Reliable quantification of white matter hyperintensities of presumed vascular origin (WMHs) is increasingly needed, given the presence of these MRI findings in patients with several neurological and vascular disorders, as well as in elderly healthy subjects.We present BIANCA (Brain Intensity AbNormality Classification Algorithm), a fully automated, supervised method for WMH detection, based on the k-nearest neighbour (k-NN) algorithm. Relative to previous k-NN based segmentation methods, BIANCA offers different options for weighting the spatial information, local spatial intensity averaging, and different options for the choice of the number and location of the training points. BIANCA is multimodal and highly flexible so that the user can adapt the tool to their protocol and specific needs.We optimised and validated BIANCA on two datasets with different MRI protocols and patient populations (a “predominantly neurodegenerative” and a “predominantly vascular” cohort).BIANCA was first optimised on a subset of images for each dataset in terms of overlap and volumetric agreement with a manually segmented WMH mask. The correlation between the volumes extracted with BIANCA (using the optimised set of options), the volumes extracted from the manual masks and visual ratings showed that BIANCA is a valid alternative to manual segmentation. The optimised set of options was then applied to the whole cohorts and the resulting WMH volume estimates showed good correlations with visual ratings and with age. Finally, we performed a reproducibility test, to evaluate the robustness of BIANCA, and compared BIANCA performance against existing methods.Our findings suggest that BIANCA, which will be freely available as part of the FSL package, is a reliable method for automated WMH segmentation in large cross-sectional cohort studies.

SummaryBackgroundA third of transient ischaemic attacks (TIAs) and ischaemic strokes are of undetermined cause (ie, cryptogenic), potentially undermining secondary prevention. If these events are due to occult atheroma, the risk-factor profile and coronary prognosis should resemble that of overt large artery events. If they have a cardioembolic cause, the risk of future cardioembolic events should be increased. We aimed to assess the burden, outcome, risk factors, and long-term prognosis of cryptogenic TIA and stroke.MethodsIn a population-based study in Oxfordshire, UK, among patients with a first TIA or ischaemic stroke from April 1, 2002, to March 31, 2014, we compared cryptogenic events versus other causative subtypes according to the TOAST classification. We compared markers of atherosclerosis (ie, risk factors, coronary and peripheral arterial disease, asymptomatic carotid stenosis, and 10-year risk of acute coronary events) and of cardioembolism (ie, risk of cardioembolic stroke, systemic emboli, and new atrial fibrillation [AF] during follow-up, and minor-risk echocardiographic abnormalities and subclinical paroxysmal AF at baseline in patients with index events between 2010 and 2014).FindingsAmong 2555 patients, 812 (32%) had cryptogenic events (incidence of cryptogenic stroke 0·36 per 1000 population per year, 95% CI 0·23–0·49). Death or dependency at 6 months was similar after cryptogenic stroke compared with non-cardioembolic stroke (23% vs 27% for large artery and small vessel subtypes combined; p=0·26) as was the 10-year risk of recurrence (32% vs 27%; p=0·91). However, the cryptogenic group had fewer atherosclerotic risk factors than the large artery disease (p<0·0001), small vessel disease (p=0·001), and cardioembolic (p=0·008) groups. Compared with patients with large artery events, those with cryptogenic events had less hypertension (adjusted odds ratio [OR] 0·41, 95% CI 0·30–0·56; p<0·0001), diabetes (0·62, 0·43–0·90; p=0·01), peripheral vascular disease (0·27, 0·17–0·45; p<0·0001), hypercholesterolaemia (0·53, 0·40–0·70; p<0·0001), and history of smoking (0·68, 0·51–0·92; p=0·01), and compared with small vessel and cardioembolic subtypes, they had no excess risk of asymptomatic carotid disease (adjusted OR 0·64, 95% CI 0·37–1·11; p=0·11) or acute coronary events (adjusted hazard ratio [HR] 0·76, 95% CI 0·49–1·18; p=0·22) during follow-up. Compared with large artery and small vessel subtypes combined, patients with cryptogenic events also had no excess of minor-risk echocardiographic abnormalities (cryptogenic 37% vs 45%; p=0·18) or paroxysmal AF (6% vs 10%; p=0·17) at baseline or of new AF (adjusted HR 1·23, 0·78–1·95; p=0·37) or presumed cardioembolic events (1·16, 0·62–2·17; p=0·64) during follow-up.InterpretationThe clinical burden of cryptogenic TIA and stroke is substantial. Although stroke recurrence rates are comparable with other subtypes, cryptogenic events have the fewest atherosclerotic markers and no excess of cardioembolic markers.FundingWellcome Trust, Wolfson Foundation, UK Stro...

Background and Purpose-To design appropriate molecular genetic studies, we first need to understand the genetic epidemiology of stroke. We therefore performed a systematic review of the literature to assess the heritability of stroke according to methodological quality of studies and to determine any heterogeneity in findings between studies and possible publication bias. Methods-We searched for twin studies and studies of family history of stroke using bibliographic databases and by hand-searching reference lists and journals. Odds ratios (ORs) for family history as a risk factor for stroke were calculated within studies and combined by meta-analysis. Heterogeneity between studies, methodological quality of studies, and the influence of the age at which stroke occurred in both probands and relatives were assessed. Results-We identified 53 independent studies (3 twin, 33 case-control, and 17 cohort). Monozygotic twins were more likely to be concordant than dizygotic twins (OR, 1.65; 95% CI, 1.2 to 2.3; Pϭ0.003). A positive family history was a risk factor for stroke in both case-control (OR, 1.76; 95% CI, 1.7 to 1.9; PϽ0.00001) and cohort (OR, 1.30; 95% CI, 1.2 to 1.5; PϽ0.00001) studies. However, there was major heterogeneity between studies (cohort Pϭ0.0001; case-control PϽ0.00001), with much stronger associations in small studies and methodologically less rigorous studies. Moreover, studies that reported insufficient data to allow meta-analysis tended to have found weaker associations. Family history of stroke was more frequent in studies that were confined to probands or relatives aged Ͻ70 years. However, few studies considered the number of affected and unaffected relatives, only 2 studies considered stroke phenotypes in detail, and only 19 studies (38%) adjusted associations for intermediate phenotypes.No twin study, only 5 cohort studies (26%), and 20 case-control studies (61%) differentiated between ischemic and hemorrhagic stroke in the proband. Family history of stroke was more frequent in large-and small-vessel stroke than in cardioembolic stroke. There were very few data on the influence of family history on stroke severity and no data on stroke recovery. Conclusions-Twin studies suggest a small genetic contribution to stroke, but reliable interpretation of published family history studies is undermined by major heterogeneity, insufficient detail, and potential publication and reporting bias.More detailed large-scale genetic epidemiology is required.

Background-To understand the mechanisms of stroke and to target prevention, we need to know how risk factors differ between etiological subtypes. Hospital-based studies may be biased because not all stroke patients are admitted. If risk factors differ between patients who are admitted and those who are not, then case-control studies will be biased. If the likelihood of admission also depends on stroke subtype, then case-case comparisons may also be biased. Methods-We compared risk factors and ischemic stroke subtypes (TOAST classification) in hospitalized and nonhospitalized patients in 2 population-based stroke incidence studies: the Oxford Vascular Study (OXVASC) and Oxfordshire Community Stroke Project (OCSP). We also performed a meta-analysis of risk factor-stroke subtype associations with other published population-based studies. Results-In OXVASC and OCSP, stroke subtypes differed between hospitalized (293 of 647) and nonhospitalized patients (PϽ0.0001), with more cardioembolic strokes (odds ratio [OR], 1.8; 95% CI, 1.3 to 2.6) and fewer lacunar strokes (OR, 0.4; 95% CI, 0.3 to 0.7). Premorbid blood pressure and cholesterol were higher in hospitalized patients (both PϽ0.0001). Risk factor-stroke subtype associations in hospitalized patients were consequently biased (Pϭ0.001). Meta-analysis of data from all patients in OXVASC, OCSP, and 2 other studies demonstrated consistent risk factor-stroke subtype associations. However, contrary to previous hospital-based studies, there was only a weak (OR, 1.4; 95% CI, 1.1 to 1.8) and inconsistent (P heterogeneity ϭ0.01) association between small-vessel stroke and hypertension and no association with diabetes (OR, 1.0; 95% CI, 0.7 to 1.3). Conclusions-Prevalences of risk factors and stroke subtypes differ between hospitalized and nonhospitalized patients with ischemic stroke, which may bias hospital-based risk factor studies. Meta-analysis of population-based studies suggests that vascular risk factors differ between stroke subtypes.

Background and Purpose-The modified Rankin Scale is widely used to assess changes in activity and lifestyle after stroke, but it has been criticized for its subjectivity. The purpose of the present study was to compare conventional assessment on the modified Rankin Scale with assessment through a structured interview. Methods-Sixty-three patients with stroke 6 to 24 months previously were interviewed and graded independently on the modified Rankin Scale by 2 observers. These observers then underwent training in use of a structured interview for the scale that covered 5 areas of everyday function. Eight weeks after the first assessment, the same observers reassessed 58 of these patients using the structured interview. Results-Interrater reliability was measured with the statistic (weighted with quadratic weights). For the scale applied conventionally, overall agreement between the 2 raters was 57% ( w ϭ0.78); 1 rater assigned significantly lower grades than the other (Pϭ0.048). On the structured interview, the overall agreement between raters was 78% ( w ϭ0.93), and there was no overall difference between raters in grades assigned (Pϭ0.17). Rankin grades from the conventional assessment and the structured interview were highly correlated, but there was significantly less disagreement between raters when the structured interview was used (Pϭ0.004). Conclusions-Variability and bias between raters in assigning patients to Rankin grades may be reduced by use of a structured interview. Use of a structured interview for the scale could potentially improve the quality of results from clinical studies in stroke.

Objective:In patients with TIA and ischemic stroke, we validated the total small vessel disease (SVD) score by determining its prognostic value for recurrent stroke.Methods:Two independent prospective studies were conducted, one comprising predominantly Caucasian patients with TIA/ischemic stroke (Oxford Vascular Study [OXVASC]) and one predominantly Chinese patients with ischemic stroke (University of Hong Kong [HKU]). Cerebral MRI was performed and assessed for lacunes, microbleeds, white matter hyperintensities (WMH), and perivascular spaces (PVS). Predictive value of total SVD score for risk of recurrent stroke was determined and potential refinements considered.Results:In 2,002 patients with TIA/ischemic stroke (OXVASC n = 1,028, HKU n = 974, 6,924 patient-years follow-up), a higher score was associated with an increased risk of recurrent ischemic stroke (adjusted hazard ratio [HR] per unit increase: 1.32, 1.16–1.51, p < 0.0001; c statistic 0.61, 0.56–0.65, p < 0.0001) and intracerebral hemorrhage (ICH) (HR 1.54, 1.11–2.13, p = 0.009; c statistic 0.65, 0.54–0.76, p = 0.006). A higher score predicted recurrent stroke in SVD and non-SVD TIA/ischemic stroke subtypes (c statistic 0.67, 0.59–0.74, p < 0.0001 and 0.60, 0.55–0.65, p < 0.0001). Including burden of microbleeds and WMH and adjusting the cutoff of basal ganglia PVS potentially improved predictive power for ICH (c statistic 0.71, 0.60–0.81, phet = 0.45), but not for recurrent ischemic stroke (c statistic 0.60, 0.56–0.65, phet = 0.76) on internal validation.Conclusions:The total SVD score has predictive value for recurrent stroke after TIA/ischemic stroke. Prediction of recurrence in patients with nonlacunar events highlights the potential role of SVD in wider stroke etiology.

Background and Purpose-Arterial stiffening reduces damping of the arterial waveform and hence increases pulsatility of cerebral blood flow, potentially damaging small vessels. In the absence of previous studies in patients with recent transient ischemic attack or stroke, we determined the associations between leukoaraiosis and aortic and middle cerebral artery stiffness and pulsatility. Methods-Patients were recruited from the Oxford Vascular Study within 6 weeks of a transient ischemic attack or minor stroke. Leukoaraiosis was categorized on MRI by 2 independent observers with the Fazekas and age-related white matter change scales. Middle cerebral artery (MCA) stiffness (transit time) and pulsatility (Gosling's index: MCA-PI) were measured with transcranial ultrasound and aortic pulse wave velocity and aortic systolic, diastolic, and pulse pressure with applanation tonometry (Sphygmocor). Results-In 100 patients, MCA-PI was significantly greater in patients with leukoaraiosis (0.91 versus 0.73, PϽ0.0001).Severity of leukoaraiosis was associated with MCA-PI and aortic pulse wave velocity (Fazekas: 2 ϭ0.39, MCA-PI Pϭ0.01, aortic pulse wave velocity Pϭ0.06; age-related white matter change: 2 ϭ0.38, MCA-PI Pϭ0.015; aortic pulse wave velocity Pϭ0.026) for periventricular and deep white matter lesions independent of aortic systolic blood pressure, diastolic blood pressure, and pulse pressure and MCA transit time with MCA-PI independent of age. In a multivariate model (r 2 ϭ0.68, PϽ0.0001), MCA-PI was independently associated with aortic pulse wave velocity (Pϭ0.016) and aortic pulse pressure (PϽ0.0001) and inversely associated with aortic diastolic blood pressure (PϽ0.0001) and MCA transit time (Pϭ0.001). Conclusions-MCA pulsatility was the strongest physiological correlate of leukoaraiosis, independent of age, and was dependent on aortic diastolic blood pressure and pulse pressure and aortic and MCA stiffness, supporting the hypothesis that large artery stiffening results in increased arterial pulsatility with transmission to the cerebral small vessels resulting in leukoaraiosis. (Stroke. 2012;43:2631-2636.)Key Words: arterial stiffness Ⅲ cerebral pulsatility Ⅲ etiology Ⅲ leukoaraiosis Ⅲ white matter disease P revention of premature leukoaraiosis by treating the underlying causes in middle age may reduce the risk of stroke 1 and dementia 2 and other consequences of cerebral small vessel disease, 3,4 but the etiology is not yet fully understood. The relative importance of hemodynamic factors as opposed to a primary microangiopathy 5 in the development of leukoaraiosis is unclear and associations with age, hypertension, and diabetes are consistent with both processes. 6 Previous studies have suggested a relationship between increased middle cerebral artery (MCA) pulsatility measured by transcranial Doppler ultrasound and leukoaraiosis or lacunar infarction in patients with hypertension 7 and diabetes, 8 although not necessarily independent of age. However, increased cerebral pulsatility has often been interpreted as a...

With the availability of improved brain imaging techniques, the high prevalence and clinical importance of cerebral small vessel disease have been increasingly recognised in recent years. As age is one of the most important risk factors for this condition, its prevalence is set to rise further as populations age. This may lead to an increase in the clinical consequences of white matter disease, namely cognitive decline, decreased mobility and increased stroke risk. Given the impact this will have on individuals and on healthcare systems, knowledge of the risk factors for small vessel disease, its prevention and its treatment is becoming more important. Although a lot of data are now available on the epidemiology, risk factors, clinical consequences and prognosis of leukoaraiosis, some of this information is conflicting. In this review, we summarise the current literature on cerebral small vessel disease, with an emphasis on its clinical aspects.