Role of Computed Tomography Perfusion in Identification of Acute Lacunar Stroke Syndromes.

BACKGROUND AND PURPOSE: Lacunar syndromes correlate with a lacunar stroke on imaging in 50% to 60% of cases. Computed tomography perfusion (CTP) is becoming the preferred imaging modality for acute stroke triage. We aimed to estimate the sensitivity, specificity, and predictive values for noncontrast computed tomography and CTP in lacunar syndromes, and for cortical, subcortical, and posterior fossa regions. METHODS: A retrospective analysis of confirmed ischemic stroke patients who underwent acute CTP and follow-up magnetic resonance imaging between 2010 and 2018 was performed. Brain noncontrast computed tomography and CTP were assessed independently by 2 stroke neurologists. Receiver operating characteristic curve analysis was performed to estimate sensitivity, specificity, and area under the curve (AUC) for the detection of strokes in patients with lacunar syndromes using different CTP maps. RESULTS: We found 106 clinical lacunar syndromes, but on diffusion-weighted imaging, these consisted of 59 lacunar, 33 cortical, and 14 posterior fossa strokes. The discrimination of ischemia identification was very poor using noncontrast computed tomography in all 3 regions, but good for cortical (AUC, 0.82) and poor for subcortical and posterior regions (AUCs, 0.55 and 0.66) using automated core-penumbra maps. The addition of delay time and mean transient time maps substantially increased subcortical (AUC, 0.80) and slightly posterior stroke detection (AUC, 0.69). CONCLUSIONS: Analysis of mean transient time and delay time maps in combination with core-penumbra maps improves detection of subcortical and posterior strokes.

Cognitive Impairment after Lacunar Stroke and the Risk of Recurrent Stroke and Death.

INTRODUCTION: Patients with poststroke cognitive impairment appear to be at higher risk of recurrent stroke and death. However, whether cognitive impairment after lacunar stroke is associated with recurrent stroke and death remains unclear. We assessed whether global or domain-specific cognitive impairment after lacunar stroke is associated with recurrent stroke and death. METHODS: We considered patients from the Secondary Prevention of Small Subcortical Strokes (SPS3) trial with a baseline cognitive exam administered in English by certified SPS3 personnel, 14-180 days after qualifying lacunar stroke. We considered a baseline score of ≤86 on the Cognitive Assessment Screening Instrument to indicate global cognitive impairment, <10 on the Clock Drawing on Command test to indicate executive function impairment, and domain-specific summary scores in the lowest quartile to indicate memory and nonmemory impairment. We used Cox proportional hazards models to estimate the association between poststroke cognitive impairment and subsequent risk of recurrent stroke and death. RESULTS: The study included 1,528 participants with a median enrollment time of 62 days after qualifying stroke. During a mean follow-up of 3.9 years, 11.4% of participants had recurrent stroke and 8.2% died. In the fully adjusted models, memory impairment was independently associated with an increased risk of recurrent stroke (hazard ratio, 1.48; 95% confidence interval [95% CI]: 1.04-2.09) and death (hazard ratio, 1.87; 95% CI: 1.25-2.79). Global impairment (hazard ratio, 1.66; 95% CI: 1.06-2.59) and nonmemory impairment (hazard ratio, 1.74; 95% CI: 1.14-2.67) were associated with an increased risk of death. DISCUSSION/CONCLUSION: After lacunar stroke, memory impairment was an independent predictor of recurrent stroke and death, while global and nonmemory impairment were associated with death. Cognitive screening in lacunar stroke may help identify populations at higher risk of recurrent stroke and death.

Advances in Understanding the Pathogenesis of Lacunar Stroke: From Pathology and Pathophysiology to Neuroimaging.

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.

[Aphasia associated with lacunar infarctions]. / Aphasien bei lakunären Hirninfarkten.

BACKGROUND: Typical lacunar syndromes do not include aphasia but aphasia has been reported in rare atypical lacunar syndromes. OBJECTIVE: Description of the phenomenology and of affected fiber tracts. MATERIAL AND METHODS: Case series of three patients with lacunar stroke as evidenced by magnetic resonance imaging. Identification of affected fiber tracts via fiber tracking from coregistered lesion sites in brains of two healthy participants. RESULTS: The lacunar strokes that produced aphasia were located in the very lateral territory of perforating branches of the middle cerebral artery and extended along the external capsule into its most rostrodorsal aspect. Even though the cortex, thalamus and most parts of the basal ganglia were unaffected, patients exhibited a mild to moderate nonfluent aphasia with syntactic deficits. Fiber tracking revealed that in contrast to the nonaphasic control patient with a neighboring lacunar stroke, the aphasic patient strokes involved particularly fibers of the left arcuate fascicle as well as fibers of the frontostriatal and frontal aslant tracts. CONCLUSION: Left lateral lacunar stroke can cause clinically relevant aphasia through disruption of speech-relevant fiber tracts.

Improving Clinical Detection of Acute Lacunar Stroke: Analysis From the IST-3.

Background and Purpose- We aim to identify factors associated with imaging-confirmed lacunar strokes and improve their rapid clinical identification early after symptom onset using data from the IST-3 (Third International Stroke Trial). Methods- We selected patients likely to have lacunar infarcts as those presenting with: Oxfordshire Community Stroke Project lacunar syndrome; a random sample with National Institutes of Health Stroke Scale (NIHSS) score <7; and recent lacunar infarct identified on imaging by IST-3 central blinded expert panel. An independent reviewer rated brain scans of this sample and classified visible infarcts according to type, size, and location. We investigated factors associated with presence of lacunar infarct on a 24 to 48 hour follow-up scan using multivariable logistic regression and calculated sensitivity and specificity of Oxfordshire Community Stroke Project alone and in combination with NIHSS score <7. Results- We included 568 patients (330 lacunar syndrome; 147 with NIHSS score <7; 91 with lacunar infarct on baseline imaging, numbers exclude overlaps between groups), mean (±SD) age, 73.2 (±13.6) years, 316 (56%) males, and median NIHSS score 5 (IQR, 4-8). On 24 to 48 hour scan, 138 (24%) patients had lacunar infarcts, 176 (31%) other infarct subtypes, 254 (45%) no visible infarct. Higher baseline systolic blood pressure (odds ratio, 1.01 [95% CI, 1.01-1.02]) and preexisting lacunes (odds ratio, 2.29 [95% CI, 1.47-3.57) were associated with recent lacunar infarcts. Sensitivity and specificity of lacunar syndrome was modest (58% and 45%, respectively), but adding NIHSS score <7 increased specificity (99%), positive and negative predictive values (97% and 87%, respectively). Conclusions- In patients presenting within 6 hours of stroke onset, adding NIHSS score <7 to Oxfordshire Community Stroke Project lacunar syndrome classification may increase specificity for identifying lacunar stroke early after stroke onset. Our findings may help selection of patients for clinical trials of lacunar stroke and should be validated externally. Registration- URL: http://www.controlled-trials.com/; Unique identifier: ISRCTN25765518.

Collateral Recruitment Is Impaired by Cerebral Small Vessel Disease.

Background and Purpose- Cerebral small vessel disease (SVD) is associated with increased stroke risk and poor stroke outcomes. We aimed to evaluate whether chronic SVD burden is associated with poor recruitment of collaterals in large-vessel occlusive stroke. Methods- Consecutive patients with middle cerebral artery or internal carotid artery occlusion presenting within 6 hours after stroke symptom onset who underwent thrombectomy from 2012 to 2017 were included. The prespecified primary outcome was poor collateral flow, which was assessed on baseline computed tomographic angiography (poor, ≤50% filling; good, >50% filling). Markers of chronic SVD on brain magnetic resonance imaging were rated for the extent of white matter hyperintensities, enlarged perivascular spaces, chronic lacunar infarctions and cerebral microbleeds using the Standards for Reporting Vascular Changes on Neuroimaging criteria. Severity of SVD was quantified by adding the presence of each SVD feature, with a total possible score of 0 to 4; each SVD type was also evaluated separately. Multivariable logistic regression analyses were performed to evaluate the relationships between SVD and poor collaterals, with adjustment for potential confounders. Results- Of the 100 eligible patients, the mean age was 65±16 years, median National Institutes of Health Stroke Scale score was 15, and 68% had any SVD. Poor collaterals were observed in 46%, and those with SVD were more likely to have poor collaterals than patients without SVD (aOR, 1.9 [95% CI, 1.1-3.2]). Of the SVD types, poor collaterals were significantly associated with white matter hyperintensities (aOR, 2.9 per Fazekas increment [95% CI, 1.6-5.3]) but not with enlarged perivascular spaces (adjusted odds ratio [aOR], 1.3 [95% CI, 0.4-4.0]), lacunae (aOR, 2.1 [95% CI, 0.6-7.1]), or cerebral microbleeds (aOR, 2.1 [95% CI, 0.6-7.8]). Having a greater number of different SVD markers was associated with a higher odds of poor collaterals (crude trend P<0.001; adjusted P=0.056). There was a dose-dependent relationship between white matter hyperintensity burden and poor collaterals: adjusted odds of poor collaterals were 1.5, 3.0, and 9.7 across Fazekas scores of 1 to 3 (Ptrend=0.015). No patient with an SVD score of 4 had good collaterals. Conclusions- Chronic cerebral SVD is associated with poor recruitment of collaterals in large vessel occlusive stroke. A prospective study to elucidate the potential mechanism of how SVD may impair the recruitment of collaterals is ongoing.

Treatment Approaches to Lacunar Stroke.

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.

Pre-Existing Cerebral Small Vessel Disease Limits Early Recovery in Patients with Acute Lacunar Infarct.

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.

Pathophysiology of Lacunar Stroke: History's Mysteries and Modern Interpretations.

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.

The Value of the CHADS2 and CHA2DS2-VASc Score for Predicting the Prognosis in Lacunar Stroke with or without Atrial Fibrillation Patients.

BACKGROUND: The CHADS2 and CHA2DS2-VASc scoring systems have been proved efficacy to stratify stroke and thromboembolism risk in patients with atrial fibrillation (AF). Whether CHADS2 and CHA2DS2-VASc score has predictive value for the prognosis in lacunar stroke (LS) patients remains unclear. METHODS: A total of 763 consecutive patients with LS (mean age: 66 ± 12 years; 464 male) were enrolled in this study between January 2013 and December 2014. Patients were divided into LS without AF (LS; n = 679) and LS with AF (LS-AF; n = 84) groups. Measures of performance for the risk scores were evaluated at predicting mortality and restroke in LS-AF and LS without AF patients. All patients were evaluated with respect to clinical features and in-hospital clinical results. RESULTS: During the mean follow-up period of 20 ± 5.8 months, 29 patients (3.8%) experienced all-cause death, 105 patients (13.8%) experienced recurrence of ischemic stroke. Multivariate analysis revealed that CHADS2 and CHA2DS2-VASc score were independently associated with all-cause death (all P < .05). On receiver operating characteristic curve analysis, area under the curve (AUC) for CHADS2 score was .942 with a similar accuracy of the CHA2DS2-VASc score (AUC: .908) in predicting mortality in LS-AF patients. Kaplan-Meier curves were conducted according to the cut-off value of CHA2DS2-VASc score. When CHADS2 score greater than or equal to 4 point or CHA2DS2-VASc score greater than or equal to 5 point, the mortality in LS-AF patients was significantly higher compared with those CHADS2 score less than 4 point or CHA2DS2-VASc score less than 5 point. However, after adjusting for clinical covariates, CHADS2 and CHA2DS2-VASc score could not predict both mortality and restroke in LS without AF patients. CONCLUSIONS: The CHADS2 and CHA2DS2-VASc score have excellent predictive value for mortality in LS-AF patients but could not predict both mortality and restroke in LS without AF patients.

Self-Reported Physical Activity and Cardiovascular Disease Risk Factors in Patients with Lacunar Stroke.

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.

Outcome in lacunar stroke: A cohort study.

OBJECTIVES: We evaluated a prospective cohort of 150 patients under observation in our centre for lacunar strokes. The purpose of this study was to evaluate the outcome at time of discharge and 6 months after lacunar stroke, as well as the correlation with cardiovascular risk factors and selected biochemical parameters already evaluated on admission. Focus was to identify possible prognostic factors, which might be targeted through appropriate intervention concentrating on reduction in the incidence and impact of early clinical deterioration. METHODS: 150 patients with a lacunar stroke were included in the present study. A clinical 6-month follow-up was available for 98.7% of the patients. Infarcts were classified by size, shape and location. RESULTS: The most important predictors of high NIHSS score at time of discharge resulted NIHSS on admission (P < .001), leukocytosis (P = .013), in-hospital infections (P = .016) and size of lacunae (P = .005). Similarly, the most important predictors of poor outcome 6 months later were NIHSS on admission (P = .01), leukocytosis (P = .014), elevated CRP (P = .019), in addition to pre-admission Rankin (P < .001). CONCLUSION: Although infections are not causatively related to lacunar strokes, their prompt recognition and early treatment, control of inflammatory markers and fever are most important in influencing functional outcome in lacunar stroke.

Effect of Intensive Versus Usual Blood Pressure Control on Kidney Function Among Individuals With Prior Lacunar Stroke: A Post Hoc Analysis of the Secondary Prevention of Small Subcortical Strokes (SPS3) Randomized Trial.

BACKGROUND: The effect of intensive blood pressure (BP) lowering on kidney function among individuals with established cerebrovascular disease and preserved estimated glomerular filtration rate (eGFR) is not established. METHODS AND RESULTS: Among 2610 participants randomized to a lower (<130 mm Hg) versus higher (130-149 mm Hg) systolic BP target with repeated measures of serum creatinine, we evaluated differences by study arm in annualized eGFR decline and rapid decline (eGFR decline >30%) using linear mixed models and logistic regression, respectively. We assessed associations of both treatment and kidney function decline with stroke, major vascular events, and the composite of stroke, death, major vascular events, or myocardial infarction using multivariable Cox regression, separately and jointly including a test for interaction. Analyses were conducted by treatment arm. Mean age was 63±11 years; 949 participants (36%) were diabetic; and mean eGFR was 80±19 mL·min(-1)·1.73 m(-2). At 9 months, achieved systolic BP was 137±15 versus 127±14 mm Hg in the higher versus lower BP group, and differences were maintained throughout follow-up (mean, 3.2 years). Compared with the higher target, the lower BP target had a -0.50-mL·min(-1)·1.73 m(-2) per year (95% confidence interval [CI], -0.79 to -0.21) faster eGFR decline. Differences were most pronounced during the first year (-2.1 mL·min(-1)·1.73 m(-2); 95% CI, -0.97 to -3.2), whereas rates of eGFR decline did not differ after year 1 (-0.095; 95% CI, -0.47 to 0.23). A total of 313 patients (24%) in the lower BP group had rapid kidney function decline compared with 247 (19%) in the higher BP group (odds ratio, 1.4; 95% CI, 1.1-1.6). Differences in rapid decline by treatment arm were apparent in the first year (odds ratio, 1.4; 95% CI, 1.1-1.8) but were not significant after year 1 (odds ratio, 1.0; 95% CI, 0.73-1.4). Rapid decline was associated with higher risk for stroke, major vascular events, and composite after full adjustment among individuals randomized to the higher BP target (stroke hazard ratio, 1.93; 95% CI, 1.15-3.21) but not the lower BP arm (stroke hazard ratio, 0.93; 95% CI, 0.50-1.75; all P for interaction <0.06). CONCLUSIONS: In patients with prior lacunar stroke and relatively preserved kidney function, intensive BP lowering was associated with a greater likelihood of rapid kidney function decline. Differences were observed primarily during the first year of antihypertensive treatment. Rapid kidney function decline was not associated with increased risk for clinical events among those undergoing intensive BP lowering. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicalTrials.gov. Unique identifier: NCT00059306.

Lacunar Infarcts and Intracerebral Hemorrhage Differences: A Nested Case-Control Analysis in the FHS (Framingham Heart Study).

BACKGROUND AND PURPOSE: Lacunar stroke (LS) and intracerebral hemorrhage (ICH) are 2 diverse manifestations of small vessel disease. What predisposes some patients to ischemic stroke and others to hemorrhage is not well understood. METHODS: We performed a nested case-control study within the FHS (Framingham Heart Study) comparing people with incident ICH and lacunar ischemic stroke, to age- and sex-matched controls for baseline prevalence and levels of cardiovascular risk factors. RESULTS: We identified 118 LS (mean age 74 years, 51% male) and 108 ICH (75 years, 46% male) events. Hypertension, diabetes mellitus, smoking, and obesity were strongly associated with LS. Hypertension, but not diabetes mellitus, smoking, or cholesterol levels increased the odds of ICH. Contrary to LS, ICH cases had lower body mass index (BMI) than their controls (26 versus 27); BMI <20 was associated with 4-fold higher odds for ICH. In direct comparison, LS cases had higher BMI (28 versus 26) and obesity prevalence (odds ratio, 3.1); BMI <20 was associated with significantly lower odds of LS (odds ratio, 0.1). CONCLUSIONS: LS and ICH share hypertension, but not diabetes mellitus, as a common risk factor. ICH cases had lower BMI compared with not only LS but their controls as well; this finding is unexplained and merits further exploration.

Increased arterial pulsatility and progression of single subcortical infarction.

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.

A CARASIL Patient from Americas with Novel Mutation and Atypical Features: Case Presentation and Literature Review.

OBJECTIVE: Reporting a novel mutation in the HTRA1 gene in a CARASIL patient from Americas. METHODS: Clinical presentation and neuroimaging were consistent with CARASIL. HTRA1 DNA sequencing was performed using advanced ("next generation") sequencing technology. The results revealed a homozygous missense mutation as c.616G>A (p.Gly206Arg) in the HTRA1 gene. RESULTS: A 24-year-old man with a history of chronic back pain presented with recurrent ischemic strokes. A diagnosis of CARASIL was made with the finding of a novel homozygous missense mutation c.616G>A in HTRA1 gene, resulting in change from Glycine to Arginine in the Serine Protease HTRA1. Brain imaging showed multiple lacunar infarcts with extensive abnormalities of the white matter that spared the external capsules. He also had unilateral decreased hearing with craniofacial asymmetry. None of the above features have been previously described in known CARASIL patients. Both parents of the proband were heterozygous for the same missense mutation. CONCLUSION: We discovered a novel missense mutation (c.616G>A) associated with a phenotype of CARASIL. This is the first genetically backed case of CARASIL in the new world. The patient's craniofacial abnormalities, including asymmetry of the head, may be related to impaired modulation of transforming growth factor-ß1, the result of loss of proteolytic activity of HTRA1. External capsules remained unaffected, despite findings of advanced changes in the rest of the cerebral white matter. Literature is briefly reviewed. The patient's history, neurological exam, neuroimaging, and genetic testing are included.

Lipidomic analysis of plasma in patients with lacunar infarction using normal-phase/reversed-phase two-dimensional liquid chromatography-quadrupole time-of-flight mass spectrometry.

Stroke is a major cause of mortality and long-term disability worldwide. The study of biomarkers and pathogenesis is vital for early diagnosis and treatment of stroke. In the present study, a continuous-flow normal-phase/reversed-phase two-dimensional liquid chromatography-quadrupole time-of-flight mass spectrometry (NP/RP 2D LC-QToF/MS) method was employed to measure lipid species in human plasma, including healthy controls and lacunar infarction (LI) patients. As a result, 13 lipid species were demonstrated with significant difference between the two groups, and a "plasma biomarker model" including glucosylceramide (38:2), phosphatidylethanolamine (35:2), free fatty acid (16:1), and triacylglycerol (56:5) was finally established. This model was evaluated as an effective tool in that area under the receiver operating characteristic curve reached 1.000 in the discovery set and 0.947 in the validation set for diagnosing LI patients from healthy controls. Besides, the sensitivity and specificity of disease diagnosis in validation set were 93.3% and 96.6% at the best cutoff value, respectively. This study demonstrates the promising potential of NP/RP 2D LC-QToF/MS-based lipidomics approach in finding bio-markers for disease diagnosis and providing special insights into the metabolism of stroke induced by small vessel disease. Graphical abstract Flow-chart of the plasma biomarker model establishment through biomarker screening and validation.

Prognostic Value of Serum D-Dimer in Noncardioembolic Ischemic Stroke.

BACKGROUND: Although D-dimer levels are significantly associated with cardioembolic infarction, the significance of D-dimer levels in relation to the severity and functional outcomes of other stroke subtypes, such as lacunar and large artery atherosclerosis infarction, remains unclear. The purpose of this study was to evaluate whether elevated initial D-dimer levels are significantly and cross-sectionally associated with poor functional outcomes at each time point during a 9-month follow-up period. We also investigated the significance of D-dimer levels in longitudinal temporal changes of functional outcomes in these patients. METHODS: We recruited 146 patients with lacunar infarction and 161 patients with large artery atherosclerosis infarction who were consecutively admitted to our hospital after acute stroke. Serum D-dimer levels were evaluated initially and the modified Rankin scale were measured initially and at 1-, 3-, 6-, and 9-month follow-up visits. RESULTS: Patients with higher D-dimer levels had significantly worse initial functional outcomes, and these worse outcomes were maintained throughout the 9-month follow-up period compared with the low D-dimer group. However, regardless of stroke subtype, D-dimer levels did not influence long-term changes in functional outcomes over the 9-month follow-up period. CONCLUSION: This study suggests that elevated D-dimer levels can be used as a surrogate marker for poor functional outcomes only during the acute stage. Further evaluation of serum D-dimer levels could provide a helpful predictive marker for stroke prognosis.

Association of MTHFR C677T Genotype With Ischemic Stroke Is Confined to Cerebral Small Vessel Disease Subtype.

BACKGROUND AND PURPOSE: Elevated plasma homocysteine levels are associated with stroke. However, this might be a reflection of bias or confounding because trials have failed to demonstrate an effect from homocysteine lowering in stroke patients, although a possible benefit has been suggested in lacunar stroke. Genetic studies could potentially overcome these issues because genetic variants are inherited randomly and are fixed at conception. Therefore, we tested the homocysteine levels-associated genetic variant MTHFR C677T for association with magnetic resonance imaging-confirmed lacunar stroke and compared this with associations with large artery and cardioembolic stroke subtypes. METHODS: We included 1359 magnetic resonance imaging-confirmed lacunar stroke cases, 1824 large artery stroke cases, 1970 cardioembolic stroke cases, and 14 448 controls, all of European ancestry. Furthermore, we studied 3670 ischemic stroke patients in whom white matter hyperintensities volume was measured. We tested MTHFR C677T for association with stroke subtypes and white matter hyperintensities volume. Because of the established association of homocysteine with hypertension, we additionally stratified for hypertension status. RESULTS: MTHFR C677T was associated with lacunar stroke (P=0.0003) and white matter hyperintensity volume (P=0.04), but not with the other stroke subtypes. Stratifying the lacunar stroke cases for hypertension status confirmed this association in hypertensive individuals (P=0.0002), but not in normotensive individuals (P=0.30). CONCLUSIONS: MTHFR C677T was associated with magnetic resonance imaging-confirmed lacunar stroke, but not large artery or cardioembolic stroke. The association may act through increased susceptibility to, or interaction with, high blood pressure. This heterogeneity of association might explain the lack of effect of lowering homocysteine in secondary prevention trials which included all strokes.

Inflammatory Markers and Outcomes After Lacunar Stroke: Levels of Inflammatory Markers in Treatment of Stroke Study.

BACKGROUND AND PURPOSE: We hypothesized that concentrations of interleukin 6 (IL-6), serum amyloid A, tumor necrosis factor-α receptor 1, CD40 ligand, and monocyte chemoattractant protein 1 would predict recurrent ischemic stroke and major vascular events after recent lacunar stroke. METHODS: Levels of Inflammatory Markers in the Treatment of Stroke (LIMITS) was an international, multicenter, prospective ancillary biomarker study nested within the Secondary Prevention of Small Subcortical Strokes (SPS3) study, a Phase III trial in patients with recent lacunar stroke. Crude and Adjusted Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CI) for recurrence risks. RESULTS: Among 1244 patients with lacunar stroke (mean age, 63.3±10.8 years), there were 115 major vascular events (stroke, myocardial infarction, and vascular death). The risk of major vascular events increased with elevated concentrations of both tumor necrosis factor-α receptor 1 (adjusted HR per SD, 1.21; 95% CI, 1.05-1.41; P=0.01) and IL-6 (adjusted HR per SD, 1.10; 95% CI, 1.02-1.19; P=0.008). Compared with the bottom quartile (tumor necrosis factor-α receptor 1 <2.24 ng/L), those in the top quartile of tumor necrosis factor-α receptor 1 (>3.63 ng/L) were at twice the risk of major vascular events after adjusting for demographics (partially adjusted HR, 1.98; 95% CI, 1.11-3.52), though the effect attenuated after adjusting for other risk factors and statin use (adjusted HR, 1.68; 95% CI, 0.93-3.04). Serum amyloid A, CD40 ligand, and monocyte chemoattractant protein 1 were not associated with prognosis. CONCLUSIONS: Among recent lacunar stroke patients, IL-6 and TNF receptor concentrations predict risk of recurrent vascular events, and they are associated with the effect of antiplatelet therapies. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00059306.