Brown, Robert D.

Background: The bicuspid aortic valve (BAV) exhibits abnormal geometry and transvalvular flow and is susceptible to calcification with subsequent cardioembolic stroke from calcific embolic material. However, the description of embolic ischemic strokes in patients with BAV is limited to case reports. Methods: Consecutive patients from 1975-2015 with BAV (n=5401) at our institution were retrospectively identified. Patients with ischemic stroke before aortic valve replacement (AVR) were analyzed, and the stroke was characterized. Patients were grouped according to stroke etiology: calcific embolism from a BAV (BAV stroke); large artery atherosclerotic or lacunar stroke (LA stroke); and non-BAV, non-large artery embolic stroke (nLA stroke). Results: There were 83/5401 (1.5%) patients with ischemic stroke. Mean age was 54 ± 12 years and 28% were female. Stroke etiology was BAV stroke in 26/83 (31%), LA stroke in 23/83 (28%), nLA stroke in 30/83 (36%), and other in 4/83 (5%). Stroke was embolic in 72/83 (87%), as shown in Figure 1. CHA 2 DS 2 -VASc score was not different in patients with BAV stroke (1.4 ± 1.2) versus nLA stroke (1.8 ± 1.2, p=0.188) but was higher in LA stroke (2.3 ± 1.2, p=0.005 vs. BAV stroke). Recurrent stroke occurred in 41% overall (50% BAV stroke vs. 30% LA stroke vs. 47% nLA stroke, both p=NS vs. BAV stroke). BAV stroke was more commonly located in the retinal circulation (39% BAV stroke vs. 13% LA stroke [p=0.044] vs. 0% nLA stroke [p=0.002]). Patients with BAV and LA stroke were more likely to have moderate-to-severe aortic stenosis and undergo AVR sooner after stroke compared to patients with nLA stroke. Conclusions: Stroke is an important complication in patients with BAV. The most common type of stroke in BAV is embolic. Greater than one-third of embolic stroke resulted from embolism from a calcific aortic valve. Patients with BAV stroke commonly have a history of recurrent cerebral ischemic events, severe valvular disease, and proceed to AVR soon after stroke.

Background Description of cerebral and retinal infarction in patients with bicuspid aortic valve (BAV) is limited to case reports. We aimed to characterize cerebral and retinal infarction and examine outcomes in patients with BAV. Methods and Results Consecutive patients from 1975 to 2015 with BAV (n=5401) were retrospectively identified from the institutional database; those with confirmed cerebral or retinal infarction were analyzed. Infarction occurring after aortic valve replacement was not included. Patients were grouped according to infarction pathogenesis: embolism from a degenerative calcific BAV (BAVi); non‐BAV, large artery atherosclerotic or lacunar infarction (LAi); and non‐BAV, non‐large artery embolic infarction (nLAi). There were 83/5401 (1.5%) patients, mean age 54±12 years and 28% female, with confirmed cerebral or retinal infarction (LAi 23/83 [28%]; nLAi 30/83 [36%]; BAVi 26/83 [31%]; other 4/83 [5%]). Infarction was embolic in 72/83 (87%), and 35/72 (49%) were cardioembolic. CHA 2 DS 2 ‐VASc score was 1.4±1.2 in BAVi ( P =0.188 versus nLAi) and 2.3±1.2 in LAi ( P =0.005). Recurrent infarction occurred in 41% overall (50% BAVi, P =0.164 and 0.803 versus LAi and nLAi). BAVi was more commonly retinal (39% BAVi versus 13% LAi, P =0.044 versus 0% nLAi, P =0.002). Patients with BAVi and LAi were more likely to have moderate‐to‐severe aortic stenosis and undergo aortic valve replacement compared with patients with nLAi. Conclusions Cardioembolism, often from degenerative calcification of the aortic valve, is a predominant cause of cerebral and retinal infarction in patients with BAV and is frequently recurrent. Cerebral and retinal infarction should be regarded as a complication of BAV.

Introduction: Cervical artery dissection (CAD) is a well-recognized cause of acute ischemic stroke, especially in young adults, accounting for up to 20-25% of all cases. Several studies reported an incidence between 2.5-5 per 100,000 in the general population. However, the actual incidence may be higher as many patients remain asymptomatic. Even though CAD is one of the leading causes of ischemic stroke, there is a lack of consensus in management. Our study surveyed practicing clinicians involved in the management of CAD to characterize current practice trends and provide a foundation for future research. Methods: An online case-based questionnaire with 11 questions regarding the management of cervical artery dissection was developed and piloted internally with 12 Mayo Clinic cerebrovascular neurologist/neurosurgeons. The survey was finalized, and initially sent to the STOP-CAD study group. We then sent the survey to practicing vascular neurologists across different academic institutions. Surveys were sent to 126 unique individuals. Results: A total of 42 clinicians completed the questionnaires. The response rate was 33% (42/126). Aspirin antiplatelet monotherapy was seen as the most appropriate therapy for asymptomatic CAD (81% [34/42]). Anticoagulation was the treatment of choice for cases with CAD and concomitant intraluminal thrombus (74% [31/42]). Most (74% [31/42]) of the participants recommended repeat imaging at three months. However, no consistent response regarding the type of antithrombotic agent for symptomatic CAD without intramural thrombus or cases with pseudoaneurysm. There was marked variability regarding the duration of antithrombotic therapy, ranging from three months to life-long treatment. Conclusion: Marked variability was seen in the management of CAD, especially regarding the choice of antithrombotic agent in symptomatic and complicated (stenosis or pseudoaneurysm) cases and the duration of such therapy, which reflects the lack of definitive clinical trial data. Ongoing research is needed to better guide the optimal management of these patients.

Background: Arterial dissection represents a rare but significant cause of ischemic stroke. We hypothesized that the detection rate of arterial dissections has increased in recent decades. Objective: To determine the incidence of cervical artery dissection in a defined population. Methods: We identified Olmsted County, Minnesota residents diagnosed with carotid artery or vertebral artery dissection between 2002 and 2020 using the Rochester Epidemiology Project database. Patients who had suffered major trauma, were under 18 years of age or had intracranial artery dissections were excluded. Virtually all Olmsted County residents receive their medical care within the participating health systems, leading to a high likelihood of complete case ascertainment. We assessed longitudinal trends by dividing the data into 5-year time windows, with the last being a 4-year interval. Incidence rates were adjusted for age and sex. Results: In a 19-year period from 2002 through 2020, 127 patients with a diagnosis of cervical artery dissection were identified. There were 64 females (50.4%) and 63 males (49.6%). The average age at diagnosis was 51.2 years (SD 15.7). There were 63 internal carotid artery dissections (ICAD), 60 vertebral artery dissections (VAD), and three common carotid artery dissections (CCAD) identified. One patient had ICAD and VAD at diagnosis. The overall incidence rate of detection for cervical artery dissection, adjusted for age and sex, was 4.9 per 100,000 person-years (py) (95% CI, 4.0 to 5.7). The incidence rate of ICAD was 2.5 per 100,000 py (95% CI, 1.8 to 3.1). The incidence rate of VAD was 2.3 per 100,000 py (95% CI, 1.7 to 2.9). The incidence rate of CAD gradually increased over time from 2.3 per 100,000 py (95% CI, 1.1 to 3.5) in 2002-2006 to 9.4 per 100,000 py (95% CI, 6.9 to 11.8) in 2017-2020, a 4.2-fold increase. Conclusion: The incidence of detection rate of cervical artery dissection increased over four-fold in the last 19 years. This can potentially be attributed to increased usage of non-invasive angiographic imaging.

ObjectiveThis study was undertaken to explore the gene expression profile of primary central nervous system vasculitis (PCNSV).MethodsBrain specimens of 4 patients with granulomatous vasculitis (GV), 5 with lymphocytic vasculitis (LV), 4 with amyloid β‐related angiitis (ABRA), and 4 normal controls were studied. RNA‐sequencing was performed using the Illumina Hiseq‐4,000 platform and the Illumina TruSeq Total‐RNA library. Student t test and false discovery rate tests were performed for each of the differentially expressed transcripts. Ingenuity Pathway Analysis was used for the pathway expression analysis. CIBERSORT was used to estimate the abundances of different immune cell subsets in the tissues based on gene expression data.ResultsTranscripts differentially expressed between PCNSV and normal brain indicated that endosomal, mitochondrial, and ribosome dysfunction, alterations in protein synthesis, and noncoding RNAs might be involved in PCNSV. Pathway analysis revealed the activation of dendritic cell maturation and antigen processing as well as neuroinflammation in PCNSV versus normal brain, whereas oxidative phosphorylation was inhibited. CIBERSORT estimation of immune cell subsets suggested that activated NK cells, M1 macrophages, memory B cells, and follicular helper T cells were likely to be more prevalent in PCNSV samples. Naïve CD4 T cells and monocytes were mainly estimated to be present in GV and ABRA. Plasma cell and γδ T‐cell signatures were mainly found in LV and normal brain. GV showed higher levels of genes associated with macrophage activities and T cells. ABRA showed higher levels of long noncoding RNAs and miR‐616. LV showed higher levels of genes encoding immunoglobulins.InterpretationRNA sequencing confirmed PCNSV heterogeneity. ANN NEUROL 2023;93:120–130

Introduction: Participation by American Indian and Alaska Natives (AI/AN) in clinical research may improve AI/AN health outcomes and generalizability of the research. Hypothesis: Cultural beliefs have a strong impact on willingness of AI/AN to participate in research. Methods: We developed a survey to identify if cultural beliefs impact perception of clinical research and the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2) protocol. Stroke neurologists and CREST-2 investigators participated in the design of the survey. Participants were stratified based on AI/AN self-identification and level of education. Likert-scale responses were tested with the Mann Whitney-U test and dichotomous responses with the Chi-Square test. Results: There were 102 participants: 61% female, mean age 39, and 37% AI/AN. Eight questions evaluated understanding of research concepts within CREST-2; 89% of these responses were correct, with no significant difference in responses between AI/AN and non-AI/AN or between low (n=42) and high (n=60) education. Compared to other ethnic groups, AI/AN identify more with their culture (p=0.002) and consider cultural beliefs when making health care decisions (p=0.005), including participating in a research study (p=0.002). Using the same questions, we found no difference between respondents with low or high education.(Figure 1) Conclusion: These data support our hypothesis that cultural beliefs have a strong impact on AI/AN willingness to participate in research. It is important for researchers to consider cultural beliefs when designing recruitment strategies for AI/AN populations. Future work will address how cultural beliefs affect AI/ANs’ understanding of and willingness to participate in clinical research.

Background: Coronary artery disease (CAD) is a significant cause of morbidity and mortality in ischemic stroke (IS) patients. IS and CAD often coexist and share common risk factors. Absolute risk and predictors of myocardial infarction (MI) in IS and by IS etiology subtype is not well known. We determined the risk of MI and its predictors in patients with incident IS in a population based cohort. Methods: Using the Rochester Epidemiology Project (REP) medical records linkage system we identified all residents with incident IS in a 5-year period between January 1, 1990, and December 31, 1994. Comprehensive medical records were reviewed and variables of interest were retrieved and analyzed. Univariate Cox proportional hazard regression models were constructed to assess hazard ratios and 95% CI for predictors of MI occurrence after IS. Results: We identified 490 persons with IS, mean age at IS was 76.6 (SD 12.9) years, mean follow up to death or final follow-up was 6.5 (SD 6.3, range 0.0-23.8) years. There were 126 recurrent strokes and 93 MIs during followup. The 1-year actuarial risk of MI was 3.6% (95% CI, 2.2% - 5.9%), and 5-year actuarial risk of MI was 11.4% (95% CI, 8.4% - 15.3%). Univariate predictors of MI included (HR; 95% CI): age (1.02;1.0-1.04), pre-IS history of MI (1.37;1.13-1.65), CHF (1.85;1.06-3.23), CABG (2.11;1.19-3.75), left ventricular dyskinesia (2.14;1.32-3.4), peripheral vascular disease (1.32;1.18-1.49), diabetes mellitus (1.54;1.21-1.96), elevated creatinine (1.93;1.44-2.59), LDL level (1.01;1.00-1.01). Conclusion: MI is common after first IS. Several factors predicted an increased risk of MI after stroke, and should be taken into account in determining CAD screening strategies at the time of IS. Recurrent stroke was more common than MI during long-term followup.

Introduction: Studies have suggested a high incidence of dementia after stroke; however data regarding risk factors are conflicting and few studies are population-based. The aims of this population-based study are to determine the frequency of diagnosis and predictors of clinical dementia after ischemic stroke. Methods: The Rochester Epidemiology Project medical records linkage system was used to ascertain all first ischemic strokes (IS) occurring among Rochester, MN residents between 1990 -1994. Comprehensive medical records were reviewed. Patient and stroke characteristics, medical comorbidities, and the development of clinical dementia any time after IS were recorded. Dementia was defined as any reflection in the chart by a clinician of memory loss resulting in functional impairment. Patients with a pre-stroke diagnosis of dementia were excluded. Associations between new dementia after the index IS and other variables of interest were analyzed using univariate logistic regression. Results: First IS was detected in 490 people, 82 of whom had a prior history of dementia, and 119 (29%) of whom developed dementia during a mean follow-up of 6.5 years (range 0-23.8). The mean age at index stroke was 76.6 years (SD 12.9). Those who developed dementia were a mean 4 years older at the time of IS (p = 0.003). The odds of developing dementia were 1.7 higher in those who had at least one recurrent stroke. There was no effect of sex, stroke location (cortical, subcortical, brainstem), stroke mechanism, or premorbid stroke risk factors (coronary artery disease, atrial fibrillation/flutter, hypertension, diabetes mellitus, left-sided valvular disease) on the occurrence of dementia. Conclusions: Dementia is commonly diagnosed following ischemic stroke. While stroke risk factors did not impact the risk of diagnosis of dementia, recurrent stroke increased this risk. Stroke risk factors may indirectly increase the risk of dementia by increasing the risk of recurrent IS. This suggests that aggressive secondary stroke prevention measures may significantly decrease the risk of being diagnosed with dementia following IS.

INTRODUCTION: Cerebral cavernous malformations (CCM) are the second commonest incidental finding on brain MRI and may cause symptomatic intracranial hemorrhage (ICH). However, the risk and predictors of ICH from CCM remain uncertain. HYPOTHESIS: Presentation with ICH or non-hemorrhagic focal neurological deficit (FND) attributable to CCM, brainstem CCM location, female sex, increasing age and multiple CCM predict ICH occurrence during follow-up without CCM treatment. METHODS: Three hospital-based cohorts and two cohorts from a population-based study provided individual patient data on clinical course from CCM diagnosis until either first CCM treatment or last available follow-up. We used survival analysis of each cohort to estimate the 5-year risk of symptomatic ICH or new FND, multivariable Cox regression to identify baseline predictors of outcome, and random-effects models to pool estimates in meta-analysis. RESULTS: Among 988 adults who experienced 62 ICHs during 3,232 person-years of follow-up, clinical presentation with ICH or FND (hazard ratio [HR] 7.4, 95% confidence interval [CI] 2.9-19.2) and brainstem CCM location (HR 5.7, 95% CI 3.2-10.3) were associated with a higher risk of a first ICH within five years of CCM diagnosis, but age, sex and CCM multiplicity were not. The 5-year estimated risk of ICH during untreated follow-up was 2.4% (95% CI 1.0-3.8) for 566 adults without ICH/FND from CCM outside the brainstem, 5.5% (95% CI 0-12.9) for 51 adults without ICH/FND from brainstem CCM, 10.6% (95% CI 5.1-16.1) for 198 adults with ICH/FND from CCM outside the brainstem, and 25.7% (95% CI 18.3-33.1) for 173 adults with ICH/FND from brainstem CCM. In secondary analyses of first ICH or FND, event rates increased but predictors remained unchanged. CONCLUSION: Mode of clinical presentation and CCM location are independently associated with ICH or FND within five years of CCM diagnosis, which can inform decisions about CCM treatment.