White Matter Hyperintensities Improve Ischemic Stroke Recurrence Prediction

Abstract

Background: Nearly one in 5 patients with ischemic stroke will invariably experience a second stroke within 5 years. Stroke risk stratification schemes based solely on clinical variables perform only modestly in non-atrial fibrillation (AF) patients and improvement of these schemes will enhance their clinical utility. Cerebral white matter hyperintensities are associated with an increased risk of incident ischemic stroke in the general population, whereas their association with the risk of ischemic stroke recurrence is more ambiguous. In a non-AF stroke cohort, we investigated the association between cerebral white matter hyperintensities and the risk of recurrent ischemic stroke, and we evaluated the predictive performance of the CHA₂DS₂VASc score and the Essen Stroke Risk Score (clinical scores) when augmented with information on white matter hyperintensities. Methods: In a registry-based, observational cohort study, we included 832 patients (mean age 59.6 (SD 13.9); 42.0% females) with incident ischemic stroke and no AF. We assessed the severity of white matter hyperintensities using MRI. Hazard ratios stratified by the white matter hyperintensities score and adjusted for the components of the CHA₂DS₂VASc score were calculated based on the Cox proportional hazards analysis. Recalibrated clinical scores were calculated by adding one point to the score for the presence of moderate to severe white matter hyperintensities. The discriminatory performance of the scores was assessed with the C-statistic. Results: White matter hyperintensities were significantly associated with the risk of recurrent ischemic stroke after adjusting for clinical risk factors. The hazard ratios ranged from 1.65 (95% CI 0.70-3.86) for mild changes to 5.28 (95% CI 1.98-14.07) for the most severe changes. C-statistics for the prediction of recurrent ischemic stroke were 0.59 (95% CI 0.51-0.65) for the CHA₂DS₂VASc score and 0.60 (95% CI 0.53-0.68) for the Essen Stroke Risk Score. The recalibrated clinical scores showed improved C-statistics: the recalibrated CHA₂DS₂VASc score 0.62 (95% CI 0.54-0.70; p = 0.024) and the recalibrated Essen Stroke Risk Score 0.63 (95% CI 0.56-0.71; p = 0.031). C-statistics of the white matter hyperintensities score were 0.62 (95% CI 0.52-0.68) to 0.65 (95% CI 0.58-0.73). Conclusions: An increasing burden of white matter hyperintensities was independently associated with recurrent ischemic stroke in a cohort of non-AF ischemic stroke patients. Recalibration of the CHA₂DS₂VASc score and the Essen Stroke Risk Score with one point for the presence of moderate to severe white matter hyperintensities led to improved discriminatory performance in ischemic stroke recurrence prediction. Risk scores based on white matter hyperintensities alone were at least as accurate as the established clinical risk scores in the prediction of ischemic stroke recurrence.

Clinical Significance of Magnetic Resonance Imaging Markers of Vascular Brain Injury

“…Adding 4 studies reporting associations with continuous WMH burden in a sample size-weighted metaanalysis confirmed the association with incident AD (n = 7123 participants; n = 708 events; P < .001). 49,50,52,56 We found a significant association in 13 138 participants from 13 studies of extensive WMH (n = 1496 participants) with mortality (n = 1700 deaths) overall (I 2 = 41%; P = .06), in the general population, 1 7, 3 6 , 3 9 , 5 9 ,6 1 and in high-risk populations 14,20,33,37,58,60,62,63 (Table; Figure 2) (eTables 3 and 6 in the Supplement). Adding 3 studies reporting associations with continuous WMH burden in a sample sizeweighted meta-analysis confirmed the association with increased mortality (n = 13 939 participants; n = 1818 events; P < .001).…”

“…In 14 529 participants from 17 studies, we found a significant association of extensive WMH burden (n = 2859 participants) with risk of incident stroke (n = 1049 events) overall (heterogeneity test results, I 2 = 56%;P = .003), in the general population, 6,17,25,27,35,36 and in high risk populations 14,19,20,23,24,28,29,[31][32][33]37 associations with continuous WMH burden in a sample sizeweighted meta-analysis confirmed the association with incident stroke (n = 14 913 participants; n = 1114 events; P < .001). 15,22,30 Regarding stroke subtypes, extensive WMH burden was significantly associated with increased risk of incident IS overall (I 2 = 67%;P = .002), in the general population, 26,27,36 and in highrisk populations 14,20,23,29,31,33 and with increased risk of incident ICH overall (I 2 = 65%; P = .008) 16,18,21,24,26,31,34 and in the general population 16,21,26 (Table) (eTables 3 and 4 and eFigure 2 in the Supplement). In 9338 participants from 12 studies, extensive WMH burden (n = 2402 participants) was significantly associated with incident dementia risk (n = 1127 events) overall (I 2 = 64%; P = .001) and in the general population, 25,39,48,52 while the association was only nominally significant in high-risk populations 38,41-46,53 (Table; Figure 2) (eTables 3 and 4 in the Supplement).…”

“…For WMH, 52 studies met our inclusion criteria: 25 for stroke, 6, 22 for dementia, 25,35,[38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57] and 16 for death. 14,15,17,20,22,33,36,37,39,[58][59][60][61][62][63][64] For BI, we included 24 studies: 14 for stroke, 16,17,21,25,33,36,39,[65][66][67][68][69][70][71] 10 for dementia, 25,39,40,48,51,54,57,[72][73][74] and 8...…”

“…As well as integrating information on multiple MRI markers of VBI, our review adds numerous new studies. 14,16,[18][19][20][21][24][25][26]28,29,32,33,35,36,41,46,[49][50][51]57,58,64,72,75,84,88,95,96,99,[102][103][104][105] We also present, to our knowledge, the first metaanalyses on the association of BI with stroke subtypes, dementia, and mortality and the first systematic review on the association of PVS with stroke, dementia, and mortality.…”

Pulmonary Arteriovenous Malformations Are Associated with Silent Brain Infarcts in Hereditary Hemorrhagic Telangiectasia Patients

“…Multiple causative mechanisms exist for SBI including small vessel disease, embolism, and hypoperfusion. The presence of SBI is clinically important due to the fact that it has been associated with recurrent clinical ischemic stroke, neurocognitive dysfunction, psychiatric disorders, and increased mortality [1,4,5]. Because hereditary hemorrhagic telangiectasia (HHT) patients are a population who do receive screening brain MRIs, identification of SBI can be important due to the fact that preventative measures can be adhered to in order to prevent future ischemic events.…”