Cerebral white matter changes, also known as leukoaraiosis [
Possible contributory factors include occlusive extra-cranial arterial disease, small vessel arteriosclerosis, transient decreases in local perfusion because of autoregulatory dysfunction, and microembolic disease [
In the current study, we examined the association of carotid atherosclerosis, defined by intima-media thickness (IMT) and prevalence of plaques, with LA in ischemic stroke patients.
One hundred and seventy patients admitted consecutively to the Department of Emergency at the Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel, with a documented event of acute ischemic stroke or transient ischemic attack (TIA) between January 2003 and April 2005 were included in the study. Stroke was diagnosed by an experienced vascular neurologist and supported by a CT scan. Exclusion criteria were stroke resulting from trauma or an invasive procedure, cerebral hemorrhage, history of malignant tumor, autoimmune disease, and coagulation disorders.
A written informed consent was obtained from all patients who were enrolled and signed by the patients or a first-degree relative in case of aphasia, as approved by the local Institutional Ethics Committee.
The stroke subtypes were classified according to the TOAST classification: large-artery atherosclerosis, cardioembolism, small-vessel occlusion, stroke of other determined etiology, and stroke of undetermined etiology [
Brain computed tomography (CT) scans were performed on all the patients within 24 hours of admission. Scanning was carried out without contrast enhancement and with 10 mm continuous slices. A single trained neurologist who was blinded to the patients’ clinical status evaluated the existence, location, and size of brain infarcts on CT images. White matter lesions were defined as periventricular or subcortical, areas of decreased attenuation below that expected for normal white matter. The changes were always diffusely distributed within the white matter.
Leukoaraiosis was defined as ill-defined and moderately hypodense areas of >5 mm in any CT scan dimension [
Duplex carotid ultrasonography was performed to evaluate the severity of carotid atherosclerosis. All ultrasound examinations were performed with a 128XP/10 Acuson equipped with a 7.5-MHz linear-array transducer, focus depth of 40 mm, and frame rate of 15 Hz. The intima-media thickness (IMT) was defined as the distance between the intimal-luminal interface and the medial-adventitial interface. We calculated the mean carotid artery IMT (mean IMT) by averaging the thickness at 4 sites at the far walls of both the right and left distal common carotid artery [
Diabetes mellitus was defined as a fasting blood glucose of >126 mg/dL or the use of insulin or oral hypoglycemic agents; hypertension as intermittent blood pressure measurements of >140/90 mmHg or the use of antihypertensive medications. For individuals without a fasting lipid profile, hyperlipidemia was recorded if the diagnosis of hyperlipidemia was included in their medical records or if they were receiving lipid-lowering medication (HMG-CoA reductase inhibitors or fibrates). For individuals with valid lipid profiles, it was defined by the low-density lipoprotein (LDL) or non-high-density lipoprotein (non-HDL) cholesterol concentrations (in individuals displaying elevated triglyceride concentrations of ≥2.26 mmol/L) above the recommended levels according to the risk profile defined by the updated ATP III recommendations [
All continuous data were summarized and displayed as mean ± SD. Since IMT values have a non-normal distribution, a logarithmic transformation was employed, and all results expressing IMT values were back-transformed to geometric means ± SD. Demographic and clinical data between stroke patients with and without LA were compared by the
Of the 170 acute stroke patients enrolled (mean ± SD age 66.4 ± 13.4 years, 104 men and 66 women), 94 had lacunar stroke, 32 had large-artery atherosclerotic stroke, 12 had cardioembolic stroke, 1 had stroke of undetermined etiology, and 31 had transient ischemic attack (TIA). In addition to stroke, 28.2% of the patients had diabetes mellitus, 46.7% had hyperlipidemia, 62.7% had hypertension, and 26.2% are current smokers. Seventy-two patients (42.4%) were found to have 1 or more white-matter lesions or leukoaraiosis (LA) on CT images located in frontal, parietal, or occipital region. Of the acute stroke patients, 49 patients (28.8%) were recorded to have advanced LA. Figure
Risk factors and clinical characteristics of stroke patients with and without leukoaraiosis.
No Leukoaraiosis | Leukoaraiosis | ||
Index | ( | ( | |
Age, years | 62.6 | 71.4 | <0.001 |
Male gender, % | 62.0 | 59.7 | 0.770 |
BMI, kg/m2 | 27 | 26.8 | 0.700 |
Diabetes mellitus, % | 22.4 | 36.1 | 0.051 |
Hypertension, % | 54.1 | 74.6 | 0.006 |
Hyperlipidemia, % | 45.9 | 47.9 | 0.800 |
Current smoker, % | 29.8 | 21.4 | 0.230 |
Ever smoker, % | 56.8 | 53.5 | 0.670 |
Mean IMT*, mm | 0.81 | 0.86 | 0.002 |
Median IMT, (IQR), mm | 0.60 (0.55–0.74) | 0.70 (0.6–0.84) | 0.002 |
Carotid plaque/s, % | 63.3 | 82.6 | 0.007 |
NIHSS | 3.9 | 4.3 | 0.580 |
Medication use | |||
Acetylsalicylic acid, % | 33.7 | 50.0 | 0.032 |
Clopidogrel, % | 1.0 | 6.9 | 0.039 |
Beta Blockers, % | 21.4 | 33.3 | 0.082 |
Calcium blockers, % | 14.3 | 29.2 | 0.018 |
ACE Inhibitors, % | 30.6 | 45.8 | 0.042 |
ARBs, % | 1.0 | 4.2 | 0.181 |
HMG-CoA reductaseinhibitors, % | 21.6 | 25.0 | 0.609 |
Within lacunar strokes, % | 50.0 | 50.0 | 0.121 |
BMI indicates body mass index; IMT: intima-media thickness; NIHSS: National Institutes of Health Stroke Scale; ACE: angiotensin converting enzyme; ARB: angiotensin receptor blockers; HMG-CoA, 3-hydroxy-3-methylglutaryl-Coenzyme A.
*Data were logarithmically transformed before analysis, presented is the geometric mean (SD).
Two examples illustrating degrees of LA in CT scan.
Leukoaraiosis in 1 region (frontal) marked by arrow
Advanced Leukoaraiosis (in bilateral frontal and occipital regions) marked by arrows
We observed significantly increased mean IMT measures in stroke patients with LA compared to those without it (
We employed a logistic regression model in a stepwise forward manner. This encompassed age, gender, body mass index, use of acetylsalicylic acid, clopidogrel, beta blockers, calcium blockers, ACE inhibitors, ARBs, HMG-CoA reductase inhibitors, vascular risk factors, stroke history, stroke etiology, and mean IMT. The only two variables retained in the model for LA occurrence were IMT above 0.65 mm and age (O.R. 1.043, 95% CI 1.012–1.075,
(a) OR (95% CI) for incidence of leukoaraiosis. (b) OR (95% CI) for severity of white-matter lesions.
Multivariate logistic regression analysis | ||
(a) OR (95% CI) | (b) OR (95% CI) | |
Adjusted for gender, BMI, ever smoking, hypertension, diabetes mellitus, hyperlipidemia, medication use, acetylsalicylic acid, clopidogrel, beta blockers, calcium blockers, ACE inhibitors, ARBs, HMG-CoA reductase inhibitors, stroke history, stroke etiology | for Leukoaraiosis occurrence | for severity of white matter lesions |
Age, years | 1.043 (1.012–1.075), | 1.065 (1.027–1.103), |
IMT above median (0.65 mm) | 2.503 (1.181–5.302), | 3.012 (1.315–6.897), |
OR indicates odds ratio; CI: confidence interval; BMI: body mass index; ACE: angiotensin converting enzyme; ARB: angiotensin receptor blockers; HMG-CoA, 3-hydroxy-3-methylglutaryl-Coenzyme A; IMT: intima-media thickness.
Prevalence (%) of leukoaraiosis by median of intima-media thickness (IMT). *
Stroke patients with advanced WMCs represented 28.8% of the sample. Stroke patients with advanced WMCs differed significantly from stroke patients without advanced WMCs in their age (
Risk factors and carotid ultrasonography characteristics by severity of WMCs.
Advanced WMCs | |||
No | Yes | ||
( | ( | ||
Age, years | 63.6 | 73.1 | <0.001 |
Male gender | 62.0 | 59.2 | 0.734 |
BMI, kg/m2 | 27.1 | 26.4 | 0.373 |
Diabetes mellitus, % | 26.4 | 32.7 | 0.415 |
Hypertension, % | 57.0 | 77.1 | 0.015 |
Hyperlipidemia, % | 46.3 | 47.9 | 0.848 |
Current smoker, % | 29.1 | 19.1 | 0.192 |
Ever smoker, % | 56.8 | 52.1 | 0.581 |
Mean IMT*, mm | 0.81 | 0.87 | 0.003 |
Carotid plaque/s, % | 64.9 | 87.5 | 0.004 |
Within Lacunar strokes, % | 68.5 | 31.5 | 0.834 |
WMC indicates white matter changes; IMT: intima-media thickness.
*Data were logarithmically transformed before analysis, presented is the geometric mean (SD).
In logistic regression analysis, including age, gender, body mass index, use of acetylsalicylic acid, clopidogrel, beta blockers, calcium blockers, ACE inhibitors, ARBs, HMG-CoA reductase inhibitors, and all vascular risk factors, severity of WMCs was found to be associated with age and IMT above 0.65 mm (O.R. 1.065, 95% CI 1.027–1.103,
This study demonstrates a significant relation between carotid atherosclerosis, reflected as IMT and existence of carotid plaques, and LA in a cohort of acute ischemic stroke and TIA patients. Previous studies have shown that white matter lesions are related to age, hypertension, diabetes, and stroke history [
Our study provided further evidence that the relation between carotid atherosclerosis and WMCs is independent of other vascular risk factors and history of stroke. Moreover, strengthening for those findings received by the multivariate analysis, where the findings that the only significant and independent predictors of advanced LA were age and elevated IMT as a marker of carotid atheroclerosis. It has been suggested that WMCs progress gradually over time with the accumulation of vascular risk factors [
The present study has a limitation of possible misclassification in the diagnosis of leukoaraiosis as the diagnosis was based on CT scans rather than MR. However, the use of CT scan for the assessment of leukoaraiosis was found to be a reliable diagnostic method. Previous studies have shown a good intrareader agreement in the use of CT scan for the assessment of leukoaraiosis [
In summary, this study reinforces the relationship between LA and carotid atherosclerosis in a population of ischemic stroke patients, although it is not possible to suggest the probable causative relation between them. This association emerged over most vascular risk factors, as seen in multivariate regression analysis. Also, severity of WMCs was strongly related to carotid IMT and plaques. Together, these observations support diagnostic measurements of carotid IMT in stroke patients as an additional clinical tool for risk stratification. We suggest that a chronic atherosclerotic disease is probably the basic pathophysiology of leukoaraiosis and its progression.
E. B. Assayag and M. Mijajlovic equally contributed to this work.
This study was partly granted (Dr. M. Mijajlovic) by the Ministry of Science and Education of Serbia, Project No. 175022.