Gillian M. Potter

Improving interrater agreement about brain microbleeds: development of the Brain Observer MicroBleed Scale (BOMBS)

Background and Purpose— If the diagnostic and prognostic significance of brain microbleeds (BMBs) are to be investigated and used for these purposes in clinical practice, observer variation in BMB assessment must be minimized. Methods— Two doctors used a pilot rating scale to describe the number and distribution of BMBs (round, low-signal lesions, <10 mm diameter on gradient echo MRI) among 264 adults with stroke or TIA. They were blinded to clinical data and their counterpart’s ratings. Disagreements were adjudicated by a third observer, who informed the development of a new Brain Observer MicroBleed Scale (BOMBS), which was tested in a separate cohort of 156 adults with stroke. Results— In the pilot study, agreement about the presence of ≥1 BMB in any location was moderate (&kgr;=0.44; 95% CI, 0.32-0.56), but agreement was worse in lobar locations (&kgr;=0.44; 95% CI, 0.30-0.58) than in deep (&kgr;=0.62; 95% CI, 0.48-0.76) or posterior fossa locations (&kgr;=0.66; 95% CI, 0.47-0.84). Using BOMBS, agreement about the presence of ≥1 BMB improved in any location (&kgr;=0.68; 95% CI, 0.49-0.86) and in lobar locations (&kgr;=0.78; 95% CI, 0.60-0.97). Conclusion— Interrater reliability concerning the presence of BMBs was moderate to good, and could be improved with the use of the BOMBS rating scale, which takes into account the main sources of interrater disagreement identified by our pilot scale.

Enlarged perivascular spaces and cerebral small vessel disease

Background and aims Enlarged perivascular spaces (also known as Virchow-Robin spaces) on T2-weighted brain magnetic resonance imaging are common, but their etiology, and specificity to small vessel as opposed to general cerebrovascular disease or ageing, is unclear. We tested the association between enlarged perivascular spaces and ischemic stroke subtype, other markers of small vessel disease, and common vascular risk factors. Methods We prospectively recruited patients with acute stroke, diagnosed and subtyped by a stroke physician using clinical features and brain magnetic resonance imaging. A neuroradiologist rated basal ganglia and centrum semiovale enlarged perivascular spaces on a five-point scale, white matter lesions, recent and old infarcts, and cerebral atrophy. We assessed associations between basal ganglia-, centrum semiovale- and total (combined basal ganglia and centrum semiovale) enlarged perivascular spaces, stroke subtype, white matter lesions, atrophy, and vascular risk factors. Results Among 298 patients (mean age 68 years), after adjusting for vascular risk factors and white matter lesions, basal ganglia-enlarged perivascular spaces were associated with increasing age (P = 0·001), centrum semiovale-enlarged perivascular spaces (P < 0·001), cerebral atrophy (P = 0·03), and lacunar stroke subtype (P = 0·04). Centrum semiovale- enlarged perivascular spaces were associated mainly with basal ganglia-enlarged perivascular spaces. Total enlarged perivascular spaces were associated with increasing age (P = 0·01), deep white matter lesions (P = 0·005), and previous stroke (P = 0·006). Conclusions Enlarged perivascular spaces are associated with age, lacunar stroke subtype and white matter lesions and should be considered as another magnetic resonance imaging marker of cerebral small vessel disease. Further evaluation of enlarged perivascular spaces in studies of ageing, stroke, and dementia is needed to determine their pathophysiological importance.

Counting Cavitating Lacunes Underestimates the Burden of Lacunar Infarction

Background and Purpose— On brain imaging, lacunes, or cerebrospinal fluid–containing cavities, are common and are often counted in epidemiological studies as old lacunar infarcts. The proportion of symptomatic lacunar infarcts that progress to lacunes is unknown. Noncavitating lacunar infarcts may continue to resemble white matter lesions. Methods— We identified patients with acute lacunar stroke, with or without an acute lacunar infarct on computed tomography or MRI, who had follow-up imaging. A neuroradiologist classified lacunar infarcts progressing to definite or possible cavities on follow-up imaging. We tested associations between cavitation and patient-related, stroke-related, and imaging-related features, including other features of small vessel disease. Results— Among 90 patients (mean age 67 years), any cavitation was present on follow-up imaging in 25 (28%), and definite cavitation in 18 (20%). Definite cavitation was associated with increasing time to follow-up imaging (median 228 days, range 54 to 1722, versus no cavitation 72 days, range 6 to 1440; P=0.0003) and deep cerebral atrophy (P=0.03) but not with age, stroke severity, larger initial infarct size, or other features of small vessel disease. Hypertension and diabetes were negatively associated with cavitation (P=0.01 and 0.02, respectively). Conclusions— Definite cavitation occurs in one fifth of symptomatic lacunar ischemic strokes, implying that most continue to resemble white matter lesions. Epidemiology and pathophysiology studies of lacunar stroke, which have only counted lacunes as lacunar infarcts, may have substantially underestimated by as much as 5 times the true burden of lacunar stroke disease.

Cerebral Perivascular Spaces Visible on Magnetic Resonance Imaging: Development of a Qualitative Rating Scale and its Observer Reliability

Background: Perivascular spaces (PVS) are an important component of cerebral small vessel disease (SVD), several inflammatory disorders, hypertension and blood-brain barrier breakdown, but are difficult to quantify. A recent international collaboration of SVD experts has highlighted the need for a robust, easy-to-use PVS rating scale for the effective investigation of the diagnostic and prognostic significance of PVS. The purpose of the current study was to develop and extend existing PVS scales to provide a more comprehensive scale for the measurement of PVS in the basal ganglia, centrum semiovale and midbrain, and to test its intra- and inter-rater agreement, assessing reasons for discrepancy. Methods: We reviewed previously published PVS scales, including site of PVS assessed, rating method, and size and morphological criteria. Retaining key features, we devised a more comprehensive scale in order to improve the reliability of PVS rating. Two neuroradiologists tested the new scale in MRI brain scans of 60 patients from two studies (stroke, ageing population), chosen to represent a full range of PVS, and demonstrating concomitant features of SVD such as lacunes and white matter hyperintensities. We rated basal ganglia, centrum semiovale, and midbrain PVS. Basal ganglia and centrum semiovale PVS were rated 0 (none), 1 (1-10), 2 (11-20), 3 (21-40) and 4 (>40), and midbrain PVS were rated 0 (none visible) or 1 (visible). We calculated kappa statistics for rating, assessed consistency in use of PVS categories (Bhapkar test) and reviewed sources of discrepancy. Results: Intra- and inter-rater kappa statistics were highest for basal ganglia PVS (range 0.76-0.87 and 0.8-0.9, respectively) than for centrum semiovale PVS (range 0.68-0.75 and 0.61-0.8, respectively) or midbrain PVS (inter-rater range 0.51-0.52). Inter-rater consistency was better for basal ganglia compared to centrum semiovale PVS (Bhapkar statistic 2.49-3.72, compared to 6.79-21.08, respectively). Most inter-rater disagreements were due to very faint PVS, coexisting extensive white matter hyperintensities (WMH) or the presence of lacunes. Conclusions: We developed a more inclusive and robust visual PVS rating scale allowing rating of all grades of PVS severity on structural brain imaging. The revised PVS rating scale has good observer reliability for basal ganglia and centrum semiovale PVS, best for basal ganglia PVS, and moderate reliability for midbrain PVS. Agreement is influenced by PVS severity and the presence of background features of SVD. The current scale can be used in further studies to assess the clinical implications of PVS.

Association between brain imaging signs, early and late outcomes, and response to intravenous alteplase after acute ischaemic stroke in the third international stroke trial (IST-3): Secondary analysis of a randomised controlled trial

Summary Background Brain scans are essential to exclude haemorrhage in patients with suspected acute ischaemic stroke before treatment with alteplase. However, patients with early ischaemic signs could be at increased risk of haemorrhage after alteplase treatment, and little information is available about whether pre-existing structural signs, which are common in older patients, affect response to alteplase. We aimed to investigate the association between imaging signs on brain CT and outcomes after alteplase. Methods IST-3 was a multicentre, randomised controlled trial of intravenous alteplase (0·9 mg/kg) versus control within 6 h of acute ischaemic stroke. The primary outcome was independence at 6 months (defined as an Oxford Handicap Scale [OHS] score of 0–2). 3035 patients were enrolled to IST-3 and underwent prerandomisation brain CT. Experts who were unaware of the random allocation assessed scans for early signs of ischaemia (tissue hypoattenuation, infarct extent, swelling, and hyperattenuated artery) and pre-existing signs (old infarct, leukoaraiosis, and atrophy). In this prespecified analysis, we assessed interactions between these imaging signs, symptomatic intracranial haemorrhage (a secondary outcome in IST-3) and independence at 6 months, and alteplase, adjusting for age, National Institutes of Health Stroke Scale (NIHSS) score, and time to randomisation. This trial is registered at ISRCTN.com, number ISRCTN25765518. Findings 3017 patients were assessed in this analysis, of whom 1507 were allocated alteplase and 1510 were assigned control. A reduction in independence was predicted by tissue hypoattenuation (odds ratio 0·66, 95% CI 0·55–0·81), large lesion (0·51, 0·38–0·68), swelling (0·59, 0·46–0·75), hyperattenuated artery (0·59, 0·47–0·75), atrophy (0·74, 0·59–0·94), and leukoaraiosis (0·72, 0·59–0·87). Symptomatic intracranial haemorrhage was predicted by old infarct (odds ratio 1·72, 95% CI 1·18–2·51), tissue hypoattenuation (1·54, 1·04–2·27), and hyperattenuated artery (1·54, 1·03–2·29). Some combinations of signs increased the absolute risk of symptomatic intracranial haemorrhage (eg, both old infarct and hyperattenuated artery, excess with alteplase 13·8%, 95% CI 6·9–20·7; both signs absent, excess 3·2%, 1·4–5·1). However, no imaging findings—individually or combined—modified the effect of alteplase on independence or symptomatic intracranial haemorrhage. Interpretation Some early ischaemic and pre-existing signs were associated with reduced independence at 6 months and increased symptomatic intracranial haemorrhage. Although no interaction was noted between brain imaging signs and effects of alteplase on these outcomes, some combinations of signs increased some absolute risks. Pre-existing signs should be considered, in addition to early ischaemic signs, during the assessment of patients with acute ischaemic stroke. Funding UK Medical Research Council, Health Foundation UK, Stroke Association UK, Chest Heart Stroke Scotland, Scottish Funding Council SINAPSE Collaboration, and multiple governmental and philanthropic national funders.

Wide Variation in Definition, Detection, and Description of Lacunar Lesions on Imaging

Background and Purpose— Variation in the definition of lacunar lesions on imaging and difficulties in their detection may be hampering lacunar stroke research. We assessed literature definitions of imaging lacunar lesions and the definitions and detection of lacunar lesions among small-vessel disease researchers. Methods— We assessed definitions of imaging lacunar lesion in 50 randomly selected articles from 3 stroke-related journals and an online survey of small-vessel disease researchers. In the literature review, we assessed clinical/imaging definitions of lacunar stroke. In the survey, we assessed lacunar lesion detection, effects of lesion appearance, background white matter lesions, and provision of relevant data. Results— Among 50 articles, imaging definitions were varied and often limited; size was stated in 21 of 43 (49%) studies of acute and in 9 of 20 (45%) studies of old lesions and site in 18 (42%) and 4 (20%), respectively. Clinical definitions also varied, and images were read mostly by nonradiologists. Among 56 survey respondents, multiple descriptions were used for recent and old, symptomatic and asymptomatic, lesions on imaging. Most agreed on definitions for site (98%) and “old lacunar infarct” (61%) size. Cavitated (vs noncavitated) lesions were usually identified as lacunar lesions; with increasing white matter lesions, however, noncavitated lesions were very unlikely to be identified, even with prior imaging available (7.8%). Conclusions— Imaging definitions of lacunar lesions vary widely, in part due to variation in lesion detection and classification. A consensus for imaging definitions of small-vessel disease features would be helpful.

Associations of Clinical Stroke Misclassification ('Clinical-Imaging Dissociation') in Acute Ischemic Stroke

Background: Up to 20% of lacunar infarcts are clinically misdiagnosed as cortical infarcts and vice versa. The reasons for this discrepancy are unclear. We assessed clinical and imaging features which might explain this ‘clinical-imaging dissociation’ (C-ID). Methods: Patients with an acute stroke syndrome (cortical or lacunar) underwent magnetic resonance imaging including diffusion-weighted imaging (DWI). We recorded DWI-positive infarcts and proximity to cortex for small subcortical infarcts. We examined factors associated with C-ID. Results: 137 patients with a mild cortical or lacunar syndrome had an acute ischemic lesion on DWI. Of these, 21/93 (23%) with a cortical syndrome had an acute lacunar infarct and 7/44 (16%) with a lacunar syndrome had an acute cortical infarct. From 72 patients with an acute lacunar infarct on DWI, lesion proximity to cortex (odds ratio (OR) 14.5, 95% confidence interval (CI) 1.61–130.1), left hemisphere location (OR 8.95, 95% CI 1.23–64.99) and diabetes (OR 17.1, 95% CI 1.49–196.16) predicted C-ID. On multivariate analysis of all 137 patients, C-ID was associated with diabetes (OR 7.12, 95% CI 1.86–27.2). Conclusions: C-ID occurs in a fifth of patients with mild stroke. Lacunar infarcts lying close to cortex are more likely to cause cortical symptoms. Diabetes is associated with any clinical-imaging mismatch. Stroke misclassification which can arise with clinical classification alone should be minimized in research by verification with high-sensitivity imaging.

Lack of association of white matter lesions with ipsilateral carotid artery stenosis

Background: White matter lesions (WML) are commonly seen on brain MRI and are generally considered a marker of tissue damage from cerebral small vessel disease. WML are associated with increasing age and vascular risk factors, but their precise cause is unknown. A role for carotid artery atherothromboemboli has been suggested. If this is the case, more WML would be expected ipsilateral to increasing degrees of carotid stenosis. Methods: We recruited patients with ischaemic stroke from two large, separate prospective stroke studies, assessed with brain MRI and carotid Doppler ultrasound. We scored hemispheric WML visually in periventricular and deep locations. We assessed the association between carotid stenosis asymmetry and WML asymmetry, and vice versa. Further, we assessed the association between carotid stenosis and ipsilateral WML, before and after adjusting for vascular risk factors, and tested associations between ipsilateral and contralateral stenoses and WML. Results: We recruited 247 (Study 1) and 253 (Study 2) patients. In Study 1 and Study 2, 36 (15%) and 29 (11%) patients had ≥50% carotid stenosis, and 27 (11%) and 15 (6%) had ≥70% stenosis, respectively. Carotid stenosis was asymmetric in 28 (11%) and 26 (10%) patients and WML were asymmetric in 22 (9%) and 11 (4%) patients in Study 1 and Study 2, respectively. We found no association between carotid stenosis and ipsilateral WML score, before or after adjusting for vascular risk factors or sidedness, but WML were strongly associated with increasing age (p < 0.001). Conclusion: In two large cohorts of ischaemic stroke patients, we found no association between carotid stenosis and ipsi- or contralateral WML. There is now substantial evidence that atherothromboemboli are unlikely to cause most WML or other forms of cerebral small vessel lesions. Future studies should focus on determining what causes the intrinsic small vessel pathological changes that appear to underlie most WML.

Effect of alteplase on the CT hyperdense artery sign and outcome after ischemic stroke

Objective: To investigate whether the location and extent of the CT hyperdense artery sign (HAS) at presentation affects response to IV alteplase in the randomized controlled Third International Stroke Trial (IST-3). Methods: All prerandomization and follow-up (24–48 hours) CT brain scans in IST-3 were assessed for HAS presence, location, and extent by masked raters. We assessed whether HAS grew, persisted, shrank, or disappeared at follow-up, the association with 6-month functional outcome, and effect of alteplase. IST-3 is registered (ISRCTN25765518). Results: HAS presence (vs absence) independently predicted poor 6-month outcome (increased Oxford Handicap Scale [OHS]) on adjusted ordinal regression analysis (odds ratio [OR] 0.66, p < 0.001). Outcome was worse in patients with more (vs less) extensive HAS (OR 0.61, p = 0.027) but not in proximal (vs distal) HAS (p = 0.420). Increasing age was associated with more HAS growth at follow-up (OR 1.01, p = 0.013). Treatment with alteplase increased HAS shrinkage/disappearance at follow-up (OR 0.77, p = 0.006). There was no significant difference in HAS shrinkage with alteplase in proximal (vs distal) or more (vs less) extensive HAS (p = 0.516 and p = 0.580, respectively). There was no interaction between presence vs absence of HAS and benefit of alteplase on 6-month OHS (p = 0.167). Conclusions: IV alteplase promotes measurable reduction in HAS regardless of HAS location or extent. Alteplase increased independence at 6 months in patients with and without HAS. Classification of evidence: This study provides Class I evidence that for patients within 6 hours of ischemic stroke with a CT hyperdense artery sign, IV alteplase reduced intra-arterial hyperdense thrombus.

Enzyme replacement therapy and white matter hyperintensity progression in Fabry disease

Objective To explore the association between enzyme replacement therapy (ERT), clinical characteristics, and the rate of progression of white matter hyperintensities (WMH) in patients with Fabry disease (FD). Methods Patients with a confirmed diagnosis of FD, aged 18 years or older, participating in an existing FD observational study (NCT00196742), with at least 2 serial MRI brain scans at least 2 years apart for the period between December 2006 and August 2016 were included in this cohort study. Total WMH volume was estimated for each image using a semiautomated procedure. We performed linear regression to calculate the primary outcome measure of WMH change rate for each participant. Associations between ERT, clinical characteristics, and the primary outcome were explored using multiple linear regression. Results Eight hundred sixty-three MRI time points were analyzed for the 149 included participants. Age (p < 0.0005; increasing age associated with faster WMH progression), total cholesterol (p = 0.03; increasing total cholesterol associated with slower WMH progression), and a history of peripheral pain (p = 0.02; peripheral pain associated with faster WMH progression) were independently associated with WMH change rate in the primary analysis. We did not find an association between “ERT at any point between baseline and final MRI” and WMH change rate (p = 0.22). Conclusion In a large cohort of patients with FD, we did not find an association between ERT and WMH progression, while higher total cholesterol was associated with slower WMH progression. Further research is needed into the pathogenesis and treatment of cerebrovascular disease in this rare condition.