Fergus N. Doubal

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.

Changes in Background Blood–Brain Barrier Integrity Between Lacunar and Cortical Ischemic Stroke Subtypes

Background and Purpose— Lacunar stroke is associated with endothelial dysfunction and histologically with intrinsic cerebral microvascular disease of unknown cause. Endothelial dysfunction could impair blood–brain barrier integrity. We assessed background blood–brain barrier leakage in patients with lacunar ischemic stroke compared with cortical stroke controls. Methods— We recruited patients with lacunar or mild cortical ischemic stroke and assessed generalized cerebral blood–brain barrier leak with MRI and intravenous gadolinium at least 1 month after stroke. We used detailed image processing to compare signal change before and for 30 minutes postcontrast throughout gray matter, white matter, and cerebrospinal fluid with summary analyses and general linear modeling. Results— Among 48 patients (29 lacunar, 19 cortical), postcontrast enhancement was significantly higher in cerebrospinal fluid (P=0.04, Mann-Whitney U), and nonsignificantly higher in white matter, in lacunar than in cortical strokes, with no difference in gray matter. General linear modeling confirmed significantly greater postcontrast enhancement in cerebrospinal fluid in lacunar patients than in cortical controls (t=3.37, P<0.0008). Conclusion— These preliminary data suggest that the blood–brain barrier may be dysfunctional throughout subcortical white matter (white matter drains via interstitial spaces to cerebrospinal fluid) in patients with lacunar stroke. Further studies are required to confirm these findings and determine whether abnormal blood–brain barrier might predate development of lacunar disease. Blood–brain barrier dysfunction may be an important mechanism for brain damage in cerebral microvascular disease.

Fractal analysis of the retinal vascular network in fundus images

Complexity of the retinal vascular network is quantified through the measurement of fractal dimension. A computerized approach enhances and segments the retinal vasculature in digital fundus images with an accuracy of 94% in comparison to the gold standard of manual tracing. Fractal analysis was performed on skeletonized versions of the network in 40 images from a study of stroke. Mean fractal dimension was found to be 1.398 (with standard deviation 0.024) from 20 images of the hypertensives sub-group and 1.408 (with standard deviation 0.025) from 18 images of the non-hypertensives subgroup. No evidence of a significant difference in the results was found for this sample size. However, statistical analysis showed that to detect a significant difference at the level seen in the data would require a larger sample size of 88 per group.

Visual neglect following stroke: current concepts and future focus.

Visual neglect is a common, yet frequently overlooked, neurological disorder following stroke characterized by a deficit in attention and appreciation of stimuli on the contralesional side of the body. It has a profound functional impact on affected individuals. A assessment and management of this condition are hindered, however, by the lack of professional awareness and clinical guidelines. Recent evidence suggests that the underlying deficit in visual attention is due to a disrupted internalized representation of the outer world rather than a disorder of sensory inputs. Dysfunction of the cortical domains and white-matter tracts, as well as inter-hemispheric imbalance, have been implicated in the various manifestations of visual neglect. Optimal diagnosis requires careful history-taking from the patient, family, and friends, in addition to clinical assessment with the line bisection test, the star cancellation test, and the Catherine Bergego Scale. Early recognition and prompt rehabilitation employing a multidisciplinary approach is desirable. Although no treatment has been definitively shown to be of benefit, those with promise include prism adaptation, visual scanning therapy, and virtual reality-based techniques. Further high quality research to seek optimum short- and long-term rehabilitative strategies for visual neglect is required.

Characteristics of patients with minor ischaemic strokes and negative MRI: a cross-sectional study

Background Diffusion-weighted (DWI) MRI is recommended in UK guidelines to evaluate minor strokes, yet can produce negative results. Objective The authors determined the rate of negative MRI (including DWI) and associated features in patients presenting to hospital with minor strokes. Methods The authors performed a prospective observational cross-sectional study in a teaching hospital of patients with a clinical diagnosis of ischaemic lacunar or minor cortical stroke. The authors performed MRI (DWI, T2, fluid-attenuated inversion recovery (FLAIR), T2* and T1) as soon as possible after presentation. The authors used multivariate analysis to determine predictors of negative DWI and MRI (all sequences). Gold standard for clinical diagnosis of stroke was the opinion of an expert panel. Results The authors recruited 246 patients, mean age 68.1u2005years (SD 11.6u2005years), 162 were males (66%), and the median NIHSS was 2 (range 0 to 8). The median time from stroke onset to MR scan was 12u2005days (IQR 4–27u2005days). Eighty-one patients (33%) did not show any ischaemia on DWI. Sixty patients (24%) did not show the recent infarct on MRI (DWI/T2/FLAIR). With multivariate analysis, less severe stroke, younger age, female gender and increased time from stroke onset to scan were associated with negative DWI. With multivariate analysis, younger age and female gender were associated with negative MRI (DWI or T2 or FLAIR) scans. Conclusions There is a high rate of negative MRI and DWI among patients with minor stroke (a third) which has important management and research implications. A negative MRI or DWI does not exclude the diagnosis of stroke.

Use of dynamic contrast-enhanced MRI to measure subtle blood-brain barrier abnormalities

There is growing interest in investigating the role of subtle changes in blood–brain barrier (BBB) function in common neurological disorders and the possible use of imaging techniques to assess these abnormalities. Some studies have used dynamic contrast-enhanced MR imaging (DCE-MRI) and these have demonstrated much smaller signal changes than obtained from more traditional applications of the technique, such as in intracranial tumors and multiple sclerosis. In this work, preliminary results are presented from a DCE-MRI study of patients with mild stroke classified according to the extent of visible underlying white matter abnormalities. These data are used to estimate typical signal enhancement profiles in different tissue types and by degrees of white matter abnormality. The effect of scanner noise, drift and different intrinsic tissue properties on signal enhancement data is also investigated and the likely implications for interpreting the enhancement profiles are discussed. No significant differences in average signal enhancement or contrast agent concentration were observed between patients with different degrees of white matter abnormality, although there was a trend towards greater signal enhancement with more abnormal white matter. Furthermore, the results suggest that many of the factors considered introduce uncertainty of a similar magnitude to expected effect sizes, making it unclear whether differences in signal enhancement are truly reflective of an underlying BBB abnormality or due to an unrelated effect. As the ultimate aim is to achieve a reliable quantification of BBB function in subtle disorders, this study highlights the factors which may influence signal enhancement and suggests that further work is required to address the challenging problems of quantifying contrast agent concentration in healthy and diseased living human tissue and of establishing a suitable model to enable quantification of relevant physiological parameters. Meanwhile, it is essential that future studies use an appropriate control group to minimize these influences.

Clinically Confirmed Stroke With Negative Diffusion-Weighted Imaging Magnetic Resonance Imaging: Longitudinal Study of Clinical Outcomes, Stroke Recurrence, and Systematic Review.

Background and Purpose— We sought to establish whether the presence (versus absence) of a lesion on magnetic resonance imaging (MRI) with diffusion weighting (DWI-MRI) at presentation with acute stroke is associated with worse clinical outcomes at 1 year. Methods— We recruited consecutive patients with a nondisabling ischemic stroke and performed DWI-MRI. Patients were followed up at 1 year to establish stroke recurrence (clinical or on MRI), cognitive impairment (Addenbrooke Cognitive Assessment Revised,<88) and modified Rankin Scale. Results— A median of 4 days post stroke, one third (76/264; 29%) of patients did not have a DWI lesion (95% confidence interval, 23%–35%). There was no statistically significant difference between those with and without a DWI lesion with respect to age or vascular risk factors. Patients without a lesion were more likely to be women or have previous stroke. At 1 year, 11 of 76 (14%) patients with a DWI-negative index stroke had a clinical diagnosis of recurrent stroke or transient ischemic attack, 33% had cognitive impairment (Addenbrooke Cognitive Assessment Revised <88), and 40% still had modified Rankin Scale >1, no different from DWI-positive patients; DWI-positive patients were more likely to have a new lesion on MRI (14%), symptomatic or asymptomatic, than DWI-negative patients (2%; P=0.02). Our data were consistent with 6 other studies (total n=976), pooled proportion of DWI-negative patients was 21% (95% confidence interval, 12%–32%). Conclusions— Nearly one third of patients with nondisabling stroke do not have a relevant lesion on acute DWI-MRI. Patients with negative DWI-MRI had no better prognosis than patients with a lesion. DWI-negative stroke patients should receive secondary prevention.

Determining the Modified Rankin Score After Stroke by Postal and Telephone Questionnaires

Background and Purpose— The modified Rankin Scale (mRS) is the most common outcome measure in large randomized controlled trials in stroke. We tested 2 postal mRS questionnaires and a telephone questionnaire to determine completion rates and intermodality agreement. Methods— We sent postal questionnaires containing 2 versions of the mRS to surviving stroke patients. One version, tick box, involved the patient/proxy ticking 1 of the 5 descriptions equating to mRS scores; the other, the simplified modified Rankin questionnaire (smRSq), included 5 questions with yes/no responses from which the mRS is derived. We performed a semistructured telephone interview to consenting respondents, blinded to postal responses, to assign an mRS. We compared the mRS obtained by these different methods. Results— We sent questionnaires to 343 of 356 surviving patients (96%) and received 225 responses (66%). The mRS could not be derived in 27 respondents (12%) and 10 respondents (4%) on the tick box and smRSq, respectively (difference in proportion, 8% [95% CI, 3–13]. One hundred three of 190 respondents (54%) to the postal questionnaire agreed on the tick box versus smRSq version (&kgr;=0.44 [0.38, 0.50]). Agreements between the tick box versus telephone and smRSq versus telephone were 57% (ie, 87/152, &kgr;=0.47 [0.40, 0.55], and 64% (ie, 104/161, &kgr;=0.55 [0.47, 0.62], respectively. Conclusions— In large studies where face-to-face assessment of mRS is impractical, a postal smRSq with telephone follow-up to nonresponders will achieve higher levels of follow-up than will the tick box version and also good levels of intermodality agreement with least risk of bias.