Morphological classification of penetrating artery pontine infarcts and association with risk factors and prognosis: The SPS3 trial.

BACKGROUND: Pontine infarcts are common and often attributed to small vessel disease ("small deep infarcts") or basilar branch atherosclerosis ("wedge shaped"). A well-described morphological differentiation using magnetic resonance images has not been reported. Furthermore, whether risk factors and outcomes differ by morphology, or whether infarct morphology should guide secondary prevention strategy, is not well characterized. METHODS: All participants in the Secondary Prevention of Small Subcortical Strokes Study with magnetic resonance imaging -proven pontine infarcts were included. Infarcts were classified as well-circumscribed small deep (small deep infarct, i.e. lacunar), paramedian, atypical paramedian, or other based on diffusion-weighted imaging, T2/fluid-attenuated inversion recovery, and T1-magnetic resonance images. Inter-rater reliability was high (90% agreement, Cohen's kappa = 0.84). Clinical and radiologic features independently associated with small deep infarct versus paramedian infarcts were identified (multivariable logistic regression). Differences in stroke risk and death were assessed using Cox proportional hazards. RESULTS: Of the 3020 patients enrolled, 644 had pontine infarcts; 619 images were available: 302(49%) small deep infarct, 245 (40%) paramedian wedge, 35 (6%) atypical paramedian, and 37 (6%) other. Among vascular risk factors, only smoking (OR 2.1, 95% CI 1.3-3.3) was independently associated with small deep infarct versus paramedian infarcts; on neuroimaging, old lacunes on T1/fluid-attenuated inversion recovery (OR 1.8, 1.3-2.6) and intracranial stenosis (any location) ≥50% (OR 0.62, 0.41-0.96). Small deep infarct versus paramedian was not predictive of either recurrent stroke or death, and there was no interaction with assigned treatment. CONCLUSIONS: Pontine infarcts can be reliably classified based on morphology using clinical magnetic resonance images. Few risk factors differed between small deep infarct and paramedian infarcts with no differences in recurrent stroke or mortality. There was no difference in response to different antiplatelet or blood pressure treatment strategies between these two groups. REGISTRATION: http://www.clinicaltrials.gov/NCT00059306.

Spatial Relationship between Acute Lacunar Infarction and White Matter Hyperintensities.

BACKGROUND: White matter hyperintensities (WMH) predict incident strokes and new lacunes; moreover, WMH may also affect infarct locations. Our aim in this study was to examine the spatial relationship between WMH and acute lacunar infarction. METHODS: Five hundred and ninety patients with acute lacunar infarction in supratentorial region were included. Four situations between infarction and WMH were assessed by axial and coronal MRI: no contact (Grade 0), contact without overlap (Grade Ia), partial overlap (Grade Ib), and complete overlap (Grade II) with preexisting WMH. Furthermore, we defined infarctions in Grades Ia and Ib as edge-localized infarctions and investigated their predictors and short-term outcome. RESULTS: 47.9% (283) of the infarctions were edge-localized infarctions (Grade Ia = 27.6% and Grade Ib = 20.3%), 51.5% (304) were Grade 0, only 0.5% (3) were Grade II. Patients with edge-localized infarction had larger infarct size, more severe WMH, higher National Institutes of Health Stroke Scale (NIHSS) and lower Barthel index (BI) score at admission than those with non-edge-localized infarction. They also had lower BI score at discharge. Infarction in subcortical white matter, diffusion-weighted imaging infarct size, periventricular WMH and deep WMH were predictors for edge-localized infarction. CONCLUSIONS: Half of lacunar infarctions were located at the edge of WMH. Both periventricular WMH and deep WMH were predictors for edge-localized infarction.

Genetic Architecture of Lacunar Stroke.

BACKGROUND AND PURPOSE: Lacunar strokes comprise ≈20% of all strokes. Despite this frequency, their pathogenesis is poorly understood. Previous genome-wide association studies in lacunar stroke have been disappointing, which may be because of phenotypic heterogeneity. Pathological and radiological studies suggest that there may be different pathologies underlying lacunar strokes. This has led to the suggestion of 2 subtypes: isolated lacunar infarcts and multiple lacunar infarcts and leukoaraiosis. METHODS: We performed genome-wide analyses in a magnetic resonance imaging-verified cohort of 1012 younger onset lacunar stroke cases and 964 controls. Using these data, we first estimated the heritability of lacunar stroke and its 2 hypothesized subtypes, and secondly, we determined whether this is enriched for regulatory regions in the genome, as defined by data from Encyclopedia of DNA Elements (ENCODE) and other sources. Finally, we determine the evidence for a polygenic contribution from rare variation to lacunar stroke and its subtypes. RESULTS: Our results indicate a substantial heritable component to magnetic resonance imaging-verified lacunar stroke (20%-25%) and its 2 subtypes (isolated lacunar infarct, 15%-18%; multiple lacunar infarcts/leukoaraiosis, 23%-28%). This heritable component is significantly enriched for sites affecting expression of genes. In addition, we show that the risk of the 2 subtypes of lacunar stroke in isolation, but not in combination, is associated with rare variation in the genome. CONCLUSIONS: Lacunar stroke, when defined on magnetic resonance imaging, is a highly heritable complex disease. Much of this heritability arises from regions of the genome affecting gene regulation. Rare variation affects 2 subtypes of lacunar in isolation, suggesting that they may have distinct genetic susceptibility factors.

Association between arterial calcifications and nonlacunar and lacunar ischemic strokes.

BACKGROUND AND PURPOSE: Nonlacunar cerebral infarcts are presumed to be caused by thromboembolism from the heart or extracranial arteries, whereas lacunar infarcts are thought to be caused by small vessel disease. We investigated to what extent arterial calcifications differ between nonlacunar and lacunar ischemic strokes. METHODS: We studied 820 consecutive patients with transient ischemic attack or ischemic stroke in the anterior circulation who underwent multidetector computed tomography angiography and had no rare cause of stroke. The presence of likely cardioembolic pathogenesis was determined according to the Trial of Org 10172 in Acute Stroke Treatment criteria. The remaining 708 patients were categorized as nonlacunar or lacunar strokes, either transient ischemic attacks or strokes, based on clinical symptoms corrected by brain imaging results. We measured volume of calcifications in the aortic arch, symptomatic extracranial and intracranial carotid artery using multidetector computed tomography angiography. The difference in calcifications between nonlacunar and lacunar strokes was assessed with a multivariable logistic regression analysis. We adjusted for degree of symptomatic carotid artery stenosis and cardiovascular risk factors. RESULTS: We found an independent association between volume of aortic arch calcifications and nonlacunar ischemic strokes (adjusted odds ratio [95% confidence interval], 1.11 [1.02-1.21]). No independent associations between extracranial and intracranial carotid artery calcifications and nonlacunar strokes were present. CONCLUSIONS: The only difference we found between nonlacunar and lacunar strokes was a higher calcification volume in the aortic arch in nonlacunar strokes. Our findings only partially confirm the notion of distinct etiologies and suggest that the potential role of other plaque components, plaque morphology, and aortic arch calcifications in ischemic stroke subtypes awaits further evaluation.

Acute simultaneous multiple lacunar infarcts: a severe disease entity in small artery disease.

BACKGROUND: We hypothesized that acute simultaneous multiple lacunar infarcts (sMLI) may have different clinico-radiological characteristics compared to acute single lacunar infarcts (SLI). METHODS: We retrospectively reviewed stroke patients with sMLI or SLI in a consecutively collected stroke registry with a predefined long-term clinical follow-up. Clinical characteristics, including vascular risk factors, rheological profiles, premorbid functional status, and clinical outcome were evaluated. In addition, radiological characteristics, including white matter ischemic changes, previous lacunes, microbleeds, and concomitant intra- or extracranial arterial stenosis were evaluated. RESULTS: Of the 548 acute ischemic stroke patients, sMLI was found in 23 (13.5%) and SLI in 148 (86.5%). There was no difference in vascular risk factors and rheological profiles between the two groups, except for advanced age and more frequent previous history of stroke in the sMLI group. The sMLI group also showed more previous lacunes (p < 0.001) and microbleeds (p < 0.001). A cardioembolic or atherothrombotic stroke mechanism was rare in both groups. Recurrent strokes were more frequent in the sMLI group. CONCLUSIONS: The main pathophysiology of sMLI may be small artery disease. However, clinico-radiological characteristics suggest that sMLI may be a more severe entity of small artery disease compared to SLI.

Lacunar versus non-lacunar syndromes.

Small-vessel disease is the accepted most frequent cause of lacunar stroke. The main clinical features seen with lacunar infarcts are motor and/or sensitive deficit, ataxic sign, without cortical involvement. A lacunar syndrome is generally the result of a small deep infarct within the territory of a single perforating artery with the maximum diameter on imaging of 15 mm. Recent studies have demonstrated alternative causes of lacunar stroke other than small-vessel disease (e.g. cardio embolism, atherosclerosis or other causes), especially in large lacunae, with a potential relevance on functional outcome. These findings suggest that lacunar stroke is not always a benign disease. Moreover, clinical features may be significant in terms of disability in lacunae in close proximity to crucial anatomical site. The following chapter reports the classical lacunar syndrome and discusses the debated etiology of lacunar stroke.

Levels of heparin-releasable TFPI are increased in first-ever lacunar stroke patients.

OBJECTIVES: New insights in the pathophysiology of lacunar stroke (LS) suggest that it is caused by increased permeability of the blood-brain barrier due to endothelial activation. Because endothelial cells are the major production and storage site of tissue factor pathway inhibitor (TFPI), this protein can be used as marker of endothelial activation. In this observational study we measured the different pools of TFPI, as a marker of endothelial function, in first-ever lacunar stroke patients. METHODS: We determined antigen levels of total and free full-length (FL) TFPI using ELISA in 149 patients and 42 controls. Heparin-releasable free FL TFPI was determined in a random subset of 17 patients and 15 controls. By brain MRI, we classified LS patients as having isolated lacunar infarct (ILA) or silent ischemic lesions (SILs). RESULTS: Plasma levels of total TFPI were highest in patients with SILs compared with those with ILA, but this association disappeared after correction for age and levels of low-density lipoprotein cholesterol. However, levels of heparin-releasable free FL TFPI were higher in patients than in controls. CONCLUSIONS: Although ambient plasma levels of total TFPI were not different in subtypes of LS, the increased levels of heparin-releasable TFPI in patients suggest a role of endothelial activation in the pathogenesis of LS.

Risk factors for lacune subtypes in the Atherosclerosis Risk in Communities (ARIC) Study.

OBJECTIVE: Lacunar infarctions are mainly due to 2 microvascular pathologies: lipohyalinosis and microatheroma. Little is known about risk factor differences for these subtypes. We hypothesized that diabetes and glycated hemoglobin (HbA(1)c) would be related preferentially to the lipohyalinotic subtype. METHODS: We performed a cross-section analysis of the brain MRI data from 1,827 participants in the Atherosclerosis Risk in Communities study. We divided subcortical lesions ≤ 20 mm in diameter into those ≤ 7 mm (of probable lipohyalinotic etiology) and 8-20 mm (probably due to microatheroma) and used Poisson regression to investigate associations with the number of each type of lesion. Unlike previous studies, we also fitted a model involving lesions <3 mm. RESULTS: Age (prevalence ratio [PR] 1.11 per year; 95% confidence interval [CI] 1.08-1.14), black ethnicity (vs white, PR 1.66; 95% CI 1.27-2.16), hypertension (PR 2.12; 95% CI 1.61-2.79), diabetes (PR 1.42; 95% CI 1.08-1.87), and ever-smoking (PR 1.34; 95% CI 1.04-1.74) were significantly associated with lesions ≤ 7 mm. Findings were similar for lesions <3 mm. HbA(1)c, substituted for diabetes, was also associated with smaller lesions. Significantly associated with 8-20 mm lesions were age (PR 1.14; 95% CI 1.09-1.20), hypertension (PR 1.79; 95% CI 1.14-2.83), ever-smoking (PR 2.66; 95% CI 1.63-4.34), and low-density lipoprotein (LDL) cholesterol (PR 1.27 per SD; 95% CI 1.06-1.52). When we analyzed only participants with lesions, history of smoking (PR 1.99; 95% CI 1.23-3.20) and LDL (PR 1.33 per SD; 95% CI 1.08-1.65) were associated with lesions 8-20 mm. CONCLUSIONS: Smaller lacunes (even those <3 mm) were associated with diabetes and HbA(1)c, and larger lacunes associated with LDL cholesterol, differences which support long-held theories relating to their underlying pathology. The findings may contribute to broader understanding of cerebral microvascular disease.