Ursula G. Schulz

Systematic Review of Methods and Results of Studies of the Genetic Epidemiology of Ischemic Stroke

Background and Purpose— To design appropriate molecular genetic studies, we first need to understand the genetic epidemiology of stroke. We therefore performed a systematic review of the literature to assess the heritability of stroke according to methodological quality of studies and to determine any heterogeneity in findings between studies and possible publication bias. Methods— We searched for twin studies and studies of family history of stroke using bibliographic databases and by hand-searching reference lists and journals. Odds ratios (ORs) for family history as a risk factor for stroke were calculated within studies and combined by meta-analysis. Heterogeneity between studies, methodological quality of studies, and the influence of the age at which stroke occurred in both probands and relatives were assessed. Results— We identified 53 independent studies (3 twin, 33 case-control, and 17 cohort). Monozygotic twins were more likely to be concordant than dizygotic twins (OR, 1.65; 95% CI, 1.2 to 2.3; P =0.003). A positive family history was a risk factor for stroke in both case-control (OR, 1.76; 95% CI, 1.7 to 1.9; P <0.00001) and cohort (OR, 1.30; 95% CI, 1.2 to 1.5; P <0.00001) studies. However, there was major heterogeneity between studies (cohort P =0.0001; case-control P <0.00001), with much stronger associations in small studies and methodologically less rigorous studies. Moreover, studies that reported insufficient data to allow meta-analysis tended to have found weaker associations. Family history of stroke was more frequent in studies that were confined to probands or relatives aged <70 years. However, few studies considered the number of affected and unaffected relatives, only 2 studies considered stroke phenotypes in detail, and only 19 studies (38%) adjusted associations for intermediate phenotypes. No twin study, only 5 cohort studies (26%), and 20 case-control studies (61%) differentiated between ischemic and hemorrhagic stroke in the proband. Family history of stroke was more frequent in large- and small-vessel stroke than in cardioembolic stroke. There were very few data on the influence of family history on stroke severity and no data on stroke recovery. Conclusions— Twin studies suggest a small genetic contribution to stroke, but reliable interpretation of published family history studies is undermined by major heterogeneity, insufficient detail, and potential publication and reporting bias. More detailed large-scale genetic epidemiology is required.

Differences in Vascular Risk Factors Between Etiological Subtypes of Ischemic Stroke: Importance of Population-Based Studies

Background— To understand the mechanisms of stroke and to target prevention, we need to know how risk factors differ between etiological subtypes. Hospital-based studies may be biased because not all stroke patients are admitted. If risk factors differ between patients who are admitted and those who are not, then case-control studies will be biased. If the likelihood of admission also depends on stroke subtype, then case-case comparisons may also be biased. Methods— We compared risk factors and ischemic stroke subtypes (TOAST classification) in hospitalized and nonhospitalized patients in 2 population-based stroke incidence studies: the Oxford Vascular Study (OXVASC) and Oxfordshire Community Stroke Project (OCSP). We also performed a meta-analysis of risk factor–stroke subtype associations with other published population-based studies. Results— In OXVASC and OCSP, stroke subtypes differed between hospitalized (293 of 647) and nonhospitalized patients (P <0.0001), with more cardioembolic strokes (odds ratio [OR], 1.8; 95% CI, 1.3 to 2.6) and fewer lacunar strokes (OR, 0.4; 95% CI, 0.3 to 0.7). Premorbid blood pressure and cholesterol were higher in hospitalized patients (both P <0.0001). Risk factor–stroke subtype associations in hospitalized patients were consequently biased (P =0.001). Meta-analysis of data from all patients in OXVASC, OCSP, and 2 other studies demonstrated consistent risk factor–stroke subtype associations. However, contrary to previous hospital-based studies, there was only a weak (OR, 1.4; 95% CI, 1.1 to 1.8) and inconsistent (Pheterogeneity=0.01) association between small-vessel stroke and hypertension and no association with diabetes (OR, 1.0; 95% CI, 0.7 to 1.3). Conclusions— Prevalences of risk factors and stroke subtypes differ between hospitalized and nonhospitalized patients with ischemic stroke, which may bias hospital-based risk factor studies. Meta-analysis of population-based studies suggests that vascular risk factors differ between stroke subtypes.

Heritability of ischemic stroke in relation to age, vascular risk factors, and subtypes of incident stroke in population-based studies.

Background— Appropriate design of molecular genetic studies of ischemic stroke requires an understanding of the genetic epidemiology of stroke. However, there are no published population-based data on heritability of aetiological subtypes of ischemic stroke, confounding by heritability of other vascular risk factors, or the relationship between heritability and age of onset. Methods— We studied family history of stroke (FHxStroke) and of myocardial infarction (FHxMI) in first-degree relatives in 2 population-based studies (Oxford Vascular Study [OXVASC]; Oxfordshire Community Stroke Project [OCSP]). We related FHxStroke and FHxMI to subtype of ischemic stroke, age, and the presence of vascular risk factors and performed a systematic review of all studies of FHxStroke by stroke subtype. Results— In our population-based studies and in 3 hospital-based studies, FHxStroke was least frequent in cardioembolic stroke (OR=0.74, 95%CI=0.58 to 0.95, P =0.02) but was equally frequent in the other subtypes. In OXVASC and OCSP, FHxStroke (P =0.02), FHxMI (P =0.04), and FHx of either (P =0.006) were associated with stroke at a younger age. Only FHxStroke was associated with previous hypertension (OR=1.59, 95%CI=1.08 to 2.35, P =0.02). FHxMI was more frequent in large-artery stroke (OR=1.63, 95%CI=0.99 to 2.69, P =0.05). Conclusion— Consistent results in our population-based studies and previous hospital-based studies suggest that inclusion bias is not a major problem for studies of the genetic epidemiology of stroke. Molecular genetic studies might be best targeted at non-cardioembolic stroke and younger patients. However, genetic susceptibility to hypertension may account for a significant proportion of the heritability of ischemic stroke.

Systematic Review of Associations Between the Presence of Acute Ischemic Lesions on Diffusion-Weighted Imaging and Clinical Predictors of Early Stroke Risk After Transient Ischemic Attack

Background and Purpose— Early risk of stroke after a transient ischemic attack can be reliably predicted with risk scores based on clinical features of the patient and of the ischemic event, but it is unclear how these features correlate with findings on brain imaging. Methods— We performed a systematic review of the literature and identified all previous studies which reported patient characteristics and the nature of transient ischemic attack symptoms in relation to appearances on diffusion-weighted imaging (DWI). We then performed a meta-analysis of the associations between the components of the risk scores and positive DWI. Authors were contacted for additional unpublished data. Results— Nineteen studies were identified by the systematic review, and additional unpublished data were obtained from 11 of these studies. On meta-analysis, several components of the risk scores were associated with positive DWI, including symptom duration ≥60 minutes (13 studies, odds ratio [OR], 1.50; 95% CI, 1.16 to 1.96; P=0.004), dysphasia (9 studies, OR, 2.25; 95% CI, 1.57 to 3.22; P<0.001), dysarthria (8 studies, OR, 1.73; 95% CI, 1.11 to 2.68; P=0.03) and motor weakness (9 studies, OR, 2.20; 95% CI, 1.56 to 3.10; P<0.001). However patient age, sex, hypertension and diabetes were not associated with the presence of DWI lesions. From an etiologic perspective, atrial fibrillation (9 studies, OR, 2.75; 95% CI, 1.78 to 4.25; P<0.001) and ipsilateral ≥50% carotid stenosis (10 studies, OR, 1.93; 95% CI, 1.34 to 2.76; P=0.001) were associated with positive DWI. Conclusions— Presence of acute ischemic lesions on DWI correlates with several clinical features known to predict stroke risk after transient ischemic attack. Large studies (sample size >1000) will therefore be required to determine the independent prognostic value of DWI and its interactions with these clinical characteristics.

Increased Cerebral Arterial Pulsatility in Patients With Leukoaraiosis: Arterial Stiffness Enhances Transmission of Aortic Pulsatility

Background and Purpose— Arterial stiffening reduces damping of the arterial waveform and hence increases pulsatility of cerebral blood flow, potentially damaging small vessels. In the absence of previous studies in patients with recent transient ischemic attack or stroke, we determined the associations between leukoaraiosis and aortic and middle cerebral artery stiffness and pulsatility. Methods— Patients were recruited from the Oxford Vascular Study within 6 weeks of a transient ischemic attack or minor stroke. Leukoaraiosis was categorized on MRI by 2 independent observers with the Fazekas and age-related white matter change scales. Middle cerebral artery (MCA) stiffness (transit time) and pulsatility (Goslings index: MCA-PI) were measured with transcranial ultrasound and aortic pulse wave velocity and aortic systolic, diastolic, and pulse pressure with applanation tonometry (Sphygmocor). Results— In 100 patients, MCA-PI was significantly greater in patients with leukoaraiosis (0.91 versus 0.73, P<0.0001). Severity of leukoaraiosis was associated with MCA-PI and aortic pulse wave velocity (Fazekas: &khgr;2=0.39, MCA-PI P=0.01, aortic pulse wave velocity P=0.06; age-related white matter change: &khgr;2=0.38, MCA-PI P=0.015; aortic pulse wave velocity P=0.026) for periventricular and deep white matter lesions independent of aortic systolic blood pressure, diastolic blood pressure, and pulse pressure and MCA transit time with MCA-PI independent of age. In a multivariate model (r2=0.68, P<0.0001), MCA-PI was independently associated with aortic pulse wave velocity (P=0.016) and aortic pulse pressure (P<0.0001) and inversely associated with aortic diastolic blood pressure (P<0.0001) and MCA transit time (P=0.001). Conclusions— MCA pulsatility was the strongest physiological correlate of leukoaraiosis, independent of age, and was dependent on aortic diastolic blood pressure and pulse pressure and aortic and MCA stiffness, supporting the hypothesis that large artery stiffening results in increased arterial pulsatility with transmission to the cerebral small vessels resulting in leukoaraiosis.

Sex Differences in Carotid Bifurcation Anatomy and the Distribution of Atherosclerotic Plaque

Background and Purpose— Plaque formation at arterial bifurcations depends on vessel anatomy, particularly the relative sizes of the branches, and the ratio of the outflow to inflow area. The facts that carotid plaque is more common in men and that carotid bruits in the absence of stenosis are more frequent in women raise the possibility that there are sex differences in carotid bifurcation anatomy. We studied 5395 angiograms from the European Carotid Surgery Trial. Methods— To minimize secondary changes we excluded angiograms with ≥50% stenosis and also studied vessels with no disease. We measured arterial diameters at disease-free points and calculated the following ratios: internal/common (ICA/CCA); external/common (ECA/CCA); internal/external (ICA/ECA) carotid arteries; carotid bulb/CCA; and outflow/inflow area. We related these to sex and also studied the distribution of plaque in the whole trial population. Results— Among 2930 angiograms with <50% stenosis, the mean ICA/CCA ratio, ICA/ECA ratio, and outflow/inflow area ratio were larger in women than in men (all P <0.0001). The findings were similar in 622 bifurcations without atheroma. There were also differences in the distribution of plaque, with men more likely to have the maximum stenosis distal to the carotid bulb (odds ratio, 2.29; 95% CI, 1.33 to 4.01;P =0.001) and women more likely to have stenosis of the ECA (odds ratio, 1.54; 95% CI, 1.30 to 1.85;P <0.0001). Conclusions— Sex differences in carotid bifurcation anatomy are not limited to absolute vessel size. In addition, the outflow to inflow area ratio is bigger in women, and relative to the CCA and ECA, women have larger ICAs than men. Irrespective of whether these differences are congenital or acquired, they may partly explain the sex differences that we found in the distribution of plaque and the sex differences in the prevalence of carotid atheroma in the general population.

Age-related cerebral white matter disease (leukoaraiosis): a review

With the availability of improved brain imaging techniques, the high prevalence and clinical importance of cerebral small vessel disease have been increasingly recognised in recent years. As age is one of the most important risk factors for this condition, its prevalence is set to rise further as populations age. This may lead to an increase in the clinical consequences of white matter disease, namely cognitive decline, decreased mobility and increased stroke risk. Given the impact this will have on individuals and on healthcare systems, knowledge of the risk factors for small vessel disease, its prevention and its treatment is becoming more important. Although a lot of data are now available on the epidemiology, risk factors, clinical consequences and prognosis of leukoaraiosis, some of this information is conflicting. In this review, we summarise the current literature on cerebral small vessel disease, with an emphasis on its clinical aspects.

Diffusion-Weighted MRI in 300 Patients Presenting Late With Subacute Transient Ischemic Attack or Minor Stroke

Background and Purpose— Many patients with transient ischemic attack (TIA) or minor stroke present to medical attention after a delay of several days or weeks, at which time it may be more difficult to obtain a clear history and clinical signs may have resolved. Because ischemic lesions on diffusion-weighted MRI (DWI) often persist for several weeks, we hypothesized that adding DWI to a standard protocol with T2-weighted imaging might be useful in the management of patients presenting late. Methods— We studied consecutive patients with TIA or minor stroke presenting ≥3 days after the event. Two independent observers recorded the presence or absence of recent ischemic lesions on 2 different occasions, first with the T2 scan only, and second with T2 and DWI. Each time, with the aid of a written clinical summary, the observers recorded their diagnosis and proposed management. Results— 300 patients (159 men) were scanned at a median of 17 (interquartile range=10 to 23) days after symptom onset. DWI showed a high signal lesion in 114/164 (70%) minor strokes versus 17/136 (13%) TIAs (P<0.0001). The presence of high-signal lesions on DWI decreased nonlinearly with time since symptom onset (P<0.0001) and increased with National Institutes of Health Stroke Score (P=0.038) and with age (P=0.01). In 90/206 (43.7%) patients with 1 or multiple lesions on T2, DWI helped to clarify whether these were related to a recent ischemic event (79 [48%] strokes; 11 [31%] TIAs). Compared with T2 alone, DWI provided additional information in 108 (36%) patients (91 [56%] strokes and 17 [13%] TIAs), such as clarification of clinical diagnosis (18 patients, 6%) or vascular territory (28 patients, 9.3%), which was considered likely to influence management in 42 (14%) patients (32 [19%] strokes; 10 [7.4%] TIAs). Conclusions— The clinically useful information available from DWI provides a further justification for an MRI-based imaging protocol in patients with subacute TIA or minor stroke.

Abnormalities on diffusion weighted magnetic resonance imaging performed several weeks after a minor stroke or transient ischaemic attack

Objectives: Diffusion weighted brain imaging (DWI) is used in acute stroke, and also shows an acute ischaemic lesion in most transient ischamic attack (TIA) patients scanned acutely. However, it may also be useful in identifying subacute ischaemic lesions in patients with minor stroke or TIA who present several weeks after symptom onset. This study investigated the sensitivity and the observer reproducibility of DWI in cerebral TIA and minor ischaemic stroke patients scanned more than two weeks after the last symptomatic event. Methods: Consecutive patients underwent magnetic resonance imaging (T2, DWI, ADC). The presence of clinically appropriate lesions was assessed by two independent observers, and related to the type of presenting event, the NIH score, persistence of symptoms and signs, and the time since the presenting event. Results: 101 patients (53 men) were scanned at a median time of 21 days (IQR=17–28) after symptom onset. Reproducibility of the assessment of DWI abnormalities was high: interobserver agreement =97% (κ=0.94, p<0.0001); intraobserver agreement =94% (κ=0.88, p<0.0001). DWI showed a clinically appropriate ischaemic lesion in 29 of 51 (57%) minor stroke patients, and in 7 of 50 (14%) TIA patients. The independent predictors of a positive DWI scan were presentation with minor stroke versus TIA (p=0.009) and increasing NIH score (p=0.009), but there was no difference between patients presenting 2–4 weeks compared with >4 weeks after symptom onset. In minor stroke patients, the presence of a clinically appropriate lesion was associated with persistent symptoms (63% versus 36%; p=0.12) and signs (64% versus 33%, p=0.06) at the time of scanning. Conclusions: DWI shows a clinically appropriate ischaemic lesion in more than half of minor stroke patients presenting more than two weeks after the symptomatic event, but only in a small proportion of patients with TIA. The persistence of lesions on DWI is closely related to markers of severity of the ischaemic event. These results justify larger studies of the clinical usefulness of DWI in subacute minor stroke.

Potential Confounding by Intermediate Phenotypes in Studies of the Genetics of Ischaemic Stroke

Background: Family history (FHx) of stroke is perceived to be an important risk factor for ischaemic stroke. However, there are several intermediate phenotypes that are often involved in the aetiology of ischaemic stroke and that have a substantial genetic component themselves. We studied FHx of ischaemic heart disease (IHD), hypertension (HTN) and diabetes mellitus (DM) as risk factors for ischaemic stroke. Methods: We performed a systematic review of case-control and cohort studies reporting on FHxIHD, FHxHTN or FHxDM as risk factors for stroke using bibliographic databases, and by hand searching reference lists and journals. Odds ratios of FHx as a risk factor for stroke were calculated within individual studies. We included unpublished data from two Oxfordshire population-based studies to assess effects on subtypes of ischaemic stroke. Results: We identified 54 studies that investigated the odds of stroke conferred by a positive FHx, 24 of which reported data on FHx of one or more intermediate phenotypes in addition to FHx of stroke. Most studies reported an increased frequency of FHxIHD and FHxHTN in stroke patients versus controls. The association was significant in 6 out of 14 studies for FHxIHD and 4 out of 11 studies for FHxHTN. In contrast, FHxDM was not associated with stroke. FHxIHD was particularly associated with large vessel strokes (OR 1.72, CI 1.3–2.2, p = 0.00004). Conclusions: FHxIHD and FHxHTN are both risk factors for stroke. It is likely that the apparent heritability of stroke is partly accounted for by heritability of HTN and large vessel atherosclerosis. Analyses of heritability of stroke and candidate gene studies should be adjusted accordingly.