Dennis Briley

Antithrombotic Drug Use, Cerebral Microbleeds, and Intracerebral Hemorrhage A Systematic Review of Published and Unpublished Studies

Background and Purpose— Cerebral microbleeds (MB) are potential risk factors for intracerebral hemorrhage (ICH), but it is unclear if they are a contraindication to using antithrombotic drugs. Insights could be gained by pooling data on MB frequency stratified by antithrombotic use in cohorts with ICH and ischemic stroke (IS)/transient ischemic attack (TIA). Methods— We performed a systematic review of published and unpublished data from cohorts with stroke or TIA to compare the presence of MB in: (1) antithrombotic users vs nonantithrombotic users with ICH; (2) antithrombotic users vs nonusers with IS/TIA; and (3) ICH vs ischemic events stratified by antithrombotic use. We also analyzed published and unpublished follow-up data to determine the risk of ICH in antithrombotic users with MB. Results— In a pooled analysis of 1460 ICH and 3817 IS/TIA, MB were more frequent in ICH vs IS/TIA in all treatment groups, but the excess increased from 2.8 (odds ratio; range, 2.3–3.5) in nonantithrombotic users to 5.7 (range, 3.4–9.7) in antiplatelet users and 8.0 (range, 3.5–17.8) in warfarin users (P difference=0.01). There was also an excess of MB in warfarin users vs nonusers with ICH (OR, 2.7; 95% CI, 1.6–4.4; P<0.001) but none in warfarin users with IS/TIA (OR, 1.3; 95% CI, 0.9–1.7; P=0.33; P difference=0.01). There was a smaller excess of MB in antiplatelet users vs nonusers with ICH (OR, 1.7; 95% CI, 1.3–2.3; P<0.001), but findings were similar for antiplatelet users with IS/TIA (OR, 1.4; 95% CI, 1.2–1.7; P<0.001; P difference=0.25). In pooled follow-up data for 768 antithrombotic users, presence of MB at baseline was associated with a substantially increased risk of subsequent ICH (OR, 12.1; 95% CI, 3.4–42.5; P<0.001). Conclusions— The excess of MB in warfarin users with ICH compared to other groups suggests that MB increase the risk of warfarin-associated ICH. Limited prospective data corroborate these findings, but larger prospective studies are urgently required.

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.

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.

Reliability of Clinical Diagnosis of the Symptomatic Vascular Territory in Patients With Recent Transient Ischemic Attack or Minor Stroke

Background and Purpose— Knowledge of the vascular territory of a recent transient ischemic attack or minor stroke determines appropriate investigations and the need for territory-specific interventions such as endarterectomy and stenting. However, there are few published data on the accuracy of clinical assessment of the vascular territory. Methods— We studied agreement of clinical diagnosis of vascular territory in consecutive patients with transient ischemic attack or minor stroke with diffusion-weighted MRI who had an acute ischemic lesion(s) in a single vascular territory (determined by a neuroradiologist). Three independent neurologists (one had seen the patients, the others had a clinical summary) diagnosed the most likely vascular territory (carotid or vertebrobasilar) for each patient blind to brain imaging. Results— One hundred thirty-three (28.0%) of 476 patients had a high signal lesion on diffusion-weighted imaging of whom 115 (86.5%) had a minor stroke and 18 (13.5%) a transient ischemic attack. Interobserver agreement (kappa statistic) on the territory ranged from 0.46 to 0.60. The agreement with diffusion-weighted imaging was only moderate (observer 1: kappa=0.54, 95% CI=0.36 to 0.72; observer 2: 0.48, 0.31 to 0.64; observer 3: 0.48, 0.28 to 0.67). Only the presence of visual symptoms improved the accuracy of the vascular territory diagnosis (range of kappa: 0.63 to 0.77) but not the presence of motor, speech, or sensory symptoms. Sensitivity and specificity for the diagnosis of vertebrobasilar territory ranged between 54.2% and 70.8% and 84.4% to 91.7%, respectively. Conclusions— The reliability of clinical diagnosis of the vascular territory is only moderate, highlighting the importance of sensitive brain imaging after transient ischemic attack or minor stroke. Further imaging-based research is required to determine the optimal clinical diagnostic criteria for classification of the vascular territory.

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.

Presence of Acute Ischaemic Lesions on Diffusion-Weighted Imaging Is Associated with Clinical Predictors of Early Risk of Stroke after Transient Ischaemic Attack

Background: Early risk of stroke after a transient ischaemic attack (TIA) can be reliably predicted with risk scores based on clinical features of the patient and the event, but it is unclear how these features correlate with findings on brain imaging and few studies have investigated this in the subacute phase. Methods: Two hundred consecutive patients attending a specialist clinic underwent diffusion-weighted brain imaging (DWI) on the day of the clinic (≧3 days after a TIA) and the presence of recent lesions (positive DWI) was related to the presence of clinical features associated with a high stroke risk and to 2 validated risk scores (ABCD and California). Results: Thirty-one patients (16%) had positive DWI. Increasing ABCD and California scores were associated with positive DWI (p = 0.02 for both) independent of the delay from TIA to scan. Conclusion: Presence of recent ischaemic lesions on DWI correlates with validated clinical scores for risk of stroke after TIA in patients scanned subacutely. Future prognostic studies of DWI after TIA should adjust for the risk scores to determine the independent predictive value of DWI and hence the likely role of DWI in refinements of the scores.

Spontaneous echo contrast and hemorheologic abnormalities in cerebrovascular disease.

Background and Purpose Spontaneous echo contrast (SEC) is thought to represent a risk factor for cardioembolic stroke. In vitro studies suggest that SEC results from interaction between red cells and fibrinogen. To better understand the relation between SEC and stroke and to investigate the in vivo genesis of SEC, we examined the relation between SEC, the constituents of the blood, and plasma and serum viscosity in patients with acute stroke or chronic cerebrovascular disease. Methods Fifty patients with acute stroke or chronic cerebrovascular disease referred for transesophageal echocardiogram (TEE) were studied by transthoracic echocardiography and TEE. Complete blood count, fibrinogen, albumin, γ-globulin, and plasma and serum viscosity determinations were made. Left atrial SEC was graded as absent, mild, or marked by means of TEE. Results SEC was absent in 31 patients, mild in 10 patients, and marked in 9 patients. Higher grade of SEC was associated with a significantly greater percentage of patients with atrial fibrillation and larger left atrial dimension. Atrial fibrillation was present in 23% of the patients in the SEC absent group, 50% of the patients in the mild SEC group, and 78% of the patients in the marked SEC group (P<.01). Left atrial diameter averaged 3.8±0.6 cm in the SEC absent group, 4.3±1.1 in the mild SEC group, and 4.9±0.7 in the marked SEC group (P<.001). Hematocrit, white blood cell count, and platelet count did not differ among the three groups. Fibrinogen, γ-globulin, plasma viscosity, and serum viscosity values were all significantly higher in the presence of SEC (P<.05). Fibrinogen values were 361 ±97 mg/dL in the SEC absent group and 427±135 mg/dL in the marked SEC group. γ-Globulin levels were 0.75±0.23 g/dL in the SEC absent group and 1.06±0.48 g/dL in the marked SEC group. Both plasma viscosity (1.97 cp) and serum viscosity (1.64 cp) were higher in the marked SEC group than in the SEC absent group (1.77 and 1.50 cp, respectively). Conclusions In patients with acute stroke or chronic cerebrovascular disease, the severity of SEC was not related to albumin, hematocrit, white cell count, or platelet count but rather to elevated fibrinogen levels and concomitant increases in both plasma and serum viscosity. Moreover, increasing grade of SEC was associated with significantly increased left atrial diameter and a higher percentage of patients in atrial fibrillation.

Leukoaraiosis and Increased Cerebral Susceptibility to Ischemia: Lack of Confounding by Carotid Disease

Background Leukoaraiosis is associated with an increased risk of stroke, but the underlying mechanism remains uncertain, as do the associations with other risk factors, such as carotid disease. We aimed to determine the role of carotid disease and of other clinical variables in the development of leukoaraiosis and to define their contributions to the associated increased risk of stroke. Methods and Results We prospectively studied a large cohort of consecutive patients with transient ischemic attack (TIA) and minor stroke who attended a TIA clinic between 2002 and 2009. Detailed clinical data were obtained, and patients underwent magnetic resonance brain and vascular imaging. We assessed the severity of leukoaraiosis with use of the ARWMC (Age Related White Matter Changes) score: 671 patients (374 [56%] men; mean [SD] age 71 [11] years) were studied, of whom 415 (62%) had leukoaraiosis. In a multivariate analysis, leukoaraiosis was associated with increasing age (P<0.0001) and hypertension (P=0.01), as well as the presence of acute (P<0.0001) and chronic (P=0.014) infarction on magnetic resonance imaging. In the univariate analysis, a current and past diagnosis of stroke versus TIA also showed a strong association. Carotid disease was not associated with leukoaraiosis, even in the presence of a flow‐limiting (>70%) stenosis or occlusion, and the risk factor profiles for leukoaraiosis and carotid disease differed. Conclusions The association with more severe ischemic events (stroke versus TIA) and infarction on imaging is consistent with leukoaraiosis being a marker of increased cerebral susceptibility to ischemia. In contrast, the presence, severity of, and risk factors for atheromatous disease showed no association with leukoaraiosis, suggesting that these are two unrelated disease processes.

Reliable estimation of the proportion of minor stroke due to intracerebral haemorrhage

Background A previous hospital clinic-based study estimated that 3·5% of minor strokes are due to primary intracerebral haemorrhage, but the confidence intervals were wide. Moreover this figure may be an underestimate in older patients, who are less likely to be referred to secondary care, and who may have higher rates of intracerebral haemorrhage. Further studies are required to validate and increase the precision of this estimate and to determine any association with age, in order to plan appropriate services for minor stroke. Method We determined the frequency of intracerebral haemorrhage and haemorrhagic transformation of infarction in consecutive patients presenting with minor stroke (National Institute of Health Stroke Scal ≥ 3) in two separate cohorts: a population-based study (Oxford Vascular Study) scanned early with computed tomography, and a hospital-based stroke clinic cohort, scanned with magnetic resonance imaging. We then pooled these data in a meta-analysis with published data from similar studies identified from a systematic literature review. Results In the Oxford Vascular Study, of 334 cases with minor stroke (58% men, median age 75 years), 17 had intracerebral haemorrhage (5·1%, 95% confidence interval 3·2-8·0%) and four had haemorrhagic transformation of infarction (1·2%, 0·5-3·0%). In the hospital-clinic cohort, of 280 patients with minor stroke (59% men, median age 73 years), 15 had intracerebral haemorrhage (5·4%, 3·3-8·7%) and six had haemorrhagic transformation of infarction (2·1%, 1·0-4·6%). There was no trend for an increase in the frequency of intracerebral haemorrhage with age, with the lowest frequency in patients aged ≥85 years (0-3%). We identified only one previous study with a reliable estimate of the proportion of minor stroke due to intracerebral haemorrhage, and in a pooled analysis including 842 patients, the overall frequency of intracerebral haemorrhage was 4·8% (4·5-5·0%). Conclusion We have shown that the proportion of minor stroke due to intracerebral haemorrhage was very similar in a population-based cohort and a hospital clinic-based cohort using different imaging strategies, and that the frequency is independent of age. A frequency of between 4·5 and 5·0% appears to be a reliable estimate at all ages.

The SCAN rule: a clinical rule to reduce CT misdiagnosis of intracerebral haemorrhage in minor stroke

Many patients with minor stroke are referred to outpatient clinics and are not scanned immediately. A clinical rule is needed to identify patients who are likely to have intracerebral haemorrhage (ICH) and require urgent brain imaging and patients who can safely start antiplatelet agents before scanning. Methods Clinical factors associated with ICH were determined in 334 consecutive patients with minor stroke (National Institute of Health Stroke Scale score ≤3), and a predictive model for ICH that was validated in a cohort of 280 patients presenting to a hospital–stroke clinic was derived. Prognostic value was quantified as the area under the ROC curve (c statistics). Results The proportion of ICH in minor stroke was 5.1% (95% CI 3.2% to 8.0%) in OXVASC, and 5.4% (3.3% to 8.7%) in the clinic cohort. Clinical factors predictive of ICH in OXVASC included blood pressure on initial assessment ≥180/110 mm Hg (OR 14.5, 95% CI 1.8 to 114, p=0.001), vomiting (OR 15.7, 95% CI 5.4 to 46, p<0.001), confusion (OR 8.2, 95% CI 2.9 to 23, p<0.001) and anticoagulation use (OR 7.8, 95% CI 2.2 to 28, p=0.006), and at least one predictive factor was identified in all 17 patients with ICH and in 35% overall (c statistic 0.92, 95% CI 0.88 to 0.97). Therefore, we derived the SCAN rule to identify ICH if ≥1 of the following were present: (S) severe hypertension, (C) confusion, (A) anticoagulation, (N) nausea and vomiting. In the clinic validation cohort, ≥1 predictive factor was identified in 14/15 of patients with ICH and in 24% overall (c statistic 0.87, 95% CI 0.79 to 0.95). Conclusion The SCAN rule appears to be specific and sensitive at identifying ICH in an independent cohort of patients with minor stroke, although further independent validations are needed.