Effects of white matter hyperintensity burden on functional outcome after mild versus moderate-to-severe ischemic stroke

Abstract

It is uncertain whether the prognostic power of white matter hyperintensity (WMH) on post-stroke outcomes is modulated as a function of initial neurological severity, a critical determinant of outcome after stroke. This multi-center MRI study tested if higher WMH quintiles were associated with 3-month poor functional outcome (modified Rankin Scale ≥ 3) for mild versus moderate-to-severe ischemic stroke. Mild and moderate-to-severe stroke were defined as admission National Institute of Health Stroke Scale scores of 1-4 and ≥ 5, respectively. Mean age of the enrolled patients (n = 8918) was 67.2 ± 12.6 years and 60.1% male. The association between WMH quintiles and poor functional outcome was modified by stroke severity (p-for-interaction = 0.008). In mild stroke (n = 4994), WMH quintiles associated with the 3-month outcome in a dose-dependent manner for the 2nd to 5th quintile versus the 1st quintile, with adjusted-odds-ratios (aOR [95% confidence interval]) being 1.29 [0.96-1.73], 1.37 [1.02-1.82], 1.60 [1.19-2.13], and 1.89 [1.41-2.53], respectively. In moderate-to-severe stroke (n = 3924), however, there seemed to be a threshold effect: only the highest versus the lowest WMH quintile was significantly associated with poor functional outcome (aOR 1.69 [1.29-2.21]). WMH burden aggravates 3-month functional outcome after mild stroke, but has a lesser modulatory effect for moderate-to-severe stroke, likely due to saturation effects.

Fig. 1

Representative images for each quintile of white matter hyperintensity volume. Topographical frequency-volume maps were generated by using the quantitative magnetic resonance data of the 8918 patients of this study, as previously reported^,. First to fifth quintile of white matter hyperintensity volume correspond to 10, 30, 50, 70, and 90 percentile maps, respectively, which provide a quantitative estimation of the severity of white matter hyperintensity.

Fig. 2

Associations of WMH burden with 3-month and 1-year mRS score (≥ 3) in mild versus moderate-to-severe ischemic stroke. (a-b) Adjusted odds ratios (with 95% confidence intervals) for the 2nd to 5th WMH quintiles relative to the 1st WMH quintiles are presented in patients with mild vs. moderate-to-severe stroke at 3 months (a) and 1 year (b). Mixed-effects logistic regression analyses were performed with adjustment for age, sex, admission NIHSS score, stroke severity (NIHSS score of 1–4 for mild and ≥ 5 for moderate-to-severe stroke), pre-stroke mRS score, previous history of stroke, hypertension, diabetes, hyperlipidemia, smoking, atrial fibrillation, coronary artery disease, stroke subtype, prior use of statin, prior use of antiplatelet agent(s), revascularization therapy, hemoglobin, fasting blood glucose, total cholesterol, and infarct volume (on diffusion-weighted MRI) with an interaction term WMH volume quintiles × stroke severity. MRI, magnetic resonance imaging; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; WMH, white matter hyperintensity.

Fig. 3

Adjusted odds ratios for 3-month mRS score (≥ 3) in mild versus moderate-to-severe ischemic stroke at different WMH volumes. (a-b) Restricted cubic spline curves (a), with an enlarged view of the graph’s red dashed square section (b), depict associations between WMH volume and poor functional outcome at 3 months after mild vs. moderate-to-severe ischemic stroke. The solid red and blue lines show the adjusted odds ratios, and the shaded regions represent the 95% confidence intervals. Vertical dotted lines represent 20th, 40th, 60th, and 80th percentiles of WMH volumes in this study cohort. Logistic regression analysis was performed with adjustment for age, sex, admission NIHSS score, stroke severity (NIHSS score of 1–4 for mild and ≥ 5 for moderate-to-severe stroke), pre-stroke mRS score, previous history of stroke, hypertension, diabetes, hyperlipidemia, smoking, atrial fibrillation, coronary artery disease, stroke subtype, prior use of statin, prior use of antiplatelet agent(s), revascularization therapy, hemoglobin, fasting blood glucose, total cholesterol, and infarct volume (on diffusion-weighted MRI) with an interaction term WMH volume × stroke severity. The adjusted OR for admission NIHSS score was 1.18 (95% CI 1.16–1.20, p < 0.001). CI, confidence interval; MRI, magnetic resonance imaging; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; WMH, white matter hyperintensity.