Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden.

OBJECTIVES: In this cross-sectional study, we tested the construct validity of a "total SVD score," which combines individual MRI features of small-vessel disease (SVD) in one measure, by testing associations with vascular risk factors and stroke subtype.
METHODS: We analyzed data from patients with lacunar or nondisabling cortical stroke from 2 prospective stroke studies. Brain MRI was rated for the presence of lacunes, white matter hyperintensities, cerebral microbleeds, and perivascular spaces independently. The presence of each SVD feature was summed in an ordinal "SVD score" (range 0-4). We tested associations with vascular risk factors, stroke subtype, and cerebral atrophy using ordinal regression analysis.
RESULTS: In 461 patients, multivariable analysis found that age (odds ratio [OR] 1.10, 95% confidence interval [CI] 1.08-1.12), male sex (OR 1.58, 95% CI 1.10-2.29), hypertension (OR 1.50, 95% CI 1.02-2.20), smoking (OR 2.81, 95% CI 1.59-3.63), and lacunar stroke subtype (OR 2.45, 95% CI 1.70-3.54) were significantly and independently associated with the total SVD score. The score was not associated with cerebral atrophy.
CONCLUSIONS: The total SVD score may provide a more complete estimate of the full impact of SVD on the brain, in a simple and pragmatic way. It could have potential for patient or risk stratification or early efficacy assessment in clinical trials of interventions to prevent SVD progression and may (after further testing) have a useful role in clinical practice.

Cerebral small-vessel disease (SVD) is an intrinsic disorder of the small perforating arterioles.[1] SVD is a common cause of dementia and stroke, and causes considerable worsening of cognitive function, gait, and balance.[2]

On brain MRI, 4 closely correlated features are markers of SVD: lacunes, white matter hyperintensities (WMH), cerebral microbleeds (CMBs), and visible perivascular spaces (PVS).[1,2] Cerebral atrophy may also be associated with SVD.[3-5] These individual SVD features are each associated with vascular risk factors.[6-9] Few studies have combined these features to capture the “total SVD burden” or tested for associations with stroke subtype or vascular risk factors.[10,11] A total SVD burden score might capture the overall effect of SVD on the brain better than by considering only 1 or 2 individual features separately. For example, WMH usually occur in white matter whereas lacunes usually occur in deep gray matter; one score including both features would reflect total brain damage better.

Recently, our Maastricht collaborative group[12] developed a pragmatic estimate of total SVD burden in patients with lacunar stroke by summing the different MRI features that were present, yielding a 0 to 4 “total SVD score.” This total SVD score was associated with blood pressure[12] and cognition[13] in patients with lacunar stroke. This pragmatic estimate of total SVD burden could be useful for rapid quantification or stratification of SVD, e.g., in clinical trials,[2] genetic studies,[10,11] and potentially in clinical practice. Before wider use, further testing of the score's generalizability in larger, more varied cohorts is required.

We investigated whether the SVD score is a valid representation of SVD by testing whether previously described risk factors for individual SVD features were associated with total SVD score, whether SVD score was higher in patients presenting with recent lacunar stroke compared with cortical stroke, and any association with cerebral atrophy.

METHODS

We report our results according to the Standards for Reporting Vascular Changes on Neuroimaging (STRIVE) for reporting studies in SVD (www.equatornetwork.org).[14] For clarity, we refer to the clinical stroke syndrome as “lacunar stroke,” the new acute small subcortical infarct seen on MRI as the recent small subcortical (or lacunar) infarct, and the small cavities that represent old lacunar infarcts as lacunes.[14]

Patients.

We used data from 2 nonoverlapping studies of patients recruited prospectively and consecutively with lacunar or mild cortical ischemic stroke (study 1, 2003–2007[7]; study 2, 2010–2012, publication pending), which used very similar methods, described previously.[7] These studies recruited patients with a definite diagnosis of clinical lacunar or mild cortical ischemic stroke who presented to the hospital stroke service (Western General Hospital, Edinburgh, UK) within 3 months of onset; patients with MRI contraindications, unstable medical condition, previous stroke, and severe (i.e., disabling) stroke were excluded.

Vascular risk factors.

In the primary studies, experienced physicians qualified in stroke medicine recorded baseline demographics, vascular risk factors, and other details. Hypertension (blood pressure ≥140/90 mm Hg), diabetes mellitus (fasting blood glucose ≥6.1 mmol/L), hypercholesterolemia (total cholesterol >5.0 mmol/L), ischemic heart disease (myocardial infarction, angina, or ECG evidence of myocardial ischemia), and peripheral vascular disease (symptoms of intermittent claudication) were defined as previously diagnosed by a physician/general practitioner, on current treatment, or newly diagnosed at stroke presentation. Symptomatic carotid stenosis was defined as stenosis ≥50% NASCET (North American Symptomatic Carotid Endarterectomy Trial criteria) in the symptomatic artery, atrial fibrillation (AF) as either previous diagnosis or AF seen on ECG, and smoking as current smoking.

Brain MRI acquisition.

Patients had brain MRI on the day of presentation (median 7; interquartile range 15 days after stroke) on a research-dedicated 1.5T MR scanner (Signa LX; General Electric, Milwaukee, WI) operated by research-dedicated technical staff and which underwent daily quality assurance monitoring. Sequences included axial diffusion-weighted imaging (DWI), T2-weighted, fluid-attenuated inversion recovery (FLAIR), gradient echo, and sagittal T1-weighted sequences (for details see table e-1 on the Neurology® Web site at Neurology.org).

Stroke subtype classification.

Strokes were initially classified into clinical lacunar or cortical stroke syndromes according to the Oxfordshire Community Stroke Project classification.[15] Final lacunar or cortical stroke diagnosis was based on both clinical and radiologic findings after review of all clinical and investigative information by a panel of stroke clinical and imaging experts, an established methodology for stroke subtype classification in research.[16] If clinical and radiologic classifications differed,[17] the radiologic classification was used. If no definite recent ischemic lesion corresponding with the presenting symptoms was visible on MRI, the clinical classification was used.

Standard protocol approvals, registrations, and patient consents.

Both studies were approved by the local research ethics committee and all participants gave written informed consent.

MRI analysis.

All MRIs were assessed blinded to clinical information by one experienced neuroradiologist for the presence, location, and size of the recent symptomatic infarct and any other vascular lesions. A recent infarct was defined as a hyperintense area on DWI with corresponding reduced signal on the apparent diffusion coefficient image, with or without increased signal on FLAIR or T2-weighted imaging, that corresponded with a typical vascular territory.[18] Recent small subcortical (lacunar) infarcts were defined as rounded or ovoid lesions with signal characteristics as above, >3- but <20-mm diameter, in the basal ganglia, internal capsule, centrum semiovale, or brainstem and carefully distinguished from WMH.[1] Cortical infarcts were defined as infarcts involving cortical ± adjacent subcortical tissue, or large (>2-cm) striatocapsular/subcortical lesions.[14] Lacunes were defined as rounded or ovoid lesions, >3- and <20-mm diameter, in the basal ganglia, internal capsule, centrum semiovale, or brainstem, of CSF signal intensity on T2 and FLAIR, generally with a hyperintense rim on FLAIR and no increased signal on DWI.[14] Microbleeds were defined as small (<5 mm), homogeneous, round foci of low signal intensity on gradient echo images in cerebellum, brainstem, basal ganglia, white matter, or cortico-subcortical junction, differentiated from vessel flow voids and mineral depositions in the globi pallidi.[14] Deep and periventricular WMH were both coded according to the Fazekas scale from 0 to 3.[19] We defined PVS as small (<3 mm) punctate (if perpendicular) and linear (if longitudinal to the plane of scan) hyperintensities on T2 images in the basal ganglia or centrum semiovale, and they were rated on a previously described, validated semiquantitative scale from 0 to 4.[7] Cerebral atrophy was classified for both deep (enlargement of the ventricles) and superficial (enlargement of the sulci) components on a 4-point scale (absent, mild, moderate, severe) in study 1, and on a modified 6-point version of the same scale in study 2.[20] The atrophy grade is determined by comparison with templates indicating normal to atrophied brains obtained in research into normal subjects on our scanner.[20] To merge the data from both studies, we condensed study 2's version to 4 categories (1 absent, 2–3 mild, 4 moderate, 5–6 severe). The intraclass correlation coefficient for WMH intraobserver rating (100 scans) was 0.96. The intrarater κ for PVS (50 scans) was 0.80 to 0.90 (unpublished data), for lacunes was 0.85 (unpublished data), and for microbleeds was 0.68 to 0.78.[21]

Determining the total MRI burden of SVD.

Based on the recently described score,[12] we rated the total MRI burden of SVD on an ordinal scale from 0 to 4, by counting the presence of each of the 4 MRI features of SVD. A point was awarded for each of the following (figure): presence of lacunes and CMBs were defined as the presence of one or more lacunes (1 point if present) or any CMB (1 point if present). Presence of PVS was counted if there were moderate to severe (grade 2–4) PVS in the basal ganglia (1 point if present). Presence of WMH was defined as either (early) confluent deep WMH (Fazekas score 2 or 3) or irregular periventricular WMH extending into the deep white matter (Fazekas score 3) (1 point if present).

Figure

Total small-vessel disease score features and categories

Because WMH are the most frequently described SVD feature in the literature,[14] we tested the effect of different cutpoints in the WMH score by lowering the cutoff of deep WMH to Fazekas score 1, 2, or 3 (punctate or [early] confluent areas), and of periventricular WMH to Fazekas score 2 or 3 (halo or extending into the deep white matter). We then calculated 2 alternative total SVD scores with these lowered deep or lowered periventricular WMH definitions.

Statistical analysis.

We used χ2 test and Mann–Whitney test to test for differences between lacunar and cortical stroke. We performed univariable ordinal regression analysis with SVD score as dependent variable to investigate the association with vascular risk factors and stroke subtype. We then performed multivariable ordinal regression analysis with age, sex, stroke subtype, risk factors that are frequently associated with individual features of SVD, i.e., hypertension, diabetes mellitus, and smoking, and any other factor that was found to be associated in the univariable analysis at p < 0.05. We explored the association between deep and superficial atrophy and SVD score by univariable and multivariable ordinal regression analysis with correction for age and sex and additionally for stroke subtype, hypertension, diabetes mellitus, and smoking. Finally, we tested the effect of the different cutoffs in the WMH score (specified above) by performing a logistic regression analysis with stroke subtype as dependent variable and SVD score as predictor variable, successively using the original SVD score and alternative SVD scores with lowered cutoff points in WMH definition. Results are presented as odds ratio (OR) with 95% confidence interval (CI). All analyses were performed with SPSS statistics version 20 (IBM Corp., Armonk, NY).

RESULTS

Of 466 patients in the original studies, 5 were excluded because of missing MRI data, leaving 461 patients for inclusion—222 patients (48%) with lacunar stroke and 239 (52%) with cortical stroke. We identified a symptomatic stroke lesion on MRI in 341 patients (74%): based on DWI-hyperintensity in 314 patients (68%) and on other sequences in 27 (6%); in 264 of these (77%), MRI classification matched clinical classification. In 120 patients (26%), the stroke subtype was based on clinical findings only. Median age was 68.1 (33.8–96.9) years; other characteristics are summarized in table 1. Patients with lacunar stroke were younger with lower rates of AF and symptomatic carotid stenosis than those with cortical stroke. Of the 4 MRI features, WMH and PVS were most prevalent; lacunar stroke patients more often had lacunes and PVS (table 1).

Table 1

Clinical and radiologic characteristics of the study population

Total SVD score.

Of the patients who scored 1, most (45%) had PVS, followed by WMH (29%), lacunes (15%), and CMBs (11%) (table 2). Of those who scored 2, all combinations were present, but the combination of PVS and WMH was predominant (64%). Of those who scored 3, all potential combinations were present, but PVS + WMH + lacunes (43%) and PVS + WMH + CMBs (44%) were most prevalent. Lacunar stroke patients had higher ratings of SVD burden compared with cortical stroke patients (table 2; p = 0.001).

Table 2

Total SVD score values for all patients and by stroke subtype

Association with vascular risk factors and stroke subtype.

In univariable analysis, total SVD score was significantly associated with age (OR 1.07, 95% CI 1.06–1.09 per year), male sex (OR 1.44, 95% CI 1.02–2.03), peripheral vascular disease (OR 2.46, 95% CI 1.15–5.30), hypertension (OR 1.82, 95% CI 1.28–2.60), and lacunar stroke subtype (OR 1.73, 95% CI 1.24–2.41), but not with diabetes, smoking, hypercholesterolemia, ischemic heart disease, AF, symptomatic carotid stenosis, or family history of stroke.

On multivariable analysis (table 3), age (OR 1.10, 95% CI 1.08–1.12), male sex (OR 1.58, 95% CI 1.10–2.29), hypertension (OR 1.50, 95% CI 1.02–2.20), smoking (OR 2.81, 95% CI 1.59–3.63), and lacunar stroke subtype (OR 2.45, 95% CI 1.70–3.54) were significantly and independently associated with total SVD score, the association for smoking and lacunar stroke subtype becoming stronger in multivariable than in univariable testing. The results were similar for just those patients with a DWI-visible recent stroke lesion.

Table 3

Associations with total SVD score in multivariable ordinal regression analysis

Association between total SVD score and cerebral atrophy.

Both deep and superficial atrophy were significantly associated with SVD burden in unadjusted analyses (table 4). After fully adjusting for age, sex, and vascular risk factors, the association with superficial atrophy was only marginally significant, and the association of deep atrophy with SVD score became nonsignificant.

Table 4

Association between cerebral atrophy and total SVD score

Total SVD score with alternative cutpoints of WMH.

With stroke subtype as the dependent variable, total SVD score was associated with lacunar vs cortical stroke subtype (OR 1.29, 95% CI 1.10–1.51). Varying the cutoff point in the definition of WMH improved the OR of the total SVD score for predicting lacunar stroke subtype only slightly to a maximal OR of 1.39 (95% CI 1.16–1.37) (see table e-2).

DISCUSSION

We showed that total SVD score has construct validity. We validated the initial version of the score[12,13] in a much larger, diverse cohort. The score was higher in patients presenting with acute lacunar stroke compared with acute cortical stroke, and was also associated with age, male sex, smoking, and hypertension. Hypertension was considered to be the strongest vascular risk factor for SVD previously; blood pressure level was also associated with total SVD score in a smaller study.[12] An important finding in the present work using the total SVD score is that smoking also was an important modifiable risk factor; the association between smoking and total SVD score was stronger than had been seen previously with individual SVD features. Smoking has been associated with both WMH[22] and reduced microstructural integrity of white matter,[23] less consistently with CMBs and lacunes,[9,24] and not with PVS.[7]

Regarding other risk factors, diabetes is often reported as a risk factor for SVD, but it is equally common in small-vessel and large-vessel stroke[25] and many studies found no association between diabetes and any of the MRI features,[8,9,26,27] nor did we find an association with total SVD score. Former results regarding sex varied, some studies reporting a male, others a female preponderance for SVD features, while others did not find an association.[8,9,24,27] Although clinical classification of stroke subtype in the absence of a recent MRI infarct may introduce some diagnostic uncertainty and bias, the association between higher total SVD score and lacunar (vs cortical) stroke subtype was also present when selecting only those patients with a DWI-visible acute infarct (68%; results not shown).

The total SVD score could be helpful for baseline stratification or as a surrogate marker for SVD in prevention and therapeutic trials if further testing confirms our results. The score provides a more complete overall view of the impact of SVD on the brain than do the individual MRI features separately. It is a simple and pragmatic visual score and allows for easy comparison and combination of data as long as standardized definitions of the individual features are adopted.[14] Some may argue that there are differences in the underlying pathogenetic mechanism leading to these different SVD features. However, all of these MRI features are considered to result from disease in the small vessels, and they often co-occur. Our approach was to compile the overall brain damage resulting from SVD, not the underlying pathways. The score could be used to define patients that are at risk of (lacunar) stroke,[28] e.g., for stratifying patients in secondary prevention trials. The usefulness of considering the whole spectrum of SVD abnormalities has also been shown in genetic studies.[10] The score might also be useful, after further validation, in clinical practice, for example, to identify subjects at risk of cognitive decline and physical impairments, although currently this would be by extrapolation from studies on the individual features[2,29-31] and not yet formally tested for the total SVD score. Further prospective studies are required to validate these suggestions.

Further developments of the proposed “total SVD score” would be testing other weightings and different cutpoints for different SVD features, and greater granularity for features that are currently only dichotomized as yes–no, e.g., lacunes and CMBs. Different cutpoints and weightings could be tested for PVS and WMH; the present ones may not be optimal. For example, punctate deep WMH (Fazekas score 1) and a periventricular halo (Fazekas score 2) were below the cutpoint definition of WMH in the present total SVD score. We tried alternative lowered cutpoints for WMH, but these led to only slightly better performance of the SVD score—larger, more diverse datasets are required to test cutpoints more thoroughly. The cutoff for WMH in the original SVD score was chosen because those Fazekas scores were related to SVD in a small histopathology study[12,32] from 2 decades ago, despite which it seems to perform reasonably well in the current study.

Cerebral atrophy is sometimes considered another MRI feature of SVD.[14] While many studies report an association between atrophy and SVD,[4,5,33] it is not specific to SVD, occurring in many other conditions including normal aging. We found only a weak association between superficial atrophy and total SVD score, but we may have introduced some inconsistency by combining 2 slightly different visual scoring methods. Alternatively, the association with atrophy may apply more in older populations or at different stages of SVD, or volumetric measurements of brain volume might be needed to explore this issue further. For now, there is no strong case for including atrophy in the total SVD score.

A limitation of our study is the cross-sectional design: longitudinal studies are required to explore the predictive ability of total SVD score and progression of MRI features, cognitive decline, and (recurrent) stroke risk, and to have more robust evidence that it can be used as an SVD predictor in trials, although the analysis presented here justifies its use to stratify patients according to SVD burden at randomization. A strength is the use of a recently published standard for describing imaging findings in SVD.[14] Other studies using the score must ensure that the same definitions of the individual SVD features are used. The total SVD score needs further testing in independent large cohorts, with varied risk factor profiles and ethnicity, to determine its generalizability and whether different cutpoints and weighting of individual SVD features might improve the score's performance. We also suggest testing in other consequences of SVD, such as cohorts with vascular cognitive impairment and dementia, or intracerebral hemorrhage.

We found that the risk factors for SVD—smoking, hypertension, age, and male sex—are associated with the total summed SVD score of individual MRI features. This score avoids overreliance on individual MRI features and provides a more complete view of SVD. It has potential application as a risk stratification for SVD in clinical trials or other clinical research and may (after further testing) have a useful role in clinical practice.