Study population
In the prospective study, we analyzed data of minor cerebrovascular events patients, aged 45 to 85 years, enrolled from March 1, 2018 to March 1, 2020 from the department of neurology, Affiliated Jiangning Hospital of Nanjing Medical University. AIS patients were defined based on their clinical presentation and/or the presence of hyperintense lesion on Diffusion Weighted Imaging (DWI). For stroke patients with no DWI lesion, stroke diagnosis was confirmed by two experienced stroke clinician based on the clinical manifestations. The patients with severe head injury, multiple sclerosis, severe cerebral infarction, cerebral hemorrhage, rheumatic diseases or brain malignancy were excluded.
Finally, a total of 388 consecutive eligible patients were enrolled according to the minor cerebrovascular events definition (National Institutes of Health Stroke Scale Score ≤ 3) and exclusion criteria [16]. All the patients were first-ever minor ischemic stroke. The exclusion criteria were as followed:(1) Premorbid modified Rankin Scale (mRS) score of ≥2 (n = 11); (2) Thrombolysis therapy for patients with strokes within 4.5 h of symptom onset (n = 51); (3) No baseline MRI (n = 17) or one or more of the sequences essential for the calculation of SVD score were missing (n = 9); (3) Lacking complete clinical data (n = 21); (4) Patients without follow-up data at 3 months missing (n = 25); (5) Refused to join in the study (n = 16); (6) Deaths from other causes (n = 8), with a total of 388 patients left (Fig. 1).
The present study was approved by the ethics committee of Jiangning Hospital.
Affiliated to Nanjing Medical University. Written informed consent was obtained.
from all participants.
Risk factors
Patients underwent a neurological examination after admission. For determination of the subtype of ischemic stroke, the original TOAST (Trial of ORG 10172 in Acute Stroke Treatment) criteria were used. These 5 major categories of the TOAST classification are as follows: large-artery atherosclerosis (LAA), including large-artery thrombosis and artery-to-artery embolism; cardioembolism (CE); small-artery occlusion (SAO); stroke of other determined cause (OC); and stroke of undetermined cause (UND).
After admission, we collected data of patients’ demographic characteristics and traditional vascular risk factors [8], including age and sex, history of hypertension, history of diabetes mellitus, history of dyslipidemia, history of atrial fibrillation, history of coronary heart disease; history of thrombolysis, history of embolectomy, cigarette or alcohol use. we also collected laboratory results, including results for fasting blood glucose (FBG) and glycosylated hemoglobin (HbA1c), total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), homocysteine (Hcy), lipoprotein-associated phospholipase A2 (Lp-PLA2), high C-reactive protein (H-CRP), and D-Dime.
Color Doppler ultrasonography (CDU) of the carotid artery
For each patient, we also measured the intima plaques and intima–media thickness (IMT) using a Philips S3000 ultrasound machine (Philips HD20, Netherlands). We observed the formation of intima plaques and measured the IMT using a 7.5- to 10-MHz probe frequency. Plaque formation was diagnosed when the local IMT was > 1.2 mm or > 1.5 times the surrounding IMT [17]. Stable plaques were hard and flat, while unstable plaques were soft, ulcerative, and mixed. The site selected for IMT quantitative measurement was 1.5 cm distal to the carotid artery bifurcation [17]. Two sonographers participated in the evaluation of CDU results.
Radiologic data
MRI acquisition
MRI scanning was performed within 7 days of stroke onset on a 3.0 T MRI scanner (Ingenia, Philips Medical Systems, the Netherlands) with an 8-channel receiver array head coil. High-resolution T1-weighted axial images covering the whole brain were obtained by a 3D-magnetization prepared rapid gradient-echo sequence: TR = 8.1 ms; FA = 90°; TE = 3.7 ms; FOV =240 × 240 mm; acquisition matrix = 240 × 222; gap = 0 mm, thickness = 1.0 mm; number of slices = 170. T2-weighted; TR = 4000 ms; TE =107 ms; FA = 90°; FOV =230 × 230 mm acquisition matrix = 384 × 384; thickness = 1.5 mm; gap = 0 mm, number of slices = 18. DWI-weighted TR = 2503 ms; TE =98 ms; FA =90°; FOV =230 × 230 mm acquisition matrix =152 × 122; thickness = 1.5 mm; gap = 0 mm, number of slices = 18. Susceptibility weighted imaging (SWI)-weighted TR = 16 ms; TE =23 ms; FA =10°; FOV =220 × 180 mm; acquisition matrix = 220 × 180; thickness = − 0.6 mm; gap = 0 mm, number of slices = 200. Additionally, the T2 fluid-attenuated inversion recovery (FLAIR) axial images were obtained with the following parameters: TR = 10,000 ms; TE = 120 ms; FA =110°; FOV =220× 220 mm; acquisition matrix = 336 × 189; thickness = 1.5 mm; gap = 0 mm, number of slices =18.
Fazekas score and SVD burden score
Results are reported in accordance with STRIVE [12]. Fazekas score was used to score WMH [18]. We used the previously described total SVD burden score [13, 14], an ordinal scale (0 to 4) counting the presence of each of the four MRI markers for SVD. In more details, SVD burden score was composed of: (1) WMH was graded using the Fazekas score on FLAIR and divided into periventricular and deep WMH according to the lesion location. If confluent WMH (Fazekas score 2 and 3) were present, one point was awarded (Fig. 2a). (2) lacunar infarcts: presence of one or more lacunes was defined as sharply demarcated hypointense lesions sized between< 15 mm in diameter on T1-weighted images with corresponding hypointense lesions with hyperintense rim on FLAIR [13, 14]. (Fig. 2b). (3) CMB were defined as round hypointense lesions on SWI-weighted gradient echo-images with a diameter < 10 mm. CMB were then divided to lobar versus deep [18]. If ≥1 deep or lobar CMB were present one point was awarded (Fig. 2c). (4) PVS were defined as smooth margin, round, oval, or linear-shaped lesions, ≤3 mm, with signal intensity equal to cerebrospinal fluid (CSF) on T1-weighted images [19, 20]. We counted PVS in the most affected hemisphere. One point was awarded if 30 or more PVS were present at any of the locations (Fig. 2d). Two experienced neurologists and a neuroradiologist participated in the evaluation of MRI results.
Patient outcomes
We rated the 90-day modified Rankin Scale (mRS) outcome and dichotomized as good functional outcome (mRS 0–1) and poor functional outcome (mRS 2–6) at 90 days [21]. Stroke progression was defined as a worsening deficit during hospitalization compare with NIHSS score at the baseline assessment [22]. A recurrent stroke was defined as a new sudden focal neurological deficit (vascular, > 24 h), which occurs at any time between the initial attack and 90-day follow-up mandating repeat imaging [22]. These outcome events were reviewed in detail by 2 experienced neurologists and a neuroradiologist, and a consensus decision was made on progression or recurrence of stroke [21, 22].
Statistical analysis
Statistical analysis was conducted using SPSS software (Version 17.0, SPSS Inc., USA). Mean (standard deviation) or median (interquartile range) measurements were used to describe continuous variables which had a normal or non-normal distribution. Frequencies were used to describe categorical variables. Normality was confirmed by the Kolmogorov-Smirnov test. Inter-group comparisons for a normally distributed.
data were performed using the independent sample t test. The χ2 tests, Mann-Whitney and the Kruskal–Wallis tests were used to assess categorical variables and non-normally distributed continuous variables. Multiple linear regression analysis was used to explore association of SVD burden and WMH with poor outcome, progression, and recurrence at 90 days controlling for age, gender, vascular risks and admission NIHSS. Furthermore, univariate and multivariate logistic regression analysis was used to ascertain the likelihood that patients will develop poor-outcome after 90 days. Variables with a P < 0.05 in univariate regression analyses and other risk factors related to prognosis of minor cerebrovascular events were included in the multivariate logistic-regression models. P < 0.05 was considered statistical significance.