ratio [95% CI], 1.12 [1.01-1.23]). However, we were unable to detect any significant causal effects of the other cSVD-related phenotypes on unexplained dizziness, with odds ratios [95% CI] of 1.03 [0.98-1.09] for LS, 0.75 [0.55-1.02] for white matter PVS, 1.02 [0.68-1.52] for basal ganglia PVS, 0.80 [0.43-1.51] for hippocampal PVS, 0.95 [0.90-1.00] for lobar CMBs, and 0.97 [0.92-1.01] for mixed CMBs respectively. The results from the sensitivity analyses were generally consistent with those of the primary analyses., Conclusions: This MR study supports a causal relationship between WMH, a phenotype associated with cSVD, and the risk of unexplained dizziness, but does not support such a relationship between other cSVD-related phenotypes and unexplained dizziness. These findings require further validation through randomized controlled trials, larger cohort studies, and MR studies based on more extensive GWASs., Competing Interests: Declaration of competing interest All authors disclosed no relevant relationships. The authors declared no potential conflicts of interest with respect to the research, author- ship, and/or publication of this article., (Copyright © 2024. Published by Elsevier Inc.)

Background: Ataxic hemiparesis (AH) is a well-recognized clinical lacunar stroke syndrome, characterized by paresis with ataxia on the same side of the body. It affects patients with stroke involving the basal ganglia, pons, internal capsule, corona radiata, and thalamus. In the past, lacunar syndrome denotes good functional recovery with low mortality and morbidity rate. However, recent evidence suggests AH has an association with more debilitating outcomes in the long term., Objective: To provide a comprehensive narrative review of published literatures on the topics related with AH and update clinical practice including rehabilitation., Methods: Literature review was performed by using the keywords "Subcortical Ataxia," "Lacunar Stroke," "Diaschisis", and "Ataxic Hemiparesis" on PubMed and Google Scholar Engines from 1978 to 2022. All papers published in English were reviewed and manual search of references from retrieved literature was performed for other relevant articles., Results: A comprehensive review was carried out on the following topics: neuroanatomical localization, pathogenesis, clinical features and clinical assessment scales, pharmacological and non-pharmacological modalities for ataxia treatment, prognosis, and outcome., Conclusion: AH imposes significant challenges on stroke survivors when it comes to remediation of balance and coordination. It is associated with increased risk of mortality, stroke recurrence, and dementia. Though application of the concept of neuroplasticity and the utilization of repetitive transcranial magnetic stimulation have shown early promising results, further research is needed to establish the practice guidelines for rehabilitation of patients with AH.

Objective: The carotid stiffness is an important factor in the pathogenesis of cerebrovascular small vessel disease. Our study aimed to evaluate the relation of the local arterial stiffness of the common carotid artery (CCA) to the hemodynamic forces and blood viscosity in patients with cerebral lacunar infarctions (LI)., Methods: Twenty-two patients with chronic LI and 15 age-matched controls were examined. An ultrasound examination of the CCA intima-media thickness (IMT), the parameters of local CCA stiffness: distensibility (DC) and compliance coefficients (CC), α and β stiffness indices and pulse wave velocity (PWV) was performed. The local hemodynamic forces were calculated: circumferential wall tension (CWT) and wall shear stress (WSS). Whole blood viscosity (WBV) and shear stresses at shear rates of 0.277 s- 1 to 94.5 s- 1 were measured in patients and controls., Results: Higher values of IMT, a significant decrease of DC and CC and an increase of α and β stiffness indices and PWV in the LI patients compared to the controls were obtained. A parallel significant increase in CWT and a decrease in WSS was found. An increase in WBV and a significant increase in shear stresses were detected. In the LI patients, the increased stiffness indices were associated with an increase in age, cholesterol and WBV at higher shear rates in the left CCA. In the controls, the IMT and stiffness indices correlated significantly with the hemodynamic factors and WBV in both CCAs, while the stiffness indices correlated with the hemodynamic forces in the left CCA., Conclusion: The results of the present study demonstrate different associations of the local carotid stiffness indices with the hemodynamic forces and WBV in patients with LI and controls.

Lacunar infarcts represent one of the most frequent subtypes of ischemic strokes and may represent the first recognizable manifestation of a progressive disease of the small perforating arteries, capillaries, and venules of the brain, defined as cerebral small vessel disease. The pathophysiological mechanisms leading to a perforating artery occlusion are multiple and still not completely defined, due to spatial resolution issues in neuroimaging, sparsity of pathological studies, and lack of valid experimental models. Recent advances in the endovascular treatment of large vessel occlusion may have diverted attention from the management of patients with small vessel occlusions, often excluded from clinical trials of acute therapy and secondary prevention. However, patients with a lacunar stroke benefit from early diagnosis, reperfusion therapy, and secondary prevention measures. In addition, there are new developments in the knowledge of this entity that suggest potential benefits of thrombolysis in an extended time window in selected patients, as well as novel therapeutic approaches targeting different pathophysiological mechanisms involved in small vessel disease. This review offers a comprehensive update in lacunar stroke pathophysiology and clinical perspective for managing lacunar strokes, in light of the latest insights from imaging and translational studies.

Insulin resistance and muscle weakness are risk factors for silent lacunar infarcts (SLI), but it is unclear whether they are still independent risk factors when adjusted for each other. In addition, the effect of their combination on SLI is completely unknown. We evaluated SLI, insulin sensitivity, and knee extensor muscle strength by magnetic resonance imaging, PREDIM, and dynamometer, respectively, in 1531 elderly people aged 65-84 years living in an urban area of Tokyo. Among the study subjects, 251 (16.4%) had SLI. Impaired insulin sensitivity (High; 1.00 [reference], Medium; 1.53 [95% confidence interval (CI) 0.94-2.48], Low; 1.86 [1.02-3.39], p for trend 0.047) and reduced muscle strength (High; 1.00 [reference], Medium; 1.40 [0.98-2.02], Low; 1.49 [1.04-2.15], p for trend 0.037) were independently associated with increased risk for SLI in the fully adjusted model. In terms of combined, subjects classified as having the lowest insulin sensitivity and lowest strength were 4.33 times (95% CI 1.64-11.45) more likely to have a SLI than those classified as having the highest insulin sensitivity and highest strength. Impaired insulin sensitivity and reduced muscle strength were independently associated with higher risk of SLI in elderly subjects, and their combination synergistically increased this risk., (© 2021. The Author(s).)

Objectives: Cerebral small vessel disease (SVD) is often associated with hypertension and may evolve towards intracerebral hemorrhage (ICH) or lacunar ischemic stroke. However, the factors favoring the evolution towards ICH or lacunar stroke are not well understood., Materials and Methods: This retrospective study included 326 consecutive patients (71.1±13.2 years, 38% women): 143 with deep ICH and 183 with lacunar lesions (LL) <2 cm, which were visible in a deep location on brain CT scan. Among LL patients, 143 had a small-artery occlusion (SAO) stroke according to the TOAST classification. Clinical characteristics plus laboratory and neuroradiological variables of these patients had been prospectively collected and a subgroup underwent echocardiography., Results: In multivariate analysis, ICH patients (97% hypertensive), compared to SAO patients (89% hypertensive), had greater left ventricular wall thickness (LVWT; OR 4.15, 95%CI 1.64-10.53, for those with LVWT ≥ 1.4 cm, 70% of whom were hemorrhagic) and lower prevalence of white matter lesions (OR 0.30, 95%CI 0.13-0.70), ever smokers (OR 0.39, 95%CI 0.18-0.82) and diabetics (OR 0.29, 95% CI 0.10-0.84). Moreover, ICH patients had a greater prevalence of atrial fibrillation than LL patients (OR 3.14, 95%CI 1.11-8.93), and so they were more often anticoagulated., Conclusions: Most SVD patients were hypertensive, but those evolving towards ICH were characterized by organ damage at the cardiac level (increase in LVWT and atrial fibrillation), while those evolving towards lacunar stroke were characterized by a higher prevalence of smokers and diabetics, and by organ damage at the cerebral level (white matter lesions)., Competing Interests: Declaration of Competing Interest none., (Copyright © 2021 Elsevier Inc. All rights reserved.)

[Figure: see text].

Background: Emerging evidence shows sex differences in manifestations of vascular brain injury in memory clinic patients. We hypothesize that this is explained by sex differences in cardiovascular function., Objective: To assess the relation between sex and manifestations of vascular brain injury in patients with cognitive complaints, in interaction with cardiovascular function., Methods: 160 outpatient clinic patients (68.8±8.5 years, 38% female) with cognitive complaints and vascular brain injury from the Heart-Brain Connection study underwent a standardized work-up, including heart-brain MRI. We calculated sex differences in vascular brain injury (lacunar infarcts, non-lacunar infarcts, white matter hyperintensities [WMHs], and microbleeds) and cardiovascular function (arterial stiffness, cardiac index, left ventricular [LV] mass index, LV mass-to-volume ratio and cerebral blood flow). In separate regression models, we analyzed the interaction effect between sex and cardiovascular function markers on manifestations of vascular brain injury with interaction terms (sex*cardiovascular function marker)., Results: Males had more infarcts, whereas females tended to have larger WMH-volumes. Males had higher LV mass indexes and LV mass-to-volume ratios and lower CBF values compared to females. Yet, we found no interaction effect between sex and individual cardiovascular function markers in relation to the different manifestations of vascular brain injury (p-values interaction terms > 0.05)., Conclusion: Manifestations of vascular brain injury in patients with cognitive complaints differed by sex. There was no interaction between sex and cardiovascular function, warranting further studies to explain the observed sex differences in injury patterns.

Lacunar stroke (LS) accounts for about one-quarter of all acute ischemic strokes, represents an important marker of cerebral small vessel disease (CSVD), and has prognostic significance in terms of recurrent vascular events and vascular cognitive impairment. Our understanding of the etiology and pathogenesis of LS is largely based on the meticulous postmortem work of C. Miller Fisher in the late 1960s, with scarce subsequent pathological analysis of the "lacunar hypothesis" and no reliable approaches for direct in vivo imaging of the small intracranial vessels. The recent development of high-resolution MRI, which allows both large-vessel wall and perforating arteries to be imaged in one setting, provides the opportunity to advance understandings of the clinical mechanisms, imaging characteristics, and pathogenesis of LS. Given accumulating evidence of endothelial dysfunction and blood-brain-barrier disruption as early features of CSVD-related LS, advanced imaging may allow various underlying pathogenetic mechanisms to be defined and for better targeting of therapeutic approaches in LS. In this review, progress in understanding the pathogenesis of LS is outlined, covering pathology, pathophysiology, and imaging characteristics, with a focus toward future directions in the complex entity of LS., (© 2021 S. Karger AG, Basel.)

Objective: To determine whether cerebral small vessel disease or disability modify the effect of SBP treatment on cognitive and vascular outcomes in older patients with recent lacunar stroke., Methods: Participants aged at least 65 years of the Secondary Prevention of Small Subcortical Strokes Trial were randomized to a higher (130-149 mmHg) or lower (<130 mmHg) SBP target. The primary outcome was change in cognitive function (Cognitive Abilities Screening Instrument); secondary outcomes were incident mild cognitive impairment, stroke, major vascular events (all-stroke, myocardial infarction), and all-cause death. Results were stratified by severity of white matter hyperintensities (WMH; none/mild, moderate, severe) on baseline MRI, and by disability (no vs. at least one limitation in activities of daily living)., Results: One thousand, two hundred and sixty-three participants (mean age 73.8 ± 5.9 years, 40% women) were included. Participants with severe WMH or disability had worse cognitive function at baseline and after a mean follow-up of 3.9 years. No significant interactions existed between treatment group and effect modifiers (WMH, disability) for change in cognitive function (P for interaction 0.42 and 0.66, respectively). A lower SBP target appeared more beneficial among those with worse WMH burden for vascular outcomes (P for interaction = 0.01 for stroke and 0.03 for major vascular events)., Conclusion: There was no difference in the effect of lowering SBP to less than 130 mmHg on cognitive function by cerebral small vessel disease or disability among older adults with a history of lacunar stroke. Those with evidence of small vessel disease may derive greater benefit from lower SBP on prevention of subsequent vascular events., Trial Registration: Clinicaltrials.gov Identifier: NCT00059306.

Immune-inflammatory, metabolic, oxidative, and nitrosative stress (IMO&NS) pathways and, consequently, neurotoxicity are involved in acute ischemic stroke (IS). The simultaneous assessment of multiple IMO&NS biomarkers may be useful to predict IS and its prognosis. The aim of this study was to identify the IMO&NS biomarkers, which predict short-term IS outcome. The study included 176 IS patients and 176 healthy controls. Modified Rankin scale (mRS) was applied within 8 h after IS (baseline) and 3 months later (endpoint). Blood samples were obtained within 24 h after hospital admission. IS was associated with increased white blood cell (WBC) counts, high sensitivity C-reactive protein (hsCRP), interleukin (IL-6), lipid hydroperoxides (LOOHs), nitric oxide metabolites (NOx), homocysteine, ferritin, erythrocyte sedimentation rate (ESR), glucose, insulin, and lowered iron, 25-hydroxyvitamin D [25(OH)D], total cholesterol, and high-density lipoprotein (HDL) cholesterol. We found that 89.4% of the IS patients may be correctly classified using the cumulative effects of male sex, systolic blood pressure (SBP), glucose, NOx, LOOH, 25(OH)D, IL-6, and WBC with sensitivity of 86.2% and specificity of 93.0%. Moreover, increased baseline disability (mRS ≥ 3) was associated with increased ferritin, IL-6, hsCRP, WBC, ESR, and glucose. We found that 25.0% of the variance in the 3-month endpoint (mRS) was explained by the regression on glucose, ESR, age (all positively), and HDL-cholesterol, and 25(OH)D (both negatively). These results show that the cumulative effects of IMO&NS biomarkers are associated with IS and predict a poor outcome at 3-month follow-up.

Objective: To assess the association of baseline imaging markers of cerebral small vessel disease (SVD) and brain frailty with clinical outcome after acute stroke in the Efficacy of Nitric Oxide in Stroke (ENOS) trial., Methods: ENOS randomized 4,011 patients with acute stroke (<48 hours of onset) to transdermal glyceryl trinitrate (GTN) or no GTN for 7 days. The primary outcome was functional outcome (modified Rankin Scale [mRS] score) at day 90. Cognition was assessed via telephone at day 90. Stroke syndrome was classified with the Oxfordshire Community Stroke Project classification. Brain imaging was adjudicated masked to clinical information and treatment and assessed SVD (leukoaraiosis, old lacunar infarcts/lacunes, atrophy) and brain frailty (leukoaraiosis, atrophy, old vascular lesions/infarcts). Analyses used ordinal logistic regression adjusted for prognostic variables., Results: In all participants and those with lacunar syndrome (LACS; 1,397, 34.8%), baseline CT imaging features of SVD and brain frailty were common and independently associated with unfavorable shifts in mRS score at day 90 (all participants: SVD score odds ratio [OR] 1.15, 95% confidence interval [CI] 1.07-1.24; brain frailty score OR 1.25, 95% CI 1.17-1.34; those with LACS: SVD score OR 1.30, 95% CI 1.15-1.47, brain frailty score OR 1.28, 95% CI 1.14-1.44). Brain frailty was associated with worse cognitive scores at 90 days in all participants and in those with LACS., Conclusions: Baseline imaging features of SVD and brain frailty were common in lacunar stroke and all stroke, predicted worse prognosis after all acute stroke with a stronger effect in lacunar stroke, and may aid future clinical decision-making., Identifier: ISRCTN99414122., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Purpose- Multilineage-differentiating stress-enduring cells are endogenous nontumorigenic reparative pluripotent-like stem cells found in bone marrow, peripheral blood, and connective tissues. Topically administered human multilineage-differentiating stress-enduring cells into rat/mouse stroke models differentiated into neural cells and promoted clinically relevant functional recovery. However, critical questions on the appropriate timing and dose, and safety of the less invasive intravenous administration of clinical-grade multilineage-differentiating stress-enduring cell-based product CL2020 remain unanswered. Methods- Using an immunodeficient mouse lacunar model, CL2020 was administered via the cervical vein in different doses (high dose=5×10 4 cells/body; medium dose=1×10 4 cells/body; low dose=5×10 3 cells/body) at subacute phase (≈9 days after onset) and chronic phase (≈30 days). Cylinder test, depletion of human cells by diphtheria toxin administration, immunohistochemistry, and human specific-genome detection were performed. Results- Tumorigenesis and adverse effects were not detected for up to 22 weeks. The high-dose group displayed significant functional recovery compared with the vehicle group in cylinder test in subacute-phase-treated and chronic-phase-treated animals after 6 weeks and 8 weeks post-injection, respectively. In the high-dose group of subacute-phase-treated animals, robust and stable recovery in cylinder test persisted up to 22 weeks compared with the vehicle group. In both groups, intraperitoneal injection of diphtheria toxin abrogated the functional recovery. Anti-human mitochondria revealed CL2020 distributed mainly in the peri-infarct area at 1, 10, and 22 weeks and expressed NeuN (neuronal nuclei)- and MAP-2 (microtubule-associated protein-2)-immunoreactivity. Conclusions- Intravenously administered CL2020 was safe, migrated to the peri-infarct area, and afforded functional recovery in experimental stroke.

Background: The link between arterial stiffness and mild cognitive impairment (MCI) is receiving increasing attention, and the goal of this study was to explore the relationship among the ankle brachial index (ABI), brachial-ankle pulse wave velocity (Ba-PWV), and MCI in patients with acute lacunar infarction (ALI)., Methods: A total of 103 hospitalized patients with ALI were divided into a non-MCI group (n = 41) and an MCI group (n = 62) according to their Montreal Cognitive Assessment (MoCA) scores. A binary logistic regression model was used to assess the association among ABI, Ba-PWV, and MCI after adjusting for confounding factors. Spearman correlation was utilized to analyse the correlations between ABI, Ba-PWV, and MoCA total scores and sub-scores in ALI patients., Results: Participants with cognitive impairment had significantly higher Ba-PWV and lower ABI than those with normal cognition. Correlation analysis suggested that Ba-PWV (r = -0.854, p < 0.05) and ABI (r = 0.734, p < 0.05) were correlated with MoCA total scores; of all MoCA sub-scores, visuospatial/executive function was the most strongly correlated with the vascular variables. In the binary logistic regression analysis, Ba-PWV (odds ratio [OR] = 4.507, 95% confidence interval [CI] = 2.152-9.441) and ABI (OR = 1.124, 95% CI = 1.015-1.254) were significantly associated with MCI, even after adjusting for lipoprotein (a) and systolic and diastolic blood pressure., Conclusion: The present study suggested that a higher Ba-PWV and a lower ABI were independent risk factors for MCI in patients with ALI., (© 2020 S. Karger AG, Basel.)

Background and Aims: The precise mechanisms underlying the expansion of lacunar and giant lacunar infarction remain unclear. We aimed to determine risk factors for lacunar and giant lacunar infarction and to clarify differences in pathophysiological mechanisms for these two groups., Methods: Patients were selected from a comprehensive stroke center with ≤24 h from onset to initial magnetic resonance imaging with lacunar and giant lacunar infarction. All patients underwent a second magnetic resonance imaging during hospitalization. Infarct size was calculated and compared by the positive region on diffusion-weighted imaging. Factors related to infarct expansion were evaluated separately in the two groups., Results: We screened 1558 consecutive ischemic stroke patients, including 154 patients with small vessel disease (lacunar infarction, 81 patients; giant lacunar infarction, 73 patients). Age (odds ratio (OR), 0.899; 95% confidence interval (CI), 0.824-0.981, p = 0.016), higher cardio-ankle vascular index (OR, 6.011; 95%CI, 2.319-15.581, p < 0.001), higher uric acid (OR, 2.584; 95%CI, 1.091-6.121, p = 0.031), and lower/normal low-density lipoprotein (LDL)-cholesterol (OR, 0.718; 95%CI, 0.557-0.926, p = 0.011) were independently associated with infarct expansion in lacunar infarction patients. Concerning giant lacunar infarction, higher LDL-cholesterol (OR 1.509, 95%CI 1.083-2.103; p = 0.015) and lower/normal body mass index (OR 0.725, 95%CI 0.567-0.926; p = 0.010) were factors independently associated with infarct expansion., Conclusions: Risk factors for infarct expansion differed between lacunar and giant lacunar infarction. The underlying pathophysiological mechanisms for infarct expansion in these two groups should be recognized individually., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Cerebral small vessel disease (SVD) lesions on MRI are common in patients with cognitive impairment. It has been suggested that cerebral hypoperfusion is involved in the etiology of these lesions., Objective: The aim of the study was to determine the relationship between cerebral blood flow (CBF) and SVD burden in patients referred to a memory clinic with SVD on MRI., Method: We included 132 memory clinic patients (mean age 73 ± 10, 56% male) with SVD on MRI. We excluded patients with large non-lacunar cortical infarcts. Global CBF (mL/min per 100 mL of brain tissue) was derived from 2-dimensional phase-contrast MRI focused on the internal carotid arteries and the basilar artery. SVD burden was defined as the sum of (each 1 point): white matter hyperintensities (WMHs) Fazekas 1 or more, lacunes, microbleeds (MBs), or enlarged perivascular spaces (PVS) presence, and each SVD feature separately. Linear regression analyses were performed to study the association between CBF and SVD burden, age- and sex-adjusted., Results: Median SVD burden score was 2, 36.4% of patients had MBs, 35.6% lacunar infarcts, 48.4% intermediate to severe enlarged PVS, and 57.6% a WMH Fazekas score 2 or more. Median WMH volume was 21.4 mL (25% quartile: 9.6 mL, 75% quartile: 32.5 mL). Mean CBF ± SD was 44.0 ± 11.9 mL/min per 100 mL brain. There was no relation between CBF and overall SVD burden (CBF difference per burden score point [95% CI]: -0.5 [-2.4; 1.4] mL/min/100 mL brain, p = 0.9). CBF did also not differ according to presence or absence or an high burden of any of the individual SVD features. Moreover, there was no significant relation between WMH volume and CBF (CBF difference per ml increase in WMH [95% CI] -0.6 [-1.5; 0.3] mL/min/100 mL brain p = 0.2)., Conclusion: Global CBF was not related to overall SVD burden or with individual SVD features in this memory clinic cohort, indicating that in this setting these lesions were not primarily due to cerebral hypoperfusion., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Background: Intravenous thrombolysis (IVT) for lacunar stroke (LS) is debated, as the underlying pathophysiological mechanism may not be thrombogenic., Aims: To investigate outcomes after IVT in LS in the SITS International Stroke Thrombolysis Register and perform a meta-analysis., Methods: LS was identified by both baseline NIHSS-subscores and discharge ICD-10 codes, and contrasted by IVT to non-IVT treated. IVT patients were predominantly from Europe, non-IVT patients predominantly from South America and Asia. Outcome measurements were functional independence (modified Rankin Scale [mRS] score ≤2), excellent outcome (mRS ≤ 1), and mortality at three months. Matched-control comparisons of symptomatic intracerebral hemorrhage (SICH) between IVT-treated LS and IVT-treated non-LS patients were performed. Additionally, we performed a meta-analysis., Results: Median age for IVT-treated LS patients ( n  = 4610) was 66 years vs. 64 years and NIHSS score was 6 vs. 3, compared to non-IVT-treated LS ( n  = 1221). Univariate outcomes did not differ; however, IVT-treated LS patients had higher adjusted odds ratios (aOR) for functional independence (aOR = 1.65, 95% CI = 1.28-2.13) but similar mortality at three months (aOR = 0.57, 0.29-1.13) than non-IVT-LS. Propensity-score matched analysis showed that IVT-treated LS patients had a 7.1% higher chance of functional independency than non-IVT LS patients ( p  < 0.001). IVT-treated LS patients had lower odds for SICH (aOR = 0.33, 0.19-0.58 per SITS, aOR = 0.40, 0.27-0.57 per ECASS-2) than matched non-LS controls, which was mirrored in the meta-analysis., Conclusions: Our adjusted results show that IVT treatment in LS patients was associated with better functional outcome than non-IVT-treated LS and less SICH than IVT-treated non-LS patients.

Background and Purpose: To assess whether neuroimaging markers of chronic cerebral small vessel disease (cSVDm) influence early recovery after acute ischemic stroke (AIS)., Methods: Retrospective analysis of patients diagnosed with AIS and included in the Spanish Neurological Society Stroke Database., Inclusion Criteria: (1) Brain MRI performed after acute stroke and (2) Premorbid modified Rankin scale (mRS) = 0., Exclusion Criteria: (1) Uncommon stroke etiologies, (2) AIS not confirmed on neuroimaging, or (3) Old territorial infarcts on neuroimaging. Patients scored from 0 to 2 according to the amount of cSVDm. Patients were divided into lacunar ischemic stroke (LIS) and nonlacunar ischemic stroke (NLIS) groups according to TOAST classification., Primary Outcome: Distribution of mRS at discharge., Secondary Outcomes: NIHSS improvement more than or equal to 3 at 24 hours and at discharge, NIHSS worsening more than or equal to 3 points at 24 hours., Results: We studied 4424 patients (3457 NLIS, 967 LIS). The presence of cSVDm increased the risk of worsening 1 category on the mRS at discharge in the LIS group ([1] cSVDm: OR 1.89 CI 95% 1.29-2.75, P = .001. [2] cSVDm: OR 1.87, CI 95% 1.37-2.56 P = .001) and was an independent factor for not achieving an improvement more than or equal to 3 points on the NIHSS at discharge for all the patients and the LIS group (all stroke patients: [1] cSVDm: OR 0.81 CI 95% .68-.97 P = .022. [2] cSVD: OR 0.58 CI95% .45-.77, P = .001./LIS: [1] cSVDm: OR 0.64, CI 95% .41-.98, P = .038. [2] cSVDm: OR 0.43, CI 95% .24-.75 P = .003)., Conclusions: Pre-existing SVD limits early functional and neurological recovery after AIS, especially in LIS patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background and Purpose- The apnea-hypopnea index (AHI) is associated with cerebral small vessel disease (cSVD), but pathogenesis of this association is elusive. We aimed to assess the effect of nighttime heart rate variability (HRV)-as a proxy of sympathetic upregulation-on the aforementioned association. Methods- Atahualpa residents aged ≥60 years undergoing brain magnetic resonance imaging, polysomnography, and 24-hour Holter monitoring (N=176) were included. The presence of moderate-to-severe white matter hyperintensities, deep cerebral microbleeds, lacunar infarcts, and >10 enlarged basal ganglia perivascular spaces were added for estimating the cSVD score. Interaction models were fitted to assess the effect modification of nighttime HRV in the association between the AHI and the cSVD score, and mediation analysis was utilized to assess the proportion of total effect by nighttime HRV on this association. Results- Generalized linear models showed a significant association between the AHI and the cSVD score (P=0.025), as well as a significant inverse association between nighttime HRV and the cSVD score (P=0.002), but no association between daytime HRV and the cSVD score (P=0.097). Interaction models showed a significant interaction of nighttime HRV on the association between AHI and the cSVD score (P=0.001), and mediation analysis found that the percent of total effect between AHI and cSVD score mediated by HRV was 30.8%. Predictive marginal means of the cSVD score were highly significant when the 10th percentile of nighttime HRV was compared across categories of 10th and 90th percentiles of the AHI (cSVD score margins, 0.61 [95% CI, 0.37-0.86] versus 1.67 [95% CI, 1.26-2.09]). Contour plots showed the effect of nighttime (but not daytime) HRV on the association between AHI and the cSVD score. Conclusions- This study shows an important effect of nighttime HRV on the association between the AHI and the cSVD score and provides further support for the role of sympathetic overactivity on this association.

Background and Aims: The association between carotid wall shear stress (WSS) and cerebral small vessel disease has yet to be fully elucidated. The major purpose of this study was to investigate this association in older subjects., Methods: Common carotid artery WSS, endothelial function, white matter hyperintensities (WMH), lacunes, and microbleeds were assessed in 1396 older adults. Participants were followed-up for an average of 69.7 months., Results: Mean (M) and peak (P) WSS and changes in endothelial function were independently associated with changes in WMH volume and fraction, lacune counts, and microbleed counts (all p < 0.05). The risks of new-incident Fazekas scale ≥2 [hazard ratio (HR) with 95% confidence interval (CI): 2.141 (1.469-3.119), p = 0.005 and 1.731 (1.197-2.505), p = 0.004, respectively], lacunes [HR (95% CI): 2.034 (1.369-3.022), p < 0.001 and 1.693 (1.151-2.490), p = 0.003, respectively], and microbleeds [HR (95% CI): 2.311 (1.509-3.541), p < 0.001 and 2.208 (1.299-3.751), p < 0.001, respectively] were significantly higher in the lowest quartile group than in the higher quartile group, as classified by either MWSS or PWSS, after adjustment for confounders., Conclusions: Low carotid WSS is an independent risk factor for the progression of cerebral small vessel disease in older adults., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Physical inactivity is a major modifiable risk factor for stroke. The aim was to explore if stroke patients admitted with lacunar stroke adhere to the international recommendations on physical activity prestroke (≥150 minutes of moderate-intensity activity, or ≥75 minutes of vigorous-intensity activity, or an equivalent combination). Further, to assess association between prestroke physical activity and cardiovascular disease (CVD) risk factors., Methods: A cross-sectional study, including patients with lacunar stroke according to the Trial of Org 10172 in Acute Stroke Treatment criteria. Data collected included prestroke physical activity using the self-reported Physical Activity Scale. Cardiorespiratory fitness was estimated as the power output from the Graded Cycling Test with Talk Test and sociodemographic factors including age, sex, education, and CVD risk factors including pre-existing diabetes, history of hypertension, body mass index, and lipids were assessed., Results: We included 19 women and 52 men (mean age 64 years). Overall, 79% of the recruited patients adhered to the physical activity recommendations prestroke, but only 35% did vigorous-intensity activity. Prestroke physical activity was associated with a history of hypertension., Conclusions: A high proportion of the lacunar stroke patients reported to adhere to the recommendations on physical activity prestroke; however, only one third engaged in vigorous-intensity activity. Studies are warranted to investigate if vigorous-intensity activity is effective as secondary prevention in patients with a lacunar stroke., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Since the term "lacune" was adopted in the 1800s to describe infarctions from cerebral small vessels, their underlying pathophysiological basis remained obscure until the 1960s when Charles Miller Fisher performed several autopsy studies of stroke patients. He observed that the vessels displayed segmental arteriolar disorganization that was associated with vessel enlargement, hemorrhage, and fibrinoid deposition. He coined the term "lipohyalinosis" to describe the microvascular mechanism that engenders small subcortical infarcts in the absence of a compelling embolic source. Since Fisher's early descriptions of lipohyalinosis and lacunar stroke (LS), there have been many advancements in the understanding of this disease process. Herein, we review lipohyalinosis as it relates to modern concepts of cerebral small vessel disease (cSVD). We discuss clinical classifications of LS as well as radiographic definitions based on modern neuroimaging techniques. We provide a broad and comprehensive overview of LS pathophysiology both at the vessel and parenchymal levels. We also comment on the role of biomarkers, the possibility of systemic disease processes, and advancements in the genetics of cSVD. Lastly, we assess preclinical models that can aid in studying LS disease pathogenesis. Enhanced understanding of this highly prevalent disease will allow for the identification of novel therapeutic targets capable of mitigating disease sequelae., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Lacunar strokes are appropriately named for their ability to cavitate and form ponds or "little lakes" (Latin: lacune -ae meaning pond or pit is a diminutive form of lacus meaning lake). They account for a substantial proportion of both symptomatic and asymptomatic ischemic strokes. In recent years, there have been several advances in the management of large vessel occlusions. New therapies such as non-vitamin K antagonist oral anticoagulants and left atrial appendage closure have recently been developed to improve stroke prevention in atrial fibrillation; however, the treatment of small vessel disease-related strokes lags frustratingly behind. Since Fisher characterized the lacunar syndromes and associated infarcts in the late 1960s, there have been no therapies specifically targeting lacunar stroke. Unfortunately, many therapeutic agents used for the treatment of ischemic stroke in general offer only a modest benefit in reducing recurrent stroke while adding to the risk of intracerebral hemorrhage and systemic bleeding. Escalation of antithrombotic treatments beyond standard single antiplatelet agents has not been effective in long-term lacunar stroke prevention efforts, unequivocally increasing intracerebral hemorrhage risk without providing a significant benefit. In this review, we critically review the available treatments for lacunar stroke based on evidence from clinical trials. For several of the major drugs, we summarize the adverse effects in the context of this unique patient population. We also discuss the role of neuroprotective therapies and neural repair strategies as they may relate to recovery from lacunar stroke., (Copyright © 2019 Elsevier Inc. All rights reserved.)

CNS small vessel disease (CSVD) causes 25% of strokes and contributes to 45% of dementia cases. Prevalence increases with age, affecting about 5% of people aged 50 years to almost 100% of people older than 90 years. Known causes and risk factors include age, hypertension, branch atheromatous disease, cerebral amyloid angiopathy, radiation exposure, immune-mediated vasculitides, certain infections, and several genetic diseases. CSVD can be asymptomatic; however, depending on location, lesions can cause mild cognitive dysfunction, dementia, mood disorders, motor and gait dysfunction, and urinary incontinence. CSVD is diagnosed on the basis of brain imaging biomarkers, including recent small subcortical infarcts, white matter hyperintensities, lacunes, cerebral microbleeds, enlarged perivascular spaces, and cerebral atrophy. Advanced imaging modalities can detect signs of disease even earlier than current standard imaging techniques. Diffusion tensor imaging can identify altered white matter connectivity, and blood oxygenation level-dependent imaging can identify decreased vascular reactivity. Pathogenesis is thought to begin with an etiologically specific insult, with or without genetic predisposition, which results in dysfunction of the neurovascular unit. Uncertainties regarding pathogenesis have delayed development of effective treatment. The most widely accepted approach to treatment is to intensively control well-established vascular risk factors, of which hypertension is the most important. With better understanding of pathogenesis, specific therapies may emerge. Early identification of pathologic characteristics with advanced imaging provides an opportunity to forestall progression before emergence of symptoms., (© 2019 American Academy of Neurology.)

Objective: Many studies examining stroke outcomes focus on more severe strokes or have short follow-up periods, so the long-term outcomes post-minor ischaemic stroke are unclear., Methods: We recruited participants from inpatient and outpatient services with a lacunar or minor cortical ischaemic stroke (National Institutes of Health Stroke Scale score <8) and assessed current and premorbid cognitive functioning (Addenbrooke's Cognitive Examination-Revised (ACE-R), National Adult Reading Test (NART)), physical functioning (Timed Get Up and Go (TUG), 9-Hole Peg Test (9HPT)), dependency (modified Rankin Scale (mRS)), depression (Beck's Depression Inventory) in-person and remotely (Stroke Impact Scale)., Results: We followed up 224/264 participants at 3 years (mean age at index stroke=67, 126 (56%) men, 25 non-contactable, 15 declined): 66/151 (44%) had cognitive impairment, mean ACE-R 88 (SD 9, range 54-100/100), 61/156 (39%) had depression and 26/223 (12%) were dependent (mRS=3-5). Cognitive impairment at 3 years affected all ACE-R subdomains and was associated with ACE-R 1 year (β=1.054, p<0.001) and NART (β=1.023, p<0.05). Poor physical function was associated with stroke severity (TUG, β=1.064, p<0.01) and recurrent stroke (9HPT, β=1.130, p<0.05 right, β=1.214, p<0.05 left). Higher ACE-R scores were associated with faster TUG (β=-0.279, p<0.05) and 9HPT (right β=-0.257, p<0.05; left β=-0.302, p=0.05) and inversely with dependency (mRS=3-5, OR 0.88, 95% CI 0.80 to 0.97). We adjusted analyses for demographic, stroke and known risk factors. In-person and remote assessments were highly correlated., Conclusions: Cognitive, physical impairments and depression are common and interrelated 3 years after minor stroke. Cognitive and physical impairments require rehabilitation after minor stroke and argue for better integration of stroke and dementia services., Competing Interests: Competing interests: VC reports grants from NHS Research Scotland and Chest, Heart, Stroke Scotland, which funded the study. JMW reports grants from Chest, Heart, Stroke Scotland, grants from the Sackler Foundation, European Union Horizon 2020 grant No 666881, ‘SVDs@target’, Fondation Leducq, UK Medical Research Council, Stroke Association, Alzheimer’s Society and British Heart Foundation., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

BACKGROUND The aim of this study was to investigate the correlations of C-reactive protein (CRP), interleukin-6 (IL-6), and insulin resistance (IR) with cerebral infarction in hypertensive patients. MATERIAL AND METHODS A total of 80 patients with cerebral infarction admitted to our hospital from March 2016 to November 2017 were selected and divided into 2 groups according to the diameter of cerebral infarction, namely, lacunar cerebral infarction group (n=40) and cerebral infarction group (n=40). The levels of high-sensitivity CRP (hs-CRP) and IL-6, homeostasis model assessment of IR (HOMA-IR) index and blood pressure level were compared between the 2 groups. The correlations of hs-CRP level, IL-6 level, and IR with the diameter of cerebral infarction, as well as the relationships of hs-CRP level and IR with the neurological function score after cerebral infarction were analyzed. RESULTS The levels of hs-CRP and IL-6 in the cerebral infarction group were significantly higher than those in the lacunar cerebral infarction group (P<0.05). The cerebral infarction group had a markedly higher HOMA-IR index than the lacunar cerebral infarction group (P<0.05), but it had remarkably decreased systolic blood pressure and diastolic blood pressure compared with those in the lacunar cerebral infarction group (P<0.05). There were positive correlations of hs-CRP level, IL-6 level, and IR with the diameter of cerebral infarction (P<0.05). The hs-CRP level and IR had positive correlations with the neurological function score after cerebral infarction (P<0.05). CONCLUSIONS In hypertensive patients complicated with cerebral infarction, the body's inflammatory factors, and IR are positively correlated with the diameter of cerebral infarction, as well as the neurological prognosis of the patients.

We report 3 cases (69-year-old man, 71-year-old man, and 82-year-old woman) of isolated cerebellar nodulus stroke patients, who presented with positional vertigo alone that lasted only for 2-4 days. Brain magnetic resonance imaging helped diagnosing these cases. Although rare, clinicians should be aware of isolated cerebellar nodulus stroke, when facing with patients with paroxysmal vertigo of acute onset., (Copyright © 2018. Published by Elsevier Inc.)

Introduction: Usefulness of intravenous thrombolysis in patients with acute lacunar cerebral infarction is questionable. The aim of this study was to evaluate the efficacy and safety of intravenous thrombolysis in patients with lacunar infarction in comparison with patients with nonlacunar infarction as well as with patients with lacunar infarction who were not treated with intravenous thrombolysis., Materials and Methods: In the first part of the study, among patients with acute ischemic stroke treated with intravenous thrombolysis, characteristics and outcomes of 46 patients with lacunar and 221 patients with nonlacunar infarction were compared. In the second part, 46 patients with lacunar infarction treated with intravenous thrombolysis were compared with 45 lacunar infarction patients who were not treated with intravenous thrombolysis., Results: Patients with lacunar infarction had a lower National Institutes of Health Stroke Scale score (9.2 versus 13.9, P < .001), a greater Alberta Stroke Program Early computed tomography (CT) score (9.7 versus 9.2, P = .002), a lower prevalence of atrial fibrillation (6.5% versus 41.2%, P < .001), and significantly more frequently an excellent outcome after 3 months (76.1% versus 36.2%, P < .001) compared with patients with nonlacunar infarction. Among patients with lacunar infarction, an excellent outcome at discharge was significantly more frequent in the intravenous thrombolysis group (41.3% versus 15.6%, P = .01), and the length of hospitalization was significantly shorter (9.5 days versus 14.3 days, P = .002). There was no hemorrhagic transformation among patients with lacunar infarction treated with intravenous thrombolysis., Conclusion: Intravenous thrombolysis has proven to be effective and safe in patients with lacunar infarction and should always be applied if there are no absolute contraindications., (Copyright © 2018. Published by Elsevier Inc.)

Background and Aims: In addition to overt stroke lesions, co-occurring covert lesions, including white matter hyperintensities (WMH) and covert lacunar infarcts (CLI), contribute to poststroke outcome. The purpose of this study was to examine the relationship between covert lesions, and motor and cognitive outcomes in individuals with chronic stroke., Methods: Volumetric quantification of clinically overt strokes, covert lesions (periventricular and deep: pWMH, dWMH, pCLI, dCLI), ventricular and sulcal CSF (vCSF, sCSF), and normal appearing white (NAWM) and gray matter (NAGM) was performed using structural magnetic resonance imaging. We assessed motor impairment and function, and global cognition, memory, and other cognitive domains. When correlation analysis identified more than one MR parameter relating to stroke outcomes, we used regression modeling to identify which factor had the strongest impact., Results: Neuropsychological and brain imaging data were collected from 30 participants at least 6 months following a clinically diagnosed stroke. Memory performance related to vCSF (r = -0.52, P = .004). The strongest predictor of nonmemory domains was pCLI (r 2 = 0.28, P = .004). Motor impairment and function were most strongly predicted by the volume of stroke and NAWM (r 2 = 0.36; P = .001), and dWMH (r 2 = 0.39; P = .001) respectively., Conclusions: Covert lesion type and location have important consequences for post-stroke cognitive and motor outcome. Limiting the progression of covert lesions in aging populations may enhance the degree of recovery post-stroke., (Copyright © 2018. Published by Elsevier Inc.)

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common familial cerebral small vessel disease, caused by NOTCH3 gene mutations. The aim of our study was to identify clinical and neuroradiological features which would be useful in identifying which patients presenting with lacunar stroke and TIA are likely to have CADASIL., Methods: Patients with lacunar stroke or TIA were included in the present study. For each patient, demographic and clinical data were collected. MRI images were centrally analysed for the presence of lacunar infarcts, microbleeds, temporal lobe involvement, global atrophy and white matter hyperintensities., Results: 128 patients (mean age 56.3 ± 12.4 years) were included. A NOTCH3 mutation was found in 12.5% of them. A family history of stroke, the presence of dementia and external capsule lesions on MRI were the only features significantly associated with the diagnosis of CADASIL. Although thalamic, temporal pole gliosis and severe white matter hyperintensities were less specific for CADASIL diagnosis, the combination of a number of these factors together with familial history for stroke result in a higher positive predictive value and specificity., Conclusions: A careful familial history collection and neuroradiological assessment can identify patients in whom NOTCH3 genetic testing has a higher yield.

Background: Recovery in function after stroke involves neuroplasticity and adaptation to impairments. Few studies have examined differences in late functional improvement beyond 3 months among stroke subtypes, although interventions for late restorative therapies are often studied in lacunar stroke. Therefore, we compared rates of functional improvement beyond 3 months in patients with lacunar versus non-lacunar strokes., Methods: In a prospective, population-based cohort of 3-month ischaemic stroke survivors (Oxford Vascular Study; 2002-2014), we examined changes in functional status (modified Rankin Scale (mRS), Rivermead Mobility Index (RMI), Barthel Index (BI)) in patients with lacunar versus non-lacunar strokes from 3 to 60 months poststroke, stratifying by age. We used logistic regression adjusted for age, sex and baseline disability to compare functional improvement (≥1 mRS grades, ≥1 RMI points and/or ≥2 BI points), particularly from 3 to 12 months., Results: Among 1425 3-month survivors, 234 patients with lacunar stroke did not differ from others in 3-month outcome (adjusted OR (aOR) for 3-month mRS >2 adjusted for age/sex/National Institutes of Health Stroke Scale score/prestroke disability: 1.14, 95% CI 0.75 to 1.74, p=0.55), but were more likely to demonstrate further improvement between 3 months and 1 year (aOR (mRS) adjusted for age/sex/3-month mRS: 1.64, 1.17 to 2.31, p=0.004). The results were similar on restricting analyses to patients with 3-month mRS 2-4 and excluding recurrent events (aOR (mRS): 2.28, 1.34 to 3.86, p=0.002), or examining BI and RMI (aOR (RMI) adjusted for age/sex/3-month RMI: 1.78, 1.20 to 2.64, p=0.004)., Conclusion: Patients with lacunar strokes have significant potential for late functional improvement from 3 to 12 months, which should motivate patients and clinicians to maximise late improvements in routine practice. However, since late recovery is common, intervention studies enrolling patients with lacunar strokes should be randomised and controlled., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY. Published by BMJ.)

Purpose: This study aims to investigate the effect of transcutaneous electrical acupoint stimulation (TEAS) on postoperative delirium (POD) in elderly patients with silent lacunar infarct and preliminarily to determine the relationship among TEAS, blood-brain barrier (BBB), neuroinflammation, and POD., Patients and Methods: Sixty-four-old patients with silent lacunar infarct were randomly divided into two groups: group TEAS and control group (group C). Patients in the group TEAS received TEAS (disperse-dense waves; frequency, 2/100 Hz) on acupoints Hegu and Neiguan of both sides starting from 30 minutes before induction of anesthesia until the end of surgery, and the intensity was the maximum current that could be tolerated. In group C, electrodes were placed on the same acupoints before anesthesia induction, but no current was given. At 0 minute before the treatment of TEAS, 30 minutes after skin incision, and after completion of surgery (T 1-3 ), blood samples were extracted to detect the concentration of serum tumor necrosis factor (TNF)-α, interleukin-6 (IL-6), matrix metalloproteinase-9 (MMP-9), and S100β. We assessed patients for delirium and coma twice daily in the first 3 postoperative days using the Confusion Assessment Method for the intensive care unit and the Richmond Agitation-Sedation Scale., Results: This study preliminarily suggests that TEAS can reduce the development of POD in elderly patients with silent lacunar infarction (6.3% vs 25.0%; P =0.039). Compared with the baseline value at T 1 , the serum concentrations of IL-6, TNF-α, MMP-9, and S100β were significantly increased at T 2-3 in both the groups ( P <0.05). Compared with group TEAS, serum levels of TNF-α and IL-6 were higher at T 2-3 and serum levels of MMP-9 and S100β were higher at T 3 in group C ( P <0.05). The intraoperative anesthetic consumptions were less in group TEAS than group C., Conclusion: TEAS can alleviate POD in older patients with silent lacunar infarction and may be related to reduce the neuroinflammation by lowering the permeability of BBB., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background and Purpose: Cerebral small-vessel disease is a major cause of cognitive impairment. Perivascular spaces (PvS) occur in small-vessel disease, but their relationship to cognitive impairment remains uncertain. One reason may be difficulty in distinguishing between lacunes and PvS. We determined the relationship between baseline PvS score and PvS volume with change in cognition over a 5-year follow-up. We compared this to the relationship between baseline lacune count and total lacune volume with cognition. In addition, we examined change in PvS volume over time., Methods: Data from the prospective SCANS study (St Georges Cognition and Neuroimaging in Stroke) of patients with symptomatic lacunar stroke and confluent leukoaraiosis were used (n=121). Multimodal magnetic resonance imaging was performed annually for 3 years and neuropsychological testing annually for 5 years. Lacunes were manually identified and distinguished from PvS. PvS were rated using a validated visual rating scale, and PvS volumes calculated using T1-weighted images. Linear mixed-effect models were used to determine the impact of PvS and lacunes on cognition., Results: Baseline PvS scores or volumes showed no association with cognitive indices. No change was detectable in PvS volumes over the 3 years. In contrast, baseline lacunes associated with all cognitive indices and predicted cognitive decline over the 5-year follow-up., Conclusions: Although a feature of small-vessel disease, PvS are not a predictor of cognitive decline, in contrast to lacunes. This study highlights the importance of carefully differentiating between lacunes and PvS in studies investigating vascular cognitive impairment., (© 2018 The Authors.)

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disease characterized by clonal hematopoietic stem cell disorder, with increased mortality and morbidity. Venous thrombosis is the most common cause of mortality in PNH. The relationship between PNH and cerebrovascular disease is unclear; few cases are reported in the literature, most of them related to cerebral venous thrombosis; In PNH the involvement of intracranial and extracranial arterial sites is very rare. We report a case of a 49-year-old woman who has a medical history of diabetes mellitus, hypertension, and PNH and presented multiple lacunar strokes in a routine consultation with a hematologist. A brain computed tomography (CT) scan showed lacunar infarcts, and magnetic resonance image showed acute ischemic stroke, multiple territory lacunar infarctions, and focal area of microbleeds in gradient echo sequence. A CT angiography showed V3 and V4 branches of the left vertebral artery occluded by a thrombus, and the posterior inferior cerebellar artery occluded, whereas the carotid system was normal. We discuss the presentation and physiopathology of stroke in PNH and other cases reported in the literature review., (Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Despite the high burden of CKD, few specific therapies are available that can halt disease progression. In animal models, clopidogrel has emerged as a potential therapy to preserve kidney function. The effect of clopidogrel on kidney function in humans has not been established., Design, Setting, Participants, & Measurements: The Secondary Prevention of Small Subcortical Strokes Study randomized participants with prior lacunar stroke to treatment with aspirin or aspirin plus clopidogrel. We compared annual eGFR decline and incidence of rapid eGFR decline (≥30% from baseline) using generalized estimating equations and interval-censored proportional hazards regression, respectively. We also stratified our analyses by baseline eGFR, systolic BP target, and time after randomization., Results: At randomization, median age was 62 (interquartile range, 55-71) years old; 36% had a history of diabetes, 90% had hypertension, and the median eGFR was 81 (interquartile range, 65-94) ml/min per 1 m 2 . Persons receiving aspirin plus clopidogrel had an average annual change in kidney function of -1.39 (95% confidence interval, -1.15 to -1.62) ml/min per 1.73 m 2 per year compared with -1.52 (95% confidence interval, -1.30 to -1.74) ml/min per 1.73 m 2 per year among persons receiving aspirin only ( P =0.42). Rapid kidney function decline occurred in 21% of participants receiving clopidogrel plus aspirin compared with 22% of participants receiving aspirin plus placebo (hazard ratio, 0.94; 95% confidence interval, 0.79 to 1.10; P =0.42). Findings did not vary by baseline eGFR, time after randomization, or systolic BP target (all P values for interaction were >0.3)., Conclusions: We found no effect of clopidogrel added to aspirin compared with aspirin alone on kidney function decline among persons with prior lacunar stroke., (Copyright © 2017 by the American Society of Nephrology.)

Rationale: The role of hypertension in cerebral small vessel disease is poorly understood. At the base of the brain (the 'vascular centrencephalon'), short straight arteries transmit blood pressure directly to small resistance vessels; the cerebral convexity is supplied by long arteries with many branches, resulting in a drop in blood pressure. Hypertensive small vessel disease (lipohyalinosis) causes the classically described lacunar infarctions at the base of the brain; however, periventricular white matter intensities (WMIs) seen on MRI and WMI in subcortical areas over the convexity, which are often also called 'lacunes', probably have different aetiologies., Objectives: We studied pressure gradients from proximal to distal regions of the cerebral vasculature by mathematical modelling., Methods and Results: Blood flow/pressure equations were solved in an Anatomically Detailed Arterial Network (ADAN) model, considering a normotensive and a hypertensive case. Model parameters were suitably modified to account for structural changes in arterial vessels in the hypertensive scenario. Computations predict a marked drop in blood pressure from large and medium-sized cerebral vessels to cerebral peripheral beds. When blood pressure in the brachial artery is 192/113 mm Hg, the pressure in the small arterioles of the posterior parietal artery bed would be only 117/68 mm Hg. In the normotensive case, with blood pressure in the brachial artery of 117/75 mm Hg, the pressure in small parietal arterioles would be only 59/38 mm Hg., Conclusion: These findings have important implications for understanding small vessel disease. The marked pressure gradient across cerebral arteries should be taken into account when evaluating the pathogenesis of small WMIs on MRI. Hypertensive small vessel disease, affecting the arterioles at the base of the brain should be distinguished from small vessel disease in subcortical regions of the convexity and venous disease in the periventricular white matter., Competing Interests: Competing interests: None declared.

Diffusion tensor imaging (DTI) metrics such as fractional anisotropy (FA) and mean diffusivity (MD) have been proposed as clinical trial markers of cerebral small vessel disease (SVD) due to their associations with outcomes such as cognition. However, studies investigating this have been predominantly single-centre. As clinical trials are likely to be multisite, further studies are required to determine whether associations with cognition of similar strengths can be detected in a multicentre setting. One hundred and nine patients (mean age =68 years) with symptomatic lacunar infarction and confluent white matter hyperintensities (WMH) on MRI was recruited across six sites as part of the PRESERVE DTI substudy. After handling missing data, 3T-MRI scanning was available from five sites on five scanner models (Siemens and Philips), alongside neuropsychological and quality of life (QoL) assessments. FA median and MD peak height were extracted from DTI histogram analysis. Multiple linear regressions were performed, including normalized brain volume, WMH lesion load, and n° lacunes as covariates, to investigate the association of FA and MD with cognition and QoL. DTI metrics from all white matter were significantly associated with global cognition (standardized β =0.268), mental flexibility (β =0.306), verbal fluency (β =0.376), and Montreal Cognitive Assessment (MoCA) (β =0.273). The magnitudes of these associations were comparable with those previously reported from single-centre studies found in a systematic literature review. In this multicentre study, we confirmed associations between DTI parameters and cognition, which were similar in strength to those found in previous single-centre studies. The present study supports the use of DTI metrics as biomarkers of disease progression in multicentre studies., (© 2017 The Author(s).)

Background: The presence of white matter hyperintensity (WMH) and lacunar infarct are recognized as risk factors of dementia, stroke and mortality. It is undetermined whether visceral adipose tissue (VAT) area is associated with an increased risk of cerebral small vessel disease. We explored whether VAT area was responsible for cerebral small vessel disease through the identification of WMH and lacunar infarct., Subjects: A total of 2046 subjects free of cerebrovascular disease who underwent brain magnetic resonance imaging and abdominal fat computed tomography during a general health check-up were enrolled., Results: The prevalence of cerebral WMH was 37.7%. Subjects with WMH had greater VAT area and higher BMI and waist circumference than those without WMH, although significant differences in subcutaneous adipose tissue (SAT) area were not shown. Subjects with lacunar infarct also had significantly greater VAT area and higher waist circumference and BMI than those without lacunar infarct. Multivariate analyses adjusted for age, sex, diabetes, hypertension, smoking and alcohol, showed VAT area was an independent risk factor of cerebral WMH (odds ratio (OR): 1.13, 95% confidence interval (CI): 1.02-1.24, P=0.016), whereas waist circumference and SAT area were not significantly associated with the risk of WMH. Likewise, VAT area was also independently associated with lacunar infarct (OR: 1.38, 95% CI: 1.06-1.81, P=0.018), whereas the other anthropometric measures were not related with lacunar infarct., Conclusions: VAT has a significant association with cerebral small vessel disease, which was defined as WMH or lacunar infarct. Visceral obesity can be a potential therapeutic target for the prevention of cerebral small vessel disease.

The aim of this study was to determine whether pulse wave velocity (PWV), a marker of vascular endothelial impairment and arteriosclerosis, predicts future ischemic stroke in patients who developed acute lacunar infarction. Patients with a first-ever ischemic stroke due to acute lacunar infarction were enrolled in this study. An oscillometric device (Form PWV/ABI; Omron Colin, Tokyo, Japan) was used to measure brachial-ankle PWV 1 week after stroke onset. Patients were followed for at least 5 years. The main end point of the study was recurrent ischemic stroke. Event-free survival was analyzed using Kaplan-Meier plots and log-rank tests. The risk of recurrent ischemic stroke was estimated using the Cox proportional-hazards model. Of the 156 patients (61% male, mean age: 69.2±11.3 years) assessed in this study, 29 developed recurrent ischemic stroke. The median brachial-ankle PWV value was 20.4 m s -1 . Patients with high PWV values had a greater risk of recurrent ischemic stroke than patients with low PWV values (28% vs. 15%, P=0.08). Kaplan-Meier curve analysis showed that patients with high PWV values had a less favorable (that is, free of recurrent ischemic stroke) survival time (P=0.015). A multivariate Cox proportional-hazards model identified high PWV as an independent predictor of recurrent ischemic stroke after adjusting for age, sex and blood pressure (hazard ratio 2.35, 95% confidence interval, 1.02-5.70, P=0.044). In patients with acute lacunar infarction, a high PWV predicts a twofold greater risk of future ischemic stroke, independent of patient age, sex and blood pressure levels.

Objective: We investigated the association of clinical, laboratory, sonographic and imaging parameters, in the progression of single subcortical infarctions., Methods: Consecutive 169 patients with lacunar (n = 89) and striatocapsular infarctions (n = 80) in the middle cerebral artery (MCA) territory with nonstenotic MCAs were recruited and examined for stroke progression. The pulsatility index (PI) was measured by transcranial Doppler from ipsilateral M1., Results: The striatocapsular infarction group exhibited more stroke progression. The patients with progressive lacunar infarctions had more diabetes, higher HbA1c levels, and higher initial National Institutes of Health Stroke Scale (NIHSS) scores, and the patients with progressive striatocapsular infarctions had more hypertension, higher cholesterol levels, and higher NIHSS scores. The MCA PI was higher in the lacunar infarction patients with progression (0.99 ± 0.19 vs. 0.90 ± 0.14, p = 0.048), while the striatocapsular infarction patients did not differ according to progression. From a multivariate analysis, higher MCA PI were independently associated with lacunar infarction progression (by 0.1 increase, OR 1.51; 95 % CI 1.06-2.15; p = 0.024)., Conclusions: Higher pulsatility was associated with progression in lacunar infarction. PI measured by transcranial Doppler sonography might reflect downstream arterial resistance and vascular/paravascular perfusion status and be a possible indicator of stroke progression., Key Points: • Higher pulsatility index was observed in progression group of lacunar infarction patients. • Higher pulsatility index seemed to be associated with progression in lacunar infarction patients. • Differences in the factors associated with stroke progression suggest different underlying pathophysiologies.

Background: Infarcts in the brain can be divided into larger cortical and smaller deep lacunar infarcts. The pathogenesis differs between these two types of infarctions., Objective: This study aims to investigate the relationship between measures of endothelium-dependent vasodilation (EDV) and occurrence of cortical and lacunar infarcts in a population-based sample., Methods: In the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study, 1016 subjects aged 70 were evaluated by the invasive forearm technique with acetylcholine (EDV) and brachial artery ultrasound to assess flow-mediated vasodilation (FMD). Six to seven years later MRI of the brain was performed, and the prevalence of cortical and lacunar infarcts was visually assessed in 407 randomly selected subjects., Results: Lacunar infarcts were found in 22% and cortical infarcts in 5·9% of the subjects. EDV and FMD were both significantly related to the occurrence of cortical, but not lacunar infarcts. In a model adjusting for gender, waist circumference, body mass index, fasting blood glucose, systolic and diastolic blood pressure, HDL and LDL cholesterol, serum triglycerides, smoking, antihypertensive treatment and statin use, both EDV and FMD were independent predictors of cortical infarcts (P = 0·035 and P = 0·008, respectively)., Conclusions: Endothelium-dependent vasodilation in both forearm resistance vessels and the brachial artery was related to the occurrence of cortical, but not lacunar, infarcts at MRI in a population-based sample independently of traditional risk factors., (© 2015 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.)

Reduced cerebrovascular reactivity (CVR) was found in patients with recent lacunar infarct. However, its mechanisms were controversial. The breath holding maneuver as a vasodilatory stimulus is clinically useful for an estimation of cerebrovasomotor reactivity in well co-operative patients. Patients with lacunar infarct have no higher cortical dysfunction and remain well co-operation. The breath holding maneuver is feasible and safe to perform in patients with lacunar infarct. Autonomic nervous system regulates systemic vascular activity. Regulation of autonomic function to cerebrovascular reactivity has been reported in the literature. We examined the correlation between autonomic functions with frequency and nonlinear heart rate variability (HRV) and cerebrovascular reactivity in patients with lacunar infarct by application of breath holding maneuver. Fifteen patients with lacunar infarct (8 women, age 65.6 ± 13.61) and 16 healthy controls (11 women, age 27.33 ± 3.85) were continuously monitored at baseline before maneuver (basal phase), during CVR induction (experimental phase) with breath holding maneuver and after maneuver (recovery phase), for arterial blood pressure (ABP), electrocardiography (EKG), mean cerebral blood flow velocity (mCBFV) of middle cerebral arteries (MCA) by transcranial doppler (TCD). The short term-one minute HRV was analyzed from EKG signals for low frequency (LF)/ high frequency (HF) ratio, nonlinear of standard deviation 1 (SD1), standard deviation 2 (SD2), cardiac Sample Entropy (SampEn) and Shannon Entropy. Significant increasing in mCBFV, LF/HF ratio, SD2/SD1, Shannon Entropy and inversely decreasing SampEn during breath holding maneuver compared with baseline were found in both groups (p<0.05). The trend of cerebrovascular reactivity is similar in both groups. However, there were differences of mCBFV, systolic blood pressure (SysBP) in the whole phases (basal, experiment and recovery) between patients and controls (p<0.05). Less scattered signals of SD1 with low value in patient group were illustrated from Poincaré (p<0.05). This indicated less degree of parasympathetic drive in the patients compared to the controls. Moreover, significant positive correlation between systolic bloods pressure and mCBFV in patients suggests impact of autonomic control and cerebral blood flow on the patho-physiological mechanism of vasodilatation, triggered by hypercapnia from breath holding maneuver in patients with lacunar infarct. Reduction of cerebrovascular reactivity in patients with lacunar infarct may relate with decreased parasympathetic activity. Further study is required to demonstrate whether these findings mean mechanisms of lacunar infarct or the effect of hypertensive response., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background and Purpose: Ozagrel sodium (ozagrel), a thromboxane A2 synthesis inhibitor, is used for ischemic stroke patients in several countries, despite a lack of strict evidence of its benefits. We investigated whether ozagrel was beneficial for patients with atherothrombotic stroke or lacunar infarction., Methods: This was a retrospective observational study using the Diagnosis Procedure Combination database in Japan. We identified patients with atherothrombotic stroke or lacunar infarction who were admitted to 781 hospitals from July 1, 2010 to March 31, 2012. Propensity score-matched analyses were performed separately for patients with atherothrombotic stroke and those with lacunar infarction, which balanced differences in baseline characteristics between patients who received ozagrel (ozagrel group) and those who did not (control group) in each stroke subtype. The modified Rankin Scale scores at discharge and occurrence of hemorrhagic complications after admission were compared between the ozagrel and control groups., Results: After the propensity score matching, 2726 pairs of patients with atherothrombotic stroke and 1612 pairs of patients with lacunar infarction were analyzed. Ordinal logistic regression analyses showed that ozagrel use was not significantly associated with modified Rankin Scale score at discharge in patients with atherothrombotic stroke (odds ratio: .99; 95% confidence interval: .88-1.11) or in those with lacunar infarction (odds ratio: 1.00; 95% confidence interval: .87-1.16). The occurrence of hemorrhagic complications did not differ significantly between the ozagrel and control groups., Conclusion: The present study suggested that ozagrel was safe to use but did not improve functional outcomes in patients with atherothrombotic or lacunar infarction., (Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.)