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Background and Objectives: White matter hyperintensities (WMHs) are frequent imaging features of small vessel disease (SVD) and related to poor clinical outcomes. WMH progression over time is well described, but regression was also noted recently, although the frequency and associated factors are unknown. This systematic review and meta-analysis aims to assess longitudinal intraindividual WMH volume changes in sporadic SVD., Methods: We searched EMBASE and MEDLINE for articles up to 28 January 2022 on WMH volume changes using MRI on ≥2 time points in adults with sporadic SVD. We classified populations (healthy/community-dwelling, stroke, cognitive, other vascular risk factors, and depression) based on study characteristics. We performed random-effects meta-analyses with Knapp-Hartung adjustment to determine mean WMH volume change (change in milliliters, percentage of intracranial volume [%ICV], or milliliters per year), 95% CI, and prediction intervals (PIs, limits of increase and decrease) using unadjusted data. Risk of bias assessment tool for nonrandomized studies was used to assess risk of bias. We followed Preferred Reporting in Systematic Review and Meta-Analysis guidelines., Results: Forty-one articles, 12,284 participants, met the inclusion criteria. Thirteen articles had low risk of bias across all domains. Mean WMH volume increased over time by 1.74 mL (95% CI 1.23-2.26; PI -1.24 to 4.73 mL; 27 articles, N = 7,411, mean time interval 2.7 years, SD = 1.65); 0.25 %ICV (95% CI 0.14-0.36; PI -0.06 to 0.56; 6 articles, N = 1,071, mean time interval 3.5 years, SD = 1.54); or 0.58 mL/y (95% CI 0.35-0.81; PI -0.26 to 1.41; 8 articles, N = 3,802). In addition, 13 articles specifically mentioned and/or provided data on WMH regression, which occurred in asymptomatic, stroke, and cognitive disorders related to SVD., Discussion: Net mean WMH volume increases over time mask wide-ranging change (e.g., mean increase of 1.75 mL ranging from 1.25 mL decrease to 4.75 mL increase), with regression documented explicitly in up to one-third of participants. More knowledge on underlying mechanisms, associated factors, and clinical correlates is needed, as WMH regression could be an important intervention target., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Objectives: Magnetic resonance susceptibility-weighted imaging (SWI) can identify small brain blood vessels that contain deoxygenated blood due to its induced magnetic field disturbance. We observed focal clusters of possible dilated small vessels on SWI in white matter in severe small vessel disease (SVD). We assessed their prevalence, associations with SVD lesions, and vascular reactivity in patients with sporadic SVD and in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)., Methods: Secondary cross-sectional analysis of a prospective multicenter observational study of patients with either sporadic SVD or CADASIL (INVESTIGATE-SVD) studied with 3 Tesla MRI including blood-oxygen-level-dependent MRI cerebrovascular reactivity (CVR). Two independent raters evaluated SWI sequences to identify "vessel-clusters" in white matter as focal low-signal dots/lines with small vessel appearance (interrater agreement, kappa statistic = 0.66). We assessed per-patient and per-cluster associations with SVD lesion type and severity on structural MRI sequences. We also assessed CVR within and at 2-voxel concentric intervals around the vessel-clusters using contralateral volumes as a reference., Results: Among the 77 patients enrolled, 76 had usable SWI sequences, 45 with sporadic SVD (mean age 64 years [SD 11], 26 men [58%]) and 31 with CADASIL (53 years [11], 15 men [48%]). We identified 94 vessel-clusters in 36 of the 76 patients (15/45 sporadic SVD, 21/31 CADASIL). In covariate-adjusted analysis, patients with vessel-clusters had more lacunes (OR, 95% CI) (1.30, 1.05-1.62), higher white matter hyperintensity (WMH) volume (per-log10 increase, 1.92, 1.04-3.56), and lower CVR in normal appearing white matter (per %/mm Hg, 0.77, 0.60-0.99), compared with patients without vessel-clusters. Fifty-seven of the 94 vessel-clusters (61%) corresponded to noncavitated or partially cavitated WMH on fluid-attenuated inversion recovery, and 37 of 94 (39%) to complete cavities. CVR magnitude was lower than in the corresponding contralateral volumes (mean difference [SD], t , p ) within vessel-cluster volumes (-0.00046 [0.00088], -3.021, 0.005) and in the surrounding volume expansion shells up to 4 voxels (-0.00011 [0.00031], -2.140, 0.039; -0.00010 [0.00027], -2.295, 0.028) in vessel-clusters with complete cavities, but not in vessel-clusters without complete cavitation., Discussion: Vessel-clusters might correspond to maximally dilated vessels in white matter that are approaching complete tissue injury and cavitation. The pathophysiologic significance of this new feature warrants further longitudinal investigation., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Objectives: The severity of white matter hyperintensities (WMH) at presentation with stroke is associated with poststroke dementia and dependency. However, WMH can decrease or increase after stroke; prediction of cognitive decline is imprecise; and there are few data assessing longitudinal interrelationships among changing WMH, cognition, and function after stroke, despite the clinical importance., Methods: We recruited patients within 3 months of a minor ischemic stroke, defined as NIH Stroke Scale (NIHSS) score <8 and not expected to result in a modified Rankin Scale (mRS) score >2. Participants repeated MRI at 1 year and cognitive and mRS assessments at 1 and 3 years. We ran longitudinal mixed-effects models assessing change in Addenbrooke's Cognitive Examination-Revised (ACE-R) and mRS scores. For mRS score, we assessed longitudinal WMH volumes (cube root; percentage intracranial volume [ICV]), adjusting for age, NIHSS score, ACE-R, stroke subtype, and time to assessment. For ACE-R score, we additionally adjusted for ICV, mRS, premorbid IQ, and vascular risk factors. We then used a multivariate model to jointly assess changing cognition/mRS score, adjusted for prognostic variables, using all available data., Results: We recruited 264 patients; mean age was 66.9 (SD 11.8) years; 41.7% were female; and median mRS score was 1 (interquartile range 1-2). One year after stroke, normalized WMH volumes were associated more strongly with 1-year ACE-R score (β = -0.259, 95% CI -0.407 to -0.111 more WMH per 1-point ACE-R decrease, p = 0.001) compared to subacute WMH volumes and ACE-R score (β = 0.105, 95% CI -0.265 to 0.054, p = 0.195). Three-year mRS score was associated with 3-year ACE-R score (β = -0.272, 95% CI -0.429 to -0.115, p = 0.001). Combined change in baseline-1-year jointly assessed ACE-R/mRS scores was associated with fluctuating WMH volumes ( F = 9.3, p = 0.03)., Discussion: After stroke, fluctuating WMH mean that 1-year, but not baseline, WMH volumes are associated strongly with contemporaneous cognitive scores. Covarying longitudinal decline in cognition and independence after stroke, central to dementia diagnosis, is associated with increasing WMH volumes., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Purpose: Stroke is the second commonest cause of death worldwide and a leading cause of severe disability, yet there are no published trials of palliative care in stroke. To design and evaluate palliative care interventions for people with stroke, researchers need to know what measurable outcomes matter most to patients and families, stroke professionals, and other service providers., Methods: A multidisciplinary steering group of professionals and laypeople managed the study. We synthesized recommendations from respected United Kingdom and international consensus documents to generate a list of outcome domains and then performed a rapid scoping literature review to identify potential outcome measures for use in future trials of palliative care after stroke. We then completed a 3-round, online Delphi survey of professionals, and service users to build consensus about outcome domains and outcome measures. Finally, we held a stakeholder workshop to review and finalize this consensus., Results: We generated a list of 36 different outcome domains from 4 key policy documents. The rapid scoping review identified 43 potential outcome measures that were used to create a shortlist of 16 measures. The 36 outcome domains and 16 measures were presented to a Delphi panel of diverse healthcare professionals and lay service users. Of 48 panelists invited to take part, 28 completed all 3 rounds. Shared decision-making and quality of life were selected as the most important outcome domains for future trials of palliative care in stroke. Additional comments highlighted the need for outcomes to be feasible, measurable, and relevant beyond the initial, acute phase of stroke. The stakeholder workshop endorsed these results., Conclusions: Future trials of palliative care after stroke should include pragmatic outcome measures, applicable to the evolving patient and family experiences after stroke and be inclusive of shared decision-making and quality of life.

Objective: In UK Biobank (UKB), a large population-based prospective study, cases of many diseases are ascertained through linkage to routinely collected, coded national health datasets. We assessed the accuracy of these for identifying incident strokes., Methods: In a regional UKB subpopulation (n = 17,249), we identified all participants with ≥1 code signifying a first stroke after recruitment (incident stroke-coded cases) in linked hospital admission, primary care, or death record data. Stroke physicians reviewed their full electronic patient records (EPRs) and generated reference standard diagnoses. We evaluated the number and proportion of cases that were true-positives (i.e., positive predictive value [PPV]) for all codes combined and by code source and type., Results: Of 232 incident stroke-coded cases, 97% had EPR information available. Data sources were 30% hospital admission only, 39% primary care only, 28% hospital and primary care, and 3% death records only. While 42% of cases were coded as unspecified stroke type, review of EPRs enabled a pathologic type to be assigned in >99%. PPVs (95% confidence intervals) were 79% (73%-84%) for any stroke (89% for hospital admission codes, 80% for primary care codes) and 83% (74%-90%) for ischemic stroke. PPVs for small numbers of death record and hemorrhagic stroke codes were low but imprecise., Conclusions: Stroke and ischemic stroke cases in UKB can be ascertained through linked health datasets with sufficient accuracy for many research studies. Further work is needed to understand the accuracy of death record and hemorrhagic stroke codes and to develop scalable approaches for better identifying stroke types., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Purpose: Cilostazol, a phosphodiesterase 3' inhibitor, is used in Asia-Pacific countries for stroke prevention, but rarely used elsewhere. In addition to weak antiplatelet effects, it stabilizes endothelium, aids myelin repair and astrocyte-neuron energy transfer in laboratory models, effects that may be beneficial in preventing small vessel disease progression., Methods: A systematic review and meta-analysis of unconfounded randomized controlled trials of cilostazol to prevent stroke, cognitive decline, or radiological small vessel disease lesion progression. Two reviewers searched for papers (January 1, 2019 to July 16, 2019) and extracted data. We calculated Peto odds ratios (ORs) and 95% CIs for recurrent ischemic, hemorrhagic stroke, death, adverse symptoms, with sensitivity analyses. The review is registered (CRD42018084742)., Results: We included 20 randomized controlled trials (n=10 505), 18 in ischemic stroke (total n=10 449) and 2 in cognitive impairment (n=56); most were performed in Asia-Pacific countries. Cilostazol decreased recurrent ischemic stroke (17 trials, n=10 225, OR=0.68 [95% CI, 0.57-0.81]; P <0.0001), hemorrhagic stroke (16 trials, n=9736, OR=0.43 [95% CI, 0.29-0.64]; P =0.0001), deaths (OR=0.64 [95% CI, 0.49-0.83], P <0.0009), systemic bleeding (n=8387, OR=0.73 [95% CI, 0.54-0.99]; P =0.04), but increased headache and palpitations, compared with placebo, aspirin, or clopidogrel. Cilostazol reduced recurrent ischemic stroke more when given long (>6 months) versus short term without increasing hemorrhage, and in trials with larger proportions (>40%) of lacunar stroke. Data were insufficient to assess effects on cognition, imaging, functional outcomes, or tolerance., Conclusions: Cilostazol appears effective for long-term secondary stroke prevention without increasing hemorrhage risk. However, most trials related to Asia-Pacific patients and more trials in Western countries should assess its effects on cognitive decline, functional outcome, and tolerance, particularly in lacunar stroke and other presentations of small vessel disease.

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 (κ=0.44 [0.38, 0.50]). Agreements between the tick box versus telephone and smRSq versus telephone were 57% (ie, 87/152, κ=0.47 [0.40, 0.55], and 64% (ie, 104/161, κ=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.