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Effects of select medications on hemorrhage risk in patients with cerebral or spinal cavernous malformations (CMs) are unknown.From a single-institution prospective cohort of patients with CM (2015-2021), demographics, mode of clinical presentation, and radiographic data were collected. Follow-up was performed with electronic medical record review, in-person visits, and written surveys. Select medication use was ascertained from the time of CM diagnosis to a censor date of first prospective symptomatic hemorrhage, complete surgical excision of sporadic form CM, last follow-up, or death. Using Cox proportional hazards regression model, we assessed effects of antithrombotic agents, fish oil, selective serotonin reuptake inhibitors (SSRIs), vitamin E and D supplementation, statins, and beta blockers on prospective hemorrhage risk.The study included 364 patients with spinal or cerebral CM (58.0% female; 20.0% familial form; 42.3% presentation to medical attention owing to hemorrhage; 25.8% brainstem location). During a follow-up of 2018 patient-years, 103 prospective hemorrhages occurred. No studied medications increased the prospective CM hemorrhage risk. Antithrombotics, vitamin D supplementation, fish oil, and SSRI were associated with lower hemorrhage risk even after adjusting for age at diagnosis, hemorrhage at diagnosis, and brainstem location.Use of select medications with antithrombotic properties do not increase the risk of CM hemorrhage. Vitamin D supplementation, any antithrombotic agent, fish oil, and SSRI were associated with a lower prospective hemorrhage risk. Further studies should evaluate the mechanism of action and potential benefit of these select medications.

Introduction: During the COVID-19 pandemic, studies reported less number of hospitalizations for acute stroke and reduction in the use of recanalization treatments. This study analyzes nationwide data on stroke admissions and management in the Czech Republic during the first wave of the COVID-19 pandemic. Methods: We compared the early COVID-19 pandemic (March–May 2020) with the pre-pandemic period (January–February 2020 and March–May 2019): (a) the National Register of Reimbursed Health Services provided volume of all admissions for subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), and ischemic stroke (IS), and volume of recanalization treatments (intravenous thrombolysis [IVT] and mechanical thrombectomy [MT]); (b) Registry of Stroke Care Quality provided door-to-needle time (DNT), onset-to-door time (ODT), and stroke severity at admission (National Institutes of Health Stroke Scale, NIHSS) for IS. Results: During the pandemic (March–May 2020), the peak number of COVID-19 patients treated in Czech hospitals was 39 per million. In March–May 2020 versus March–May 2019, hospital admissions decreased as follows: stroke overall by 14% (p < 0.001), IS by 14% (p < 0.001), SAH by 15% (p = 0.07), and ICH by 7% (p = 0.17). The mean age was 74 years versus 74 years (p = 0.33), and 52% versus 51% were men (p = 0.34). The volumes of IVT and MT decreased by 14% (p = 0.001) and 19% (p = 0.01), respectively. The proportions of all IS patients receiving IVT or MT remained unchanged, with, respectively, 17% versus 17% receiving IVT (p = 0.86) and 5% versus 5% receiving MT (p = 0.48). DNT and ODT were 24 versus 25 min (p = 0.58) and 168 versus 156 min (p = 0.23), respectively. NIHSS at admission did not differ (6 vs. 6; p = 0.54). Conclusion: Even with a low burden of COVID-19 during the first wave and no change in organization and logistics of stroke services, stroke admissions and volume of recanalization treatments decreased. Public health communication campaigns should encourage people to seek emergency medical care for stroke symptoms during the COVID-19 pandemic.

OBJECTIVERecent population-based and hospital cohort studies have reported a decreasing incidence of aneurysmal subarachnoid hemorrhage (aSAH) and declining aSAH-associated case-fatality rates. Principal drivers of these trends are debated, but improvements in smoking cessation and hypertension control may be critical factors.METHODSThe population-based medical records linkage system of the Rochester Epidemiological Project was used to document aSAH incidence and 30-day case fatality rates during a 20-year study period (1996–2016) in Olmsted County, Minnesota. Incidence rates in the study period were compared with data from a previous Olmsted County study concerning aSAH incidence from 1965 to 1995 and with regional trends in tobacco use.RESULTSOne hundred nineteen incident cases of aSAH were included. The median age at hemorrhage was 59 years (range 16–94 years), and 74 patients were female (62.2%). The overall average annual aSAH incidence rate was 4.2/100,000 person-years (P-Y). The aSAH incidence rate decreased from 5.7/100,000 in 1996 to 3.5/100,000 P-Y in 2011–2016. The overall aSAH-associated 30-day case-fatality rate was 21.9% and declined by approximately 0.5% annually. An accelerated decline in the fatality rate (0.9%/year) was observed from 2006–2016. Smoking among adult Olmsted County residents decreased from 20.4% in 2000 to 9.1% in 2018.CONCLUSIONSA decline in the incidence of aSAH and 30-day case-fatality rate from 1996 to 2016 was observed, as well as an accelerated decline of the fatality rate from 2006 to 2016. These findings confirm and extend the trends reported by prior studies in the same population. The decrease in aSAH in the years studied paralleled a noticeable reduction in the population smoking rates.

Many children growing up in cities are spending less time outdoors to escape the heat. This is contributing to childhood obesity and the prospect of a range of diseases in adulthood. When landscape architects and urban designers use a human thermal comfort model to test their designs for children's comfort, they would have to use a model essentially designed to simulate healthy adults. Yet there are many differences between the body of a child and an adult. The aim of this paper was to modify the thermal comfort model COMFA into a children's energy budget model through the consideration of the heat exchange of a child. The energy budget of a child can be up to 21 W/m2 higher than adults in hot summertime conditions, and 26 W/m2 lower in cold conditions. The model was validated through field studies of 65 children (32 boys and 33 girls) aged from 7-12 years old in 9 days from March to June in 2019, in 68 different microclimates ranging from cool to hot. A 5-point thermal comfort scale of energy budget for children was created using multinomial logistic regression, which revealed that children have a different range of thermal acceptability than adults. The frequency distribution of the actual thermal sensation and the predicted thermal comfort was improved using the new scale. The actual thermal sensation responses from children and the predicted thermal sensation using the model was determined to be positively significantly related. The accuracy of the model was 93.26%. This study has provided an effective children's energy budget model to predict children's thermal comfort. Its application can contribute to the design of thermally comfortable children's outdoor play areas by landscape architects and urban designers.

The coronavirus disease 2019 pandemic has disrupted the lives of whole communities and nations. The multinational multicenter National Institute of Neurological Disorders and Stroke Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial stroke prevention trial rapidly experienced the effects of the pandemic and had to temporarily suspend new enrollments and shift patient follow-up activities from in-person clinic visits to telephone contacts. There is an ethical obligation to the patients to protect their health while taking every feasible step to ensure that the goals of the trial are successfully met. Here, we describe the effects of the pandemic on the trial and steps that are being taken to mitigate the effects of the pandemic so that trial objectives can be met.

Background: Cavernous malformations (CM) are angiographically occult vascular malformations that may be incidental or present with intracerebral or spinal hemorrhage, seizures, or nonhemorrhagic focal neurologic deficit (FND). Recently in vitro data have suggested vitamin D may play a role in stabilizing CCM2 endothelial cells. Little is known about the effect of vitamin D in human CM disease. Methods: Beginning in 2015, consecutive patients at our institution with radiologically confirmed CM were recruited to participate in a prospective clinical registry as well as 25-hydroxy-vitamin D study. A structured interview, survey, and examination were performed at baseline. Medical records and magnetic resonance imaging studies were reviewed and data collected included comorbid conditions, medication use, and location of CM. Standard definition of clinical hemorrhage, FND, and seizures was used. Univariate and multivariate logistic regression models were used, and OR, 95% CIs, and likelihood-ratio p values were calculated to determine the influence of the 25-hydroxy-vitamin D level on clinical presentation with hemorrhage. Results: Of 213 patients enrolled in the clinical registry between January 2015 and October 2018, 70 participated in the vitamin D study (median age: 38.3 years; 51.4% female). Of the 70 participants, 30 (42.9%) presented with hemorrhage. 25-Hydroxy-vitamin D levels were performed within 1 year of symptoms in 64.1% of patients. Patients presenting with hemorrhage had a lower 25-hydroxy-vitamin D level compared to those presenting with seizure without hemorrhage, FND, or as an incidental finding (median 25.5 ng/mL; range 11–59 hemorrhage vs. median 31.0; range 14–60, no hemorrhage; p = 0.04). After adjusting for age, month of blood draw, and body mass index, 25-hydroxy-vitamin D remained a significant predictor of hemorrhagic presentation. Brainstem location also predicted hemorrhage at presentation. Conclusion: Low 25-hydroxy-vitamin D level was more common in patients with CM presenting with hemorrhage. This study supports the potential role of modifiable factor in the initial clinical presentation of CM. Further study is needed to determine the role of vitamin D on prospective hemorrhage risk and whether supplementation may be beneficial.

The behavioral repertoire and environmental feature needs for thermoregulatory comfort have not been reported in the literature for large captive exotics. An observational study was done to investigate the behavioral repertoire of tigers via continuous observation, while focusing on thermoregulatory behavior, in order to examine behavioral and thermoregulatory needs of these animals, and inform microclimatic landscape design for thermal comfort. Nine Bengal tigers (n = 6 females, n = 3 males) were observed in June 2012, and behavior data were recorded every minute, while thermal images of each individual, wind speed, ambient temperature, and relative humidity were recorded every 15 min. Descriptive statistics were used to analyze the data due to the observatory nature of the study. All tigers spent on average over 45% of the time lying down, less than 19% of the time in direct sunlight and over 20% of their time in the shade. Males did more panting (25.6%) than females (15.1%). There was more individual variation in water and cave usage, compared with shade use and lying behaviors, which could be related to social pressures or basic individual preferences. In summary, shade is a very valuable thermoregulatory resource for tigers. Adding more shade structures to increase thermal comfort and increase activity in these cats (around 10% on average active behaviors) by adding to the space available in the shaded areas.

Although white matter hyperintensities have traditionally been viewed as a marker of vascular disease, recent pathology studies have found an association between white matter hyperintensities and Alzheimer’s disease pathologies. The objectives of this study were to investigate the topographic patterns of white matter hyperintensities associated with Alzheimer’s disease biomarkers measured using PET. From the population-based Mayo Clinic Study of Aging, 434 participants without dementia (55% male) with FLAIR and gradient recall echo MRI, tau-PET (AV-1451) and amyloid-PET scans were identified. A subset had cerebral microbleeds detected on T2* gradient recall echo scans. White matter hyperintensities were semi-automatically segmented using FLAIR MRI in participant space and normalized to a custom template. We used statistical parametric mapping 12-based, voxel-wise, multiple-regression analyses to detect white matter hyperintense regions associated with Alzheimer’s biomarkers (global amyloid from amyloid-PET and meta-regions of interest tau uptake from tau-PET) after adjusting for age, sex and hypertension. For amyloid associations, we additionally adjusted for tau and vice versa. Topographic patterns of amyloid-associated white matter hyperintensities included periventricular white matter hyperintensities (frontal and parietal lobes). White matter hyperintense volumes in the detected topographic pattern correlated strongly with lobar cerebral microbleeds (P < 0.001, age and sex adjusted Cohen’s d = 0.703). In contrast, there were no white matter hyperintense regions significantly associated with increased tau burden using voxel-based analysis or region-specific analysis. Among non-demented elderly, amyloid load correlated with a topographic pattern of white matter hyperintensities. Further, the amyloid-associated, white matter hyperintense regions strongly correlated with lobar cerebral microbleeds suggesting that cerebral amyloid angiopathy contributes to the relationship between amyloid and white matter hyperintensities. The study did not support an association between increased tau burden and white matter hyperintense burden.

Objective To describe the clinical, laboratory, and imaging features and course of patients with primary central nervous system vasculitis (PCNSV) presenting with an intracranial tumor-like mass (TLM). Methods We retrospectively studied a cohort of 191 consecutive patients with PCNSV seen at the Mayo Clinic, Rochester, MN over a 35-year period (1982–2017). 13/191 patients presented with a TLM. We compared the findings in these 13 patients with those from the 178 without this presentation. Results In 13 of 191 (6.8%) patients with TLM the diagnosis of PCNSV was established by cerebral biopsy. Granulomatous vasculitis was found in 11/13 patients, accompanied by vascular deposits of β-amyloid peptide in 7. Compared to the 178 patients without TLM, the patients with TLM were more likely to be male (p = 0.04), and less likely to have a transient ischemic attack (p = 0.023), bilateral cerebral infarcts (p = 0.018), or vasculitic lesions on angiography (p = 0.045). They were more likely to have seizures (p = 0.022), gadolinium-enhanced lesions (p = 0.007), and amyloid angiopathy (p = 0.046). All 13 patients responded to therapy and 8/13 (61.5%) had a Rankin disability score of 0 at last visit. Overall, high disability scores (Rankin scores 4–6) at last follow-up were associated with increasing age (odds ratio, OR, 1.49) and cerebral infarction (OR, 3.47), but were less likely in patients with gadolinium-enhanced lesions (OR, 0.36) and amyloid angiopathy (OR, 0.21). Conclusion In PCNSV a TLM at presentation represents a definable subgroup of patients with a favourable treatment response.

ObjectiveTo describe the prevalence of cerebral microbleeds (CMBs) and determine the association between CMBs and β-amyloid burden on PET.MethodsFrom the population-based Mayo Clinic Study of Aging, 1,215 participants (53% male) underwent 3-tesla MRI scans with T2* gradient recalled echo sequences from October 2011 to February 2017. A total of 1,123 participants (92%) underwent 11C-Pittsburgh compound B (PiB)-PET scans. The prevalence of CMBs was derived by adjusting for nonparticipation and standardizing to the Olmsted County, MN, population. The relationship between β-amyloid burden and CMB presence and location was tested using logistic regression models. Ordinal logistic models tested the relationship between CMB frequency and β-amyloid burden.ResultsTwo hundred seventy-four participants (22.6%) had at least one CMB. CMB frequency increased with age by decade (11% aged 60–69 years, 22% 70–79 years, and 39% 80 years and older). After adjusting for age, sex, and hypertension, PiB standardized uptake value ratio (SUVR) was associated with increased odds of a CMB. The association between PiB SUVR and CMBs was location-specific; PiB SUVR was associated with lobar CMBs but not deep CMBs. Age, hypertension, and PiB SUVR were associated with increasing CMB count. CMB density was greatest in parietal and occipital regions; β-amyloid burden correlated with concentration of CMBs in all lobar regions. Among participants with multiple CMBs, greater PiB uptake occurred in the pre- and postcentral gyri superiorly, the superior parietal lobe and precuneus, the angular gyrus, inferior temporal gyrus, and temporal poles.ConclusionsThe prevalence of CMBs increases with age. In this population-based sample, β-amyloid load was associated with lobar but not with deep CMBs.

Treatment of unruptured intracranial arteriovenous malformations (AVMs) has become controversial since the ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformations) study was published in 2014. We sought to analyze changes in the demographics, clinical presentation, and treatment strategies in 2 patient cohorts from the same institution separated by 40 years.We retrospectively reviewed the electronic medical records for a consecutive series of patients with unruptured intracranial AVMs seen at the Mayo Clinic between 2003 and 2017 and compared them with a previously published historical cohort from the same institution seen between 1974 and 1985.There were 273 patients in the contemporary cohort, of which discovery of the AVM was incidental in 123 (45.1%), a 3.5-fold increase compared with the 13.1% out of 168 patients in the historical cohort (P0.0001). Consequently, the percentage of patients with seizures as the presenting symptom leading to the diagnosis of AVM decreased from 57.7% in the historical cohort to 28.9% in the contemporary cohort (P0.0001). Interventional treatment was utilized in 220 (81.5%) contemporary patients compared with 49 (29.2%) historical patients (P0.0001).Compared to 40 years ago, more patients are presenting with incidentally discovered intracranial AVMs and are undergoing interventional treatment. Better understanding of the natural history, developments in endovascular therapy, and stereotactic radiosurgery, as well as improvements in microsurgical techniques have led to a substantial increase in patients undergoing invasive treatment.

Objectives To evaluate long-term treatment and outcomes of patients with primary central nervous system vasculitis (PCNSV). Methods In this cohort of 191 consecutive patients with PCNSV seen at Mayo Clinic, Rochester, MN, over 35 years with long-term follow-up we analyzed response to and duration of therapy, frequency of relapses, long-term remission, efficacy of maintenance therapy and initial intravenous glucocorticoid (GC) pulses, survival and degree of disability. We also compared the efficacy of initial IV and oral cyclophosphamide (CYC). Results A favorable initial response was observed in 83% of patients treated with prednisone (PDN) alone, 81% of those treated with PDN and CYC and 95% of those initially treated with PDN and an immunosuppressant other than CYC. One or more relapses were observed in 30% of patients, 35% had discontinued therapy by last follow-up, and 21.5% maintained remission for at least 12 months after discontinuing therapy. Maintenance therapy was prescribed in 19% of all patients and 34% of patients initially treated with CYC and PDN. High disability scores (Rankin 4–6) and deaths were less frequently observed in patients receiving maintenance therapy and more frequently in patients with Aβ-related angiitis. Large vessel involvement and cerebral infarction at diagnosis were associated with a poor treatment response. Aspirin use was positively associated with long-term remission and having gadolinium-enhanced cerebral lesions or meninges was negatively associated. A high disability score at last follow-up and higher mortality rate were associated with increasing age, cerebral infarction and cognitive dysfunction at diagnosis. Lymphocytic vasculitis on biopsy was associated with a more benign course with reduced disability and mortality. Patients initially treated with mycophenolate mofetil had better outcomes compared to those treated with CYC and PDN. No therapeutic advantages were observed in the patients initially treated with intravenous GC pulses. Intravenous and oral CYC were equally effective in inducing the remission. Conclusions The majority of patients with PCNSV responded to treatment. We found patient subsets with different outcomes. Mycophenolate mofetil may be an effective alternative to CYC.

Objective Describe the range of procedures associated with spinal cord infarction (SCI) as a complication of a medical/surgical procedure and define clinical and imaging characteristics that could be applied to help diagnose spontaneous SCI, where the diagnosis is often less secure. Methods We used an institution-based search tool to identify patients evaluated at Mayo Clinic, Rochester, MN from 1997 to 2016 with a periprocedural SCI. We performed a descriptive analysis of clinical features, MRI and other laboratory findings, and outcome. Results Seventy-five patients were identified with SCI related to an invasive or non-invasive surgery including: aortic aneurysm repair (49%); other aortic surgery (15%); and a variety of other procedures (e.g., cardiac surgery, spinal decompression, epidural injection, angiography, nerve block, embolization, other vascular surgery, thoracic surgery) (36%). Deficits were severe (66% para/quadriplegia) and maximal at first post-procedural evaluation in 61 patients (81%). Impaired dorsal column function was common on initial examination. Imaging features included classic findings of owl eyes or anterior pencil sign on MRI (70%), but several other T2-hyperintensity patterns were also seen. Gadolinium enhancement of the SCI and/or cauda equina was also common when assessed. Six patients (10%) had an initial normal MRI despite a severe deficit. Conclusions Procedures associated with SCI are many, and this complication does not exclusively occur following aortic surgery. The clinical and radiologic findings that we describe with periprocedural SCI may be used in future studies to help distinguish spontaneous SCI from alternate causes of acute myelopathy.

The aim of the study was to test the hypothesis that high levels of preoperative C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are associated with an increased risk of systemic inflammatory response syndrome (SIRS) following percutaneous nephrolithotomy (PCNL).This is a retrospective study of patients who underwent PCNL at our institution between October 2012 and October 2013 when ESR and CRP levels were part of our standard preoperative order set. The primary endpoint was development of SIRS. Receiver operating characteristic curves were used to evaluate the discriminative ability of the test.Among the 107 PCNLs performed during the study period, 35 (33%) patients had evidence of SIRS during the postoperative stay. Patients who experienced SIRS had a longer operative time (99 min vs. 85 min, p = 0.016), were more likely to have been transferred to the intensive care unit (ICU) (15% vs. 0%, p = 0.002), and experienced a longer length of stay (2 days vs. 1 day, p 0.001). On multivariable analysis controlling for operative time and positive urine culture, ESR (odds ratio [OR] 1.32, 95% confidence interval [CI]: 1.01-1.72, p = 0.04) and CRP (OR 1.59; 95% CI: 1.07-2.37, p = 0.02) were associated with development of SIRS. Among patients without a positive urine culture, an ESR6.5 mm/hr (AUC 0.62; 95% CI: 0.52-0.78) had sensitivity, specificity, and negative predictive value (NPV) of 70.4%, 61.5%, and 80.0%, respectively, for development of SIRS. Among all patients, a CRP0.65 mg/dL (AUC 0.63; 95% CI: 0.51-0.74) had sensitivity, specificity, and NPV of 51.4%, 69.4%, and 74.6%.A preoperative blood test for ESR and CRP was predictive for the development of SIRS after PCNL. This knowledge could be used to risk stratify patients and guide duration of antibiotic prophylaxis before PCNL, particularly among those without a positive urine culture.

Providing the correct level of care for patients with intracerebral hemorrhage (ICH) is crucial, but the level of care needed at initial presentation may not be clear. This study evaluated factors associated with admission to intensive care unit (ICU) level of care. This is an observational study of all adult patients admitted to our institution with non-traumatic supratentorial ICH presenting within 72 h of symptom onset between 2009–2012 (derivation cohort) and 2005–2008 (validation cohort). Factors associated with neuroscience ICU admission were identified via logistic regression analysis, from which a triage model was derived, refined, and retrospectively validated. For the derivation cohort, 229 patients were included, of whom 70 patients (31 %) required ICU care. Predictors of neuroscience ICU admission were: younger age [odds ratio (OR) 0.94, 95 % CI 0.91–0.97; p = 0.0004], lower Full Outline of UnResponsiveness (FOUR) score (0.39, 0.28–0.54; p

Background This retrospective cross-sectional study reports 1 month and 1 year intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH) case fatality rates and their temporal trends in the Czech Republic between 1998 and 2015. Methods Utilizing the National Register of Hospitalized Patients, we randomly selected 600 patients hospitalized for ICH and 600 patients hospitalized for SAH for each year from 1998 to 2015, and identified those who died, regardless of cause, using the Czech National Mortality Registry. We calculated crude and age-adjusted 1 month and 1 year case fatality rates for ICH and SAH. Long-term trends of the crude rates were analyzed using a one-sided Cochran Armitage test. Results A total of 21,600 cases hospitalized for SAH and ICH (10,800 for each) between 1998 and 2015 were randomly selected for analysis. One month case fatality of SAH overall and in women has decreased by 0.2% (P = .006) and 0.3% per year (P = .04), respectively. Overall 1 year case fatality of SAH has decreased by 0.2% per year (P = .03). One month case fatality rate of ICH overall and in men has decreased by 0.2% (p=0.01) and 0.4% (P = .0007), respectively. One year case fatality of ICH in men has decreased by 0.2% per year (P = .047). Conclusions One month and 1 year case fatality rates for SAH and ICH have been decreasing in the Czech Republic between 1998 and 2015, and are similar or lower than those reported from other developed European countries.

Background It is not known if risk factors differ between ischemic stroke (IS) subtypes in Central and Eastern Europe. Aims We performed a community-based analysis of risk factors in patients admitted with IS over a 1 year period in Brno, the second largest city in the Czech Republic (CR). Methods Based on the National Register of Hospitalized Patients, all patients with IS admitted in Brno in 2011 were identified. Comprehensive discharge summaries from hospital admissions were collected and reviewed. IS subtype and relevant risk factors were ascertained for all patients. The age- and sex-adjusted association of risk factors with IS subtypes was determined. Results Overall, 682 patients with IS were admitted in 2011 to Brno hospitals. The distribution of IS subtypes was: 35% cardioembolism, 28% large-artery atherosclerosis, 23% small-artery occlusion, 7% stroke of undetermined etiology, 7% stroke of other determined etiology. Several of the risk factors showed high prevalence in the overall sample – e.g. hypertension (84%) and hyperlipidemia (61%). Cardioembolism as compared to other subtypes was positively associated with a history of myocardial infarction, cardiac failure, and atrial fibrillation. Small-artery occlusion was positively associated with history of dementia. No significant association was found between IS subtypes and history of IS, hypertension, diabetes, obesity, alcohol abuse or smoking. Conclusions We found high frequency of stroke risk factors in all IS subtypes. These findings have implications for stroke prevention strategies in the CR and across Central Europe.

Objectives Nontraumatic convexal subarachnoid hemorrhages in the elderly can be a manifestation of cerebral amyloid angiopathy associated with a high risk of future intracerebral hemorrhage. The incidence in the elderly population is unknown. Our objectives were to: 1) determine the incidence of convexal subarachnoid hemorrhage in a population-based study, and, 2) to compare apopolipoprotein-E genotype and amyloid positron emission tomographic (PET) imaging for those with versus without hemorrhage. Methods Between 11/29/2004 and 3/11/2017, 4462 individuals without hemorrhage at baseline participated in the population-based Mayo Clinic Study of Aging. We used the Rochester Epidemiology Project medical records-linkage system to identify intracerebral hemorrhages. Records and images were reviewed to identify convexal subarachnoid hemorrhage. Neuroimaging characteristics, demographics, medications, and apopolipoprotein-E genotype were recorded. Results Four cases were identified. The incidence of convexal subarachnoid hemorrhage was 14.1 per 100,000 person years. Three occurred in women, median age, 79 (range: 71-84). One patient had coexisting cerebral microbleeds. Two participants developed a subsequent lobar intracerebral hemorrhage at a median of 4.75 years after convexal subarachnoid hemorrhage. The apopolipoprotein-E -allele combinations of the 4 were: 3/3, 3/3, 2/2, and 2/3. On Pittsburgh Compound B-PET imaging, median standardized uptake value ratio with convexal subarachnoid hemorrhage was 1.86 (range: 1.38-2.34). Conclusions Convexal subarachnoid hemorrhage is rare in the older population, occurring with an incidence of about 14 per 100,000 person years. Yet, when present, it may be associated with a high risk of future intracerebral hemorrhage.

ObjectiveTo determine the incidence of cerebral microbleeds (CMBs) and the association of amyloid PET burden with incident CMBs.MethodsA total of 651 participants, age ≥50 years (55% male), underwent 3T MRI scans with ≥2 separate T2*-weighted gradient recalled echo sequences from October 2011 to August 2017. Eighty-seven percent underwent 11C Pittsburgh compound B (PiB) PET scans. Age-specific CMB incidence rates were calculated by using the piecewise exponential model. Using structural equation models (SEMs), we assessed the effect of amyloid load and baseline CMBs on future CMBs after considering the direct and indirect age, sex, vascular risk factors, and APOE effects.ResultsParticipants' mean age (SD) was 69.8 (10.0) years at baseline MRI, and 111 participants (17%) had ≥1 baseline CMB. The mean (SD) of the time interval between scans was 2.7 (1.0) years. The overall population incidence rate for CMBs was 3.6/100 person-years and increased with age: from 1.5/100 new CMBs at age 50 to 11.6/100 person-years at age 90. Using the piecewise exponential model regression, the incidence rates increased with age and the presence of baseline CMBs. The SEMs showed that (1) increasing age at MRI or carrying an APOE4 allele was associated with more amyloid at baseline, and higher amyloid, particularly occipital amyloid load, in turn increased the risk of a new lobar CMB; and (2) the presence of CMBs at baseline increased the risk of a lobar CMB and had a larger effect size than amyloid load.ConclusionsAge and APOE4 carrier status act through amyloid load to increase the risk of subsequent lobar CMBs, but the presence of baseline CMBs is the most important risk factor for future CMBs.

BACKGROUND AND OBJECTIVES: Intracranial aneurysm rupture is the most devastating complication of autosomal dominant polycystic kidney disease. Whether selective or widespread intracranial aneurysm screening is indicated remains controversial. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: Records of 3010 patients with autosomal dominant polycystic kidney disease evaluated at the Mayo Clinic between 1989 and 2017 were reviewed. Those who had presymptomatic magnetic resonance angiography screening were included. RESULTS: Ninety-four intracranial aneurysms were diagnosed in 75 of 812 (9%) patients who underwent magnetic resonance angiography screening. Sex, age, race, and genotype were similar in the groups with and without aneurysms; hypertension and history of smoking were more frequent in the aneurysm group. Twenty-nine percent of patients with aneurysms compared with 11% of those without aneurysms had a family history of subarachnoid hemorrhage (P

Background and Purpose Administration of evidence-based pharmacotherapy improves stroke outcome while the use of non–evidence-based medications may not be of benefit and leads to unnecessary patient care costs. The aim of our study was to determine the frequency of guideline-approved and guideline-disapproved pharmacotherapy use in acute stroke management in the Czech Republic (CR). Methods Using the ICD-10 codes, 500 stroke and transient ischemic attack (TIA) patients were randomly selected (random selection of 10 hospitals and then 50 patients from each hospital) from the National Registry of Hospitalized Patients for strokes occurring in 2011. Discharge summaries were reviewed for medications prescribed during hospitalization and at discharge. Results Of the 500 requested discharge summaries, 484 were available for review (response rate 97%). Up to 479 (96%) summaries were sufficient for evaluation and of these, 393 were confirmed to have a stroke or TIA diagnosis. Brain imaging (computed tomography or magnetic resonance imaging) was performed in 97% of the 393 cases. Intravenous thrombolysis was administered to 7% of patients with ischemic stroke (rate was 0%-25% in different hospitals). Up to 97% of patients with ischemic events (TIA or ischemic stroke) were treated with antiplatelets or anticoagulants. At least 1 non–evidence-based medication was administered to 28% of the 393 patients (rate was 5%-89% in different hospitals). Conclusions Guideline-disapproved pharmacotherapy is common in stroke and TIA patients in the CR and processes should be put into place to lessen the frequency of their use. The use of guideline-approved medications is also high and should be further promoted.

We previously found that aspirin decreases the risk of cerebral aneurysm rupture in humans. We aim to assess whether a sex differential exists in the response of human cerebral aneurysms to aspirin and confirm these observations in a mouse model of cerebral aneurysm. A nested case–control analysis from the International Study of Unruptured Intracranial Aneurysms was performed to assess whether a sex differential exists in the response of human cerebral aneurysms to aspirin. A series of experiments were subsequently performed in a mouse model of cerebral aneurysms. Aneurysms were induced with hypertension and elastase injection into mice basal cisterns. We found that aspirin decreased the risk of aneurysm rupture more significantly in men than in women in the International Study of Unruptured Intracranial Aneurysms. In mice, aspirin and cyclooxygenase-2 inhibitor did not affect cerebral aneurysm formation but significantly decreased the incidence of rupture. The incidence of rupture was significantly lower in male versus female mice on aspirin. Gene expression analysis from cerebral arteries showed higher 15-hydroxyprostaglandin dehydrogenase levels in male mice. The rate of cerebral aneurysm rupture was similar in male mice receiving aspirin and 15-hydroxyprostaglandin dehydrogenase inhibitor compared with females receiving aspirin and 15-hydroxyprostaglandin dehydrogenase agonist, signaling a reversal of the sex-differential response to aspirin. Aspirin decreases aneurysm rupture in human and mice, in part through cyclooxygenase-2 pathways. Evidence from animal and human studies suggests a consistent differential effect by sex. 15-Hydroxyprostaglandin dehydrogenase activation in females reduces the incidence of rupture and eliminates the sex-differential response to aspirin.

Objectives To estimate the risk of fatal and non-fatal myocardial infarction (MI) and stroke in patients with bipolar I disorder compared to people without bipolar I disorder. Method Utilizing a records-linkage system spanning 30 years (1966–1996), a population-based cohort of 334 subjects with bipolar I disorder and 334 age and sex-matched referents from Olmsted County, Minnesota, U.S. was identified. Longitudinal follow-up continued until incident MI or stroke (confirmed by board-certified cardiologist/neurologist), death, or study end date (December 31, 2013). Cox proportional hazards models assessed the hazard ratio (HR) for MI or stroke, adjusting for potential confounders. Results There was an increased risk of fatal or non-fatal MI or stroke (as a composite outcome) in patients with bipolar I disorder [HR 1.54, 95% confidence interval (CI) 1.02, 2.33; p=0.04]. However, after adjusting for baseline cardiovascular risk factors (alcoholism, hypertension, diabetes, and smoking), the risk was no longer significantly increased (HR 1.19, 95% CI 0.76, 1.86; p =0.46). Limitations Small sample size for the study design. Findings were not retained after adjustment for cardiovascular disease risk factors. Psychotropic medication use during the follow-up was not ascertained and was not included in the analyses. Conclusion This study in a geographically defined region in the U.S. demonstrated a significant increased risk of MI or stroke in bipolar I disorder, which was no longer significant after adjustment for cardiovascular risk factors.

Background: Cerebral cavernous malformations (CCMs) can cause symptomatic intracranial haemorrhage (ICH), but the estimated risks are imprecise and predictors remain uncertain. We aimed to obtain precise estimates and predictors of the risk of ICH during untreated follow-up in an individual patient data meta-analysis.Methods: We invited investigators of published cohorts of people aged at least 16 years, identified by a systematic review of Ovid MEDLINE and Embase from inception to April 30, 2015, to provide individual patient data on clinical course from CCM diagnosis until first CCM treatment or last available follow-up. We used survival analysis to estimate the 5-year risk of symptomatic ICH due to CCMs (primary outcome), multivariable Cox regression to identify baseline predictors of outcome, and random-effects models to pool estimates in a meta-analysis.Findings: Among 1620 people in seven cohorts from six studies, 204 experienced ICH during 5197 person-years of follow-up (Kaplan-Meier estimated 5-year risk 15·8%, 95% CI 13·7–17·9). The primary outcome of ICH within 5 years of CCM diagnosis was associated with clinical presentation with ICH or new focal neurological deficit (FND) without brain imaging evidence of recent haemorrhage versus other modes of presentation (hazard ratio 5·6, 95% CI 3·2–9·7) and with brainstem CCM location versus other locations (4·4, 2·3–8·6), but age, sex, and CCM multiplicity did not add independent prognostic information. The 5-year estimated risk of ICH during untreated follow-up was 3·8% (95% CI 2·1–5·5) for 718 people with non-brainstem CCM presenting without ICH or FND, 8·0% (0·1–15·9) for 80 people with brainstem CCM presenting without ICH or FND, 18·4% (13·3–23·5) for 327 people with non-brainstem CCM presenting with ICH or FND, and 30·8% (26·3–35·2) for 495 people with brainstem CCM presenting with ICH or FND.Interpretation: Mode of clinical presentation and CCM location are independently associated with ICH within 5 years of CCM diagnosis. These findings can inform decisions about CCM treatment.Funding: UK Medical Research Council, Chief Scientist Office of the Scottish Government, and UK Stroke Association.

Objectives To assess the efficacy and safety of Rituximab (RTX) in adult primary central nervous system vasculitis (PCNSV). Methods We retrospectively assessed the effect of RTX in 6 patients with PCNSV. Five of the 6 were refractory to high dose glucocorticoids (GCs) and/or conventional immunosuppressants (IS). The sixth was newly diagnosed and received RTX in combination with GCs. Clinical evaluation, laboratory tests, and imaging modalities were performed at initial RTX administration and during the follow-up. Treatment response was assessed using the treating physician's global opinion regarding response and the degree of disability using the modified Rankin scale (mRS). We also performed a literature review for previous use of RTX in PCNSV using PubMed, Ovid Medline, and the Cochrane library. Results The six patients (3 females) had a median age at diagnosis of 50.5 years (range 17–68 years). All had active disease when RTX was started. In 4 patients, RTX administration was associated with a marked reduction in the number of flares (from 18 before starting RTX to 3 after). One patient, after an initial improvement, had 2 flares when B cells were depleted and he was not able to reduce prednisone below 20 mg/day. A 6th patient had a flare when B cells recovered and retreatment with RTX re-induced and maintained remission. The median mRS score at last visit (median: 2; range 0–4) was lower than that prior to treatment (median 3; range 1–5). The median prednisone daily dose before RTX administration was significantly higher than that at last follow-up (p = .006). In the literature review, we identified 5 papers describing 7 patients treated with RTX. Six patients responded to RTX with clinical and MRI improvement with no reported flares after RTX treatment. Conclusions Our data support a potential role for RTX treatment in selected patients with PCNSV.

Study objectives To assess etiology of ischemic stroke in patients with obstructive sleep apnea (OSA) compared with controls. This information may aid in determining how OSA increases stroke risk and facilitate recurrent stroke prevention in patients with OSA. Design Retrospective, case-control study. Setting Academic tertiary referral center. Patients Consecutive patients who underwent polysomnography and had an ischemic stroke within 1 year were identified. Stroke subtype was determined using two validated algorithms. Polysomnographic results were used to separate patients into OSA cases and controls. Information regarding cardiovascular risks, neuroimaging, and echocardiographic data were collected. Interventions N/A. Measurements and results In 53 subjects, cardioembolic (CE) strokes were more common among OSA cases than controls (72% versus 33%, P = 0.01). The majority of CE strokes occurred in those with moderate to severe OSA. Atrial fibrillation (AF) was more frequent in OSA cases (59% versus 24%, P = 0.01). The association between OSA and CE stroke remained significant after controlling for AF (P = 0.03, odds ratio 4.5). Conclusions There appears to be a strong association between obstructive sleep apnea (OSA) and cardioembolic (CE) stroke. In patients with OSA presenting with cryptogenic stroke, high clinical suspicion for CE is warranted. This may lead to consideration of diagnostic studies to identify CE risk factors such as paroxysmal atrial fibrillation (AF). CE strokes are more common in patients with OSA even after adjusting for AF. This finding may reflect a high rate of occult paroxysmal AF in this population; alternatively, OSA may lead to CE strokes through mechanisms independent of AF.

Background Stroke is a common cause of mortality and morbidity in Eastern Europe. However, detailed epidemiological data are not available. The National Registry of Hospitalized Patients (NRHOSP) is a nationwide registry of prospectively collected data regarding each hospitalization in the Czech Republic since 1998. As a first step in the evaluation of stroke epidemiology in the Czech Republic, we validated stroke cases in NRHOSP. Methods Any hospital in the Czech Republic with a sufficient number of cases was included. We randomly selected 10 of all 72 hospitals and then 50 patients from each hospital in 2011 stratified according to stroke diagnosis (International Classification of Diseases Tenth Revision [ICD-10] cerebrovascular codes I60, I61, I63, I64, and G45). Discharge summaries from hospitalization were reviewed independently by 2 reviewers and compared with NRHOSP for accuracy of discharge diagnosis. Any disagreements were adjudicated by a third reviewer. Results Of 500 requested discharge summaries, 484 (97%) were available. Validators confirmed diagnosis in NRHOSP as follows: transient ischemic attack (TIA) or any stroke type in 82% (95% confidence interval [CI], 79-86), any stroke type in 85% (95% CI, 81-88), I63/cerebral infarction in 82% (95% CI, 74-89), I60/subarachnoid hemorrhage in 91% (95% CI, 85-97), I61/intracerebral hemorrhage in 91% (95% CI, 85-96), and G45/TIA in 49% (95% CI, 39-58). The most important reason for disagreement was use of I64/stroke, not specified for patients with I63. Conclusions The accuracy of coding of the stroke ICD-10 codes for subarachnoid hemorrhage (I60) and intracerebral hemorrhage (I61) included in a Czech Republic national registry was high. The accuracy of coding for I63/cerebral infarction was somewhat lower than for ICH and SAH.

Purpose— The aim of this updated statement is to provide comprehensive and evidence-based recommendations for management of patients with unruptured intracranial aneurysms. Methods— Writing group members used systematic literature reviews from January 1977 up to June 2014. They also reviewed contemporary published evidence-based guidelines, personal files, and published expert opinion to summarize existing evidence, indicate gaps in current knowledge, and when appropriate, formulated recommendations using standard American Heart Association criteria. The guideline underwent extensive peer review, including review by the Stroke Council Leadership and Stroke Scientific Statement Oversight Committees, before consideration and approval by the American Heart Association Science Advisory and Coordinating Committee. Results— Evidence-based guidelines are presented for the care of patients presenting with unruptured intracranial aneurysms. The guidelines address presentation, natural history, epidemiology, risk factors, screening, diagnosis, imaging and outcomes from surgical and endovascular treatment.

Author(s): Patel, Nishant; Brown, Robert D; Sarkissian, Carl; De, Shubha; Monga, Manoj | Abstract: BackgroundWith a high rate of recurrence, urolithiasis is a chronic disease that impacts quality of life. The Patient Reported Outcomes Measurement Information System is an NIH validated questionnaire to assess patient quality of life. We evaluated the impact of urolithiasis on quality of life using the NIH-sponsored PROMIS-43 questionnaire.Materials and methodsPatients reporting to the kidney stone clinic were interviewed to collect information on stone history and demographic information and were asked to complete the PROMIS-43 questionnaire. Quality of life scores were analyzed using gender and age matched groups for the general US population. Statistical comparisons were made based on demographic information and patient stone history. Statistical significance was Pl0.05.Results103 patients completed the survey. 36% of respondents were male, the average age of the group was 52 years old, with 58% primary income earners, and 35% primary caregivers. 7% had never passed a stone or had a procedure while 17% passed 10 or more stones in their lifetime. Overall, pain and physical function were worse in patients with urolithiasis. Primary income earners had better quality of life while primary caregivers and those with other chronic medical conditions were worse. Patients on dietary and medical therapy had better quality of life scores.ConclusionsUrolithiasis patients subjectively have worse pain and physical function than the general population. The impact of pain on quality of life was greatest in those patients who had more stone episodes, underscoring the importance of preventive measures. Stone prevention measures improve quality of life.

Background and Purpose— Superficial siderosis (SS) is characterized by hemosiderin deposition in the superficial layers of the central nervous system and can be seen during postmortem examination or with iron-sensitive magnetic resonance imaging techniques. The distribution of SS may predict the probable underlying cause. This study aimed to report the prevalence and natural history of SS in a population-based study. Methods— Brain magnetic resonance imaging scans from the MCSA (Mayo Clinic Study of Aging), a population-based study of residents 50 to 89 years of age in Olmsted County, Minnesota, were reviewed. Participants with imaging consistent with SS were identified from 2011 through 2016. An inverse probability weighting approach was used to convert our observed frequencies to population prevalence of SS. Additional data abstracted included amyloid positron emission tomography, Apolipoprotein E genotype, coexisting cerebral microbleeds, and extent of SS. Results— A total of 1412 participants had eligible magnetic resonance imaging scans. Two participants had infratentorial SS, restricted to the posterior fossa. Thirteen participants had cortical SS involving the cerebral convexities (7 focal and 6 disseminated). Only 3 of the participants with cortical SS (23%) also had cerebral microbleeds. The population prevalence of SS was 0.21% (95% confidence interval, 0–0.45) in those 50 to 69 years old and 1.43% (confidence interval, 0.53–2.34) in those over 69 years old. Apolipoprotein E ε2 allele was more common in those with SS (57.1% versus 15.0%; P P Conclusions— SS may be encountered in the general elderly population. The association with increased amyloid burden and Apolipoprotein E ε2 genotype supports cerebral amyloid angiopathy as the most common mechanism. Longitudinal follow-up is needed to evaluate the risk of subsequent hemorrhage in cases of incidentally discovered SS.

Importance The prevalence of cerebral cavernous malformation (CCM) is unknown. Case ascertainment in most previous studies was based on autopsy data or clinical convenience samples, often without detailed clinical or radiologic information. Objective To determine the prevalence of CCM in a population-based sample of older adults. Design, Setting, and Participants This prospective imaging study included 4721 participants aged 50 to 89 years who were enrolled between January 1, 2004, and December 15, 2015, in the Mayo Clinic Study of Aging, a longitudinal, population-based study of residents of Olmsted County, Minnesota. An age- and sex-stratified sampling strategy was used to randomly select participants from Olmsted County using the medical records linkage system of the Rochester Epidemiology Project. Participants were invited to undergo brain magnetic resonance imaging (MRI). Of the 4721 participants, 2715 had an evaluable MRI. All images were reviewed by a board-certified neuroradiologist, and MRI reports were searched for the terms cavernous malformation, cavernous angioma, and cavernoma . Two vascular neurologists reviewed MRIs, and potential CCMs were classified using Zabramski classification. Medical records of the identified individuals with CCM were reviewed along with their demographic information, medical history, and any symptoms referable to the identified CCM lesion. Main Outcomes and Measures Prevalence of CCM and clinical and radiologic characteristics of study participants with CCM. Results Of the 2715 participants who underwent MRI scans, 12 (0.44%) had CCM. With the use of inverse probability weights to adjust for participation bias, the overall prevalence was 0.46% (95% CI, 0.05-0.86). The age-adjusted prevalence was found to be 0.61% (95% CI, 0-1.47) for the 50- to 59-year age group, 0.17% (95% CI, 0-0.50) for the 60- to 69-year age group, 0.45% (95% CI, 0.09-0.81) for the 70- to 79-year age group, and 0.58% (95% CI, 0-1.29) for the 80- to 89-year age group. The sex-adjusted prevalence was 0.41% (95% CI, 0-1.00) for women and 0.51% (95% CI, 0-1.07) for men. Observed frequencies were similar in men and women, with a slight male predominance. Of the 12 participants with CCM, 9 (75%) had a single Zabramski type 2 lesion in a supratentorial location. Only 1 participant (0.037%) was symptomatic from the CCM during the study period. Conclusions and Relevance The findings and data from this study are important for determining the potential number of patients available for cohort studies and anticipated clinical trials in older patients with CCM.

Rationale Trials conducted decades ago demonstrated that carotid endarterectomy by skilled surgeons reduced stroke risk in asymptomatic patients. Developments in carotid stenting and improvements in medical prevention of stroke caused by atherothrombotic disease challenge understanding of the benefits of revascularization. Aim Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2) will test whether carotid endarterectomy or carotid stenting plus contemporary intensive medical therapy is superior to intensive medical therapy alone in the primary prevention of stroke in patients with high-grade asymptomatic carotid stenosis. Methods and design CREST-2 is two multicenter randomized trials of revascularization plus intensive medical therapy versus intensive medical therapy alone. One trial randomizes patients to carotid endarterectomy plus intensive medical therapy versus intensive medical therapy alone; the other, to carotid stenting plus intensive medical therapy versus intensive medical therapy alone. The risk factor targets of centrally directed intensive medical therapy are LDL cholesterol Study outcomes The primary outcome is the composite of stroke and death within 44 days following randomization and stroke ipsilateral to the target vessel thereafter, up to four years. Change in cognition and differences in major and minor stroke are secondary outcomes. Sample size Enrollment of 1240 patients in each trial provides 85% power to detect a treatment difference if the event rate in the intensive medical therapy alone arm is 4.8% higher or 2.8% lower than an anticipated 3.6% rate in the revascularization arm. Discussion Management of asymptomatic carotid stenosis requires contemporary randomized trials to address whether carotid endarterectomy or carotid stenting plus intensive medical therapy is superior in preventing stroke beyond intensive medical therapy alone. Whether carotid endarterectomy or carotid stenting has favorable effects on cognition will also be tested. Trial registration United States National Institutes of Health Clinicaltrials.gov NCT02089217

ObjectivesTo record the clinical findings, response to therapy, and course of patients with primary CNS vasculitis (PCNSV) associated with lymphoma.Patients and MethodsWe reviewed the histories of 936 patients with a diagnosis of any type of vasculitis and lymphoma who were seen at the Mayo Clinic over a 32-year period. Ten patients with both PCNSV and lymphoma were identified. We compared the findings in these 10 patients with those from 158 patients with PCNSV without lymphoma seen over 29 years.ResultsTen of a total of 168 (5.9%) patients with PCNSV also had a history of lymphoma: 6 with Hodgkin lymphoma (HL) and 4 with non-HL (NHL). A granulomatous vasculitis was found in all 8 patients with cerebral biopsies, accompanied by vascular deposits of β-amyloid peptide in 2. In 7 patients, medical diagnostic workup for PCNSV revealed the lymphoma. Compared to the 158 patients with PCNSV without lymphoma, patients with lymphoma were more frequently male (p = 0.04), had increased gadolinium leptomeningeal enhancement (p = 0.03) at presentation, and had more neurologic disability at last follow-up (p = 0.01). No significant differences in treatment response were observed in the 2 groups (p = 0.202). Considering all 168 patients, increased disability at last follow-up was associated with increasing age at diagnosis (odds ratio [OR] 1.4), lymphoma (OR 5.9), and cerebral infarction (OR 3.2), while reduced disability was associated with gadolinium–enhanced lesions (OR 0.43) and amyloid angiopathy (OR O.23).ConclusionsLymphoma may be diagnosed simultaneously with PCNSV, suggesting an immunologic paraneoplastic mechanism.

To study the long-term risk of cerebrovascular events, seizures, and cognitive impairment in patients with transient global amnesia (TGA).Data for all patients diagnosed with possible TGA in Olmsted County, Minnesota, between January 1, 1985, through December 31, 2010, were retrieved from the Rochester Epidemiology Project database. Transient global amnesia was defined clinically. End points were cerebrovascular event (stroke or transient ischemic attack), seizure, or cognitive impairment (mild cognitive impairment or dementia) during follow-up. End points were studied using Kaplan-Meier survival plots and log-rank test.A total of 221 patients with TGA were identified and 221 age- and sex-matched controls were included in the analysis. The mean duration of follow-up was 12 years in both groups (range, 0.07-29.93). Prevalence of vascular risk factors and history of seizures were similar between both groups. Previous migraine was more common in the TGA group (42 patients [19.1%] vs 12 patients [5.4%]; P.001). There was no statistically significant difference between survival curves for the TGA group and the control group using time to any type of cerebrovascular event (log-rank P=.30), time to seizures event (log-rank P=.55), and time to cognitive impair event (log-rank P=.88) as end points. The TGA recurrence occurred in 5.4% of patients after a median interval of 4.21 years (interquartile range, 2.82-8.44). Modified Rankin scale and death rates at last follow-up were also similar between both groups.Our findings indicate that having an episode of TGA does not increase the risk of subsequent cerebrovascular events, seizures, or cognitive impairment.

To determine the prevalence and outcomes of intracranial aneurysm (IA) in patients with bicuspid aortic valve (BAV).Retrospective review of patients with BAV who underwent brain MR angiography at the Mayo Clinic from 1994 to 2013.There were 678 patients included in this study-mean age 57±13 years, men 480 (71%), mean follow-up 10±3 years (5913 patient-years). Coarctation of aorta (COA) was present in 154 (23%) patients.There were 59 IAs identified in 52 of 678 patients (7.7%). IA was present in 20/154 patients (12.9%) with COA and 32/524 patients (5.7%) without COA (p0.001). For the patients without COA, female gender and right-left cusp fusion were risks factors for IA in women after adjustment for all potential variables (HR 1.76, CI 1.31 to 2.68, p=0.03). There was no significant trend in the risk for IA across age tertiles: age ≤40 years versus 41-60 years (HR 1.19, p=0.34), and age 41-60 years versus 61-80 years (HR 1.06, p=0.56).Among the 52 patients with IA, enlargement occurred in three patients (6%), rupture in two patients (4%) and four patients (8%) underwent coil embolisation. For the 626 patients without IA at baseline, no patient developed IA over 7±2 years of imaging follow-up.BAV is associated with a higher prevalence of IA compared to the general population, and this risk is higher in patients with COA, right-left cusp fusion and female gender.

The objective was to determine if there was seasonal variation in the month of symptom onset in patients with intracerebral cavernous malformations (ICM). Patients seen at our institution between 1989 and 1999 with ICM identified from a radiologic database were included. Demographic data and symptoms at onset were abstracted. Symptomatic patients in this ICM database were included if the month of symptom onset was known. Comparison of proportions of patients presenting in fall and winter and during flu season were performed with the chi squared test and Fisher's exact test with significance at p0.05. Of 292 patients identified, 179 patients had symptomatic ICM. Of these, 135 patients with symptomatic ICM were identified for whom the exact month of symptom onset was known. Eighty-seven (64.4%) presented with intracerebral hemorrhage (ICH) or focal neurologic deficit (FND) and 48 (35.6%) due to seizures. When assessing all 135 patients, 75 (55.5%) presented in the fall and winter compared to the spring and summer (p=0.1962). Eighty-three (61.4%) patients presented during flu season (p=0.0074). When assessing only those initially presenting with ICH or FND, 53 (60.9%) patients presented in the fall and winter compared to spring and summer (p=0.041) and 54 (62.8%) presented during flu season (p=0.017). Patients with recurrent ICH more commonly presented in the fall and winter compared to summer and spring and during flu season. Patients with ICM who presented with FND or ICH or had recurrent ICH tended to present in the fall and winter or during flu season.

Background Bleeding events are the major obstacle to the widespread use of warfarin for secondary stroke prevention. Previous studies have not examined the use of risk stratification scores to estimate lifetime bleeding risk associated with warfarin treatment in a population-based setting. The purpose of this study is to determine the lifetime risk of bleeding events in ischemic stroke patients with atrial fibrillation (AF) undergoing warfarin treatment in a population-based cohort and to evaluate the use of bleeding risk scores to identify patients at high risk for lifetime bleeding events. Methods The resources of the Rochester Epidemiology Project Medical Linkage System were used to identify acute ischemic stroke patients with AF undergoing warfarin treatment for secondary stroke prevention from 1980 to 1994. Medical information for patients seen at Mayo Clinic and at Olmsted Medical Center was used to retrospectively risk-stratify stroke patients according to bleeding risk scores (including the HAS-BLED and HEMORR 2 HAGES scores) before warfarin initiation. These scores were reassessed 1 and 5 years later and compared with lifetime bleeding events. Results One hundred patients (mean age, 79.3 years; 68% women) were studied. Ninety-nine patients were observed until death. Major bleeding events occurred in 41 patients at a median of 19 months after warfarin initiation. Patients with a history of hemorrhage before warfarin treatment were more likely to develop major hemorrhage (15% versus 3%, P = .04). Patients with baseline HAS-BLED scores of 2 or more had a higher lifetime risk of major bleeding events compared with those with scores of 1 or less (53% versus 7%, P 2 HAGES scores of 2 or more had a higher lifetime risk of major bleeding events compared with those with scores of 1 or less (52% versus 16%, P = .03). Patients with an increase in the HAS-BLED and HEMORR 2 HAGES scores during follow-up had a higher remaining lifetime risk of major bleeding events compared with those with no change. Conclusions Our findings indicate high lifetime bleeding risk associated with warfarin treatment for patients with ischemic stroke. Risk stratification scores are useful to identify patients at high risk of developing bleeding complications and should be recalculated at regular intervals to evaluate the bleeding risk in anticoagulated patients with ischemic stroke.

Obstructive sleep apnea (OSA) has been shown to be an independent risk factor for ischemic stroke and may increase the risk of atrial fibrillation (AF) by up to fourfold. Given these relationships, it is possible that OSA may provide a link between stroke and AF. A case-control study was conducted to examine the association between AF and stroke in patients with OSA.Olmsted County, MN, USA, residents with a new diagnosis of OSA based on polysomnography (PSG) between 2005 and 2010 (N = 2980) who suffered a first-time ischemic stroke during the same period were identified as cases. Controls with no history of stroke were randomly chosen from the same database. Univariate and multiple logistic regression analyses were performed with age, gender, body mass index (BMI), smoking, hypertension, hyperlipidemia, diabetes mellitus, apnea-hypopnea index (AHI) and coronary artery disease (CAD) as co-variates, with the diagnosis of AF as the variable of interest.A total of 108 subjects were studied. Mean age of cases (n = 34) was 73 ± 12 years and 53% were men. Among controls (n = 74), mean age was 61 ± 16 years and 55% were male. On univariate analyses, AF was significantly more common in the cases than among controls (50.0% vs 10.8%, p0.01). On multivariate regression analyses, the association between AF and stroke was significant after controlling for age, BMI, coronary artery disease, hypertension, diabetes mellitus, hyperlipidemia and smoking status (corrected odds ratio (OR): 5.34; 95% confidence interval (CI): 1.79-17.29).Patients with OSA who had a stroke had higher rates of AF even after accounting for potential confounders.

Background and Purpose— The best management of patients with unruptured brain arteriovenous malformations (BAVM) is controversial. In this study, we analyzed the stroke rate and functional outcomes of patients having stereotactic radiosurgery (SRS) for unruptured BAVM using the same eligibility criteria and primary end points as the ARUBA trial. Methods— Retrospective observational study of 174 ARUBA-eligible patients having SRS from 1990 to 2005. Results— The median follow-up after SRS was 64 months. Fifteen patients (8.7%) had a hemorrhagic stroke at a median of 21 months after SRS. Six patients (3.5%) had a focal neurological deficit and 4 patients died (2.3%). The risk of stroke or death was 10.3% at 5 years and 11.5% at 10 years. Twelve additional patients (6.9%) had a focal neurological deficit from either radiation-related complications (n=7) or subsequent resection (n=5). The risk of patients’ having clinical impairment (modified Rankin Score ≥2) was 8.4% at 5 years and 12.0% at 10 years. Increasing BAVM volume was associated with both stroke or death (hazard ratio=1.06; 95% confidence interval, 1.0–1.11; P =0.04) and clinical impairment (hazard ratio=1.06; 95% confidence interval, 1.01–1.09; P =0.01). The 10-year risk of stroke or death and clinical impairment for patients with BAVM ≤5.6 cm 3 was 5% and 4%, respectively. Conclusions— The observed risk of stroke or death after SRS was approximately 2% per year for the first 5 years after SRS, declining to 0.2% annually for years 6 to 10. Patients with small volume BAVM may benefit from SRS compared with the natural history of unruptured BAVM over the planned follow-up interval of the ARUBA trial (5–10 years).

The effect of age on risk of intracranial aneurysm rupture is not well understood. We investigated the clinical course of patients 65 years and older with conservatively managed unruptured intracranial aneurysms (UIA) and determined risk factors for rupture in this population.We reviewed prospectively collected data on baseline characteristics and long-term follow-up for patients aged 65 years and older with an UIA that were initially managed with observation. The association between patient and aneurysmal characteristics and risk of rupture was performed using a multivariate Cox proportional hazard regression model.There were 214 patients (mean age: 74.7 years, SD: 6.0) included in our study. The median follow-up time was 3.7 years, with a cumulative follow-up time of 883.7 person-years. During the study period, seven patients (3.3%) received interventional treatment of their UIA and eight patients (3.7%) experienced aneurysmal subarachnoid hemorrhage, yielding an annual risk of rupture of 0.9%. All aneurysms that ruptured were at least 10 mm in size. Increasing patient age [unit relative risk (RR) 1.19, 95% CI: 1.07-1.36, P=0.002], larger aneurysmal size (unit RR 1.10, 95% CI: 1.02-1.17, P=0.021), and increasing PHASES Score (unit RR 1.62, 95% CI: 1.32-2.06, P0.001) were associated with higher risk of rupture.Our data do not suggest that UIA in older patients carry a high risk of rupture. A conservative approach appears justified in these patients, with the exception of selected patients with larger aneurysms (10 mm in diameter) and low risk of interventional procedure.

Winter clothing provides insulation for almost all of a person’s body, but in most situations, a person’s face remains uncovered even in cold windy weather. This exploratory study used thermal imagery to record the rate of cooling of the faces of volunteers in a range of winter air temperatures and wind speeds. Different areas of the faces cooled at different rates with the areas around the eyes and neck cooling at the slowest rate, and the nose and cheeks cooling at the fastest rate. In all cases, the faces cooled at an approximately logarithmic decay for the first few minutes. This was followed by a small rise in the temperature of the face for a few minutes, which was then followed by an uninterrupted logarithmic decay. Volunteers were told to indicate when their face was so cold that they wanted to end the test. The total amount of time and the facial temperature at the end of each trial were recorded. The results provide insight into the way faces cool in uncontrolled, outdoor winter conditions.

Background While atrial fibrillation is a recognized risk factor for stroke, contemporary data on trends in stroke incidence after the diagnosis of atrial fibrillation are scarce. Methods and Results Olmsted County, MN residents with incident atrial fibrillation or atrial flutter (collectively referred to as AF ) from 2000 to 2010 were identified. Cox regression determined associations of year of AF diagnosis with ischemic stroke and transient ischemic attack ( TIA ) occurring through 2013. Among 3247 AF patients, 321 (10%) had an ischemic stroke/ TIA over a mean of 4.6 years (incidence rate [95% CI ] per 100 person‐years: 2.14 [1.91–2.38]). Two hundred thirty‐nine (7%) of 3265 AF patients experienced an ischemic stroke (incidence rate: 1.54 [1.35–1.75]). The risk of both outcomes remained unchanged over time after adjusting for demographics and comorbidities (hazard ratio [95% CI ] per year of AF diagnosis: 1.00 [0.96–1.04] for ischemic stroke/ TIA ; 1.01 [0.96–1.06] for ischemic stroke only). In analyses restricted to patients with prescription information, the rates of anticoagulation use did not change over time, reaching 50.8% at 1 year after AF diagnosis. Further adjustment for anticoagulation use did not alter the temporal trends in stroke incidence (hazard ratio [95% CI ] per year of AF diagnosis: 1.06 [0.97–1.15] for ischemic stroke/ TIA ; 1.08 [0.98–1.20] for ischemic stroke only). Conclusions Strokes/ TIA s are frequent after AF , occurring in 10% of patients after 5 years of follow‐up. The occurrence of stroke/ TIA did not decline over the last decade, which may be influenced by a leveling off of anticoagulation use. This concerning trend has major public health implications.

To determine post-stroke 30-d readmission rate, its predictors, its impact on mortality and to identify potentially preventable causes of post-stroke 30-d readmission in a population-based study.We identified all acute ischemic strokes (AIS) using the International Classification of Diseases 9th revision codes (433.x1, 434.xx and 436) via the Rochester Epidemiology Project (REP) between January 2007 and December 2011. Acute stroke care in Olmsted County is provided by two medical centers, Saint Marys Hospital and Olmsted Medical Center Hospital. All readmissions to these two hospitals were accounted for this study. Thirty-day readmission data was abstracted through manual chart review. The REP linkage database was used to identify the status (living/dead) of all patients at last follow up.Forty-one (7.6%, 95% CI 5.7%-10.2%) of total 537 AIS patients were readmitted 30-d post-stroke. In a multivariable logistic regression model, discharge to nursing home following index stroke (OR: 0.29, 95% CI 0.08-0.84) was an independent negative predictor of unplanned 30-d readmission. In a subgroup of patients with dementia, being married at time of index stroke was found to be a negative predictor of readmission (OR: 0.10, 95% CI 0.005-0.58). Only 2.8% of the patients had potentially preventable readmissions. Hospital readmission had no significant impact on patient's short-term (three months) or long-term (one or two years) mortality (p0.05).Post-stroke 30-d readmission rate is low in AIS patients from Olmsted County. Further research is needed in regarding discharge checklists, protocols and stroke transitional programs to reduce potentially preventable readmissions.

Background Contemporary stroke incidence data are not available in some countries and regions, including in Eastern Europe. Based on previous validation of the accuracy of the National Registry of Hospitalized Patients (NRHOSP), we report the incidence of hospitalized stroke in the Czech Republic (CR) using the NRHOSP. Methods The results of the prior validation study assessing the accuracy of coding of stroke diagnoses in the NRHOSP were applied, and we calculated (1) the overall incidence of hospitalized stroke and (2) the incidence rates of hospitalized stroke for the three main stroke types: cerebral infarction (International Classification of Diseases Tenth Revision, CI I63), subarachnoid hemorrhage (SAH I60), and intracerebral hemorrhage (ICH I61). We calculated the average annual age- and sex-standardized incidence. Results The overall incidence of hospitalized stroke was 241 out of 100,000 individuals. The incidence of hospitalized stroke for the main stroke types was 8.2 cases in SAH, 29.5 in ICH, and 211 in CI per 100,000 individuals. The standardized annual stroke incidence adjusted to the 2000 World Health Organization population for overall stroke incidence of hospitalized stroke was 131 per 100,000 individuals. Standardized stroke incidence for stroke subtypes was 5.7 cases in SAH, 16.7 in ICH, and 113 in CI per 100,000 individuals. Conclusions These studies provide an initial assessment of the burden of stroke in this part of the world. The estimates of hospitalized stroke in the CR and Eastern Europe suggest that ICH is about three times more common than SAH, and hemorrhagic stroke makes up about 18% of strokes.

Pancreatic adenocarcinoma is mostly fatal and generally resistant to conventional treatments, such that effective therapies with tolerable side effects are desperately needed. Ion channels including the transient receptor potential (TRP) channels have been implicated in human malignancies, but their roles in pancreatic cancer were mostly unknown. Recent identification of the melastatin-subfamily members of the TRP family of ion channels, and their functions in pancreatic epithelia and adenocarcinoma, is expected to provide a new perspective to understanding the mechanism underlying pancreatic tumorigenesis. In this report, we present the clinical and pathological features of a mini-series of patients with pancreatic adenocarcinoma, which aberrantly exhibits immunoreactivity against the TRPM8 channel. We have recently demonstrated the proliferative role of TRPM8 channel in pancreatic cancer cells. Here, we present evidence that RNA interference-mediated silencing of TRPM8 induces replicative senescence in pancreatic adenocarcinoma cells. This suggests that the aberrantly expressed TRPM8 channel may contribute to pancreatic tumorigenesis by preventing oncogene-induced senescence, and targeted inhibition of TRPM8 may enhance tumor sensitivity to therapeutics. Based on these observations, we hypothesize that the TRPM8 ion channel plays a crucial role in the growth and progression of pancreatic neoplasia during tumorigenesis. We propose that TRPM8 can be exploited as a clinical biomarker and as a therapeutic target for developing personalized therapy in pancreatic adenocarcinoma.

Background and objectives Autosomal dominant polycystic kidney disease (ADPKD) patients have an increased risk for intracranial aneurysms (IAs). The importance of screening for unruptured IAs (UIAs) depends on their risks for growth and rupture. Design, setting, participants, & measurements ADPKD patients with UIAs found by presymptomatic screening with magnetic resonance angiography (MRA) during 1989 to 2009 were followed initially at 6 months and annually, and less frequently after demonstration of stability. Results Forty-five saccular aneurysms were detected in 38 patients from 36 families. Most were small (median diameter 3.5 mm) and in the anterior circulation (84%). Median age at diagnosis was 49 years. During cumulative imaging follow-up of 243 years, one de novo UIA was detected and increased in size from 2 to 4.4 mm over 144 months and two UIAs grew from 4.5 to 5.9 mm and 4.7 to 6.2 mm after 69 and 184 months, respectively. Seven patients did not have imaging follow-up. No change was detected in the remaining 28 patients. During cumulative clinical follow-up of 316 years, no aneurysm ruptured. Five patients died from unrelated causes and two were lost to follow-up after 8 and 120 months. Three patients underwent surgical clipping. Conclusions Most UIAs detected by presymptomatic screening in ADPKD patients are small and in the anterior circulation. Growth and rupture risks are not higher than those of UIAs in the general population. These data support very selective screening for UIAs in ADPKD patients, and widespread screening is not indicated.

Background and Purpose— Coronary artery disease is the leading cause of death after TIA. Reliable estimates of the risk of MI after TIA, however, are lacking. Methods— Our purpose was to determine the incidence of and risk factors for MI after TIA. We cross-referenced preexisting incidence cohorts from the Rochester Epidemiology Project for TIA (1985–1994) and MI (1979–2006) to identify all community residents with incident MI after incident TIA. Incidence of MI after TIA was determined using Kaplan–Meier life-table methods. This was compared to the age-, sex-, and period-specific MI incidences in the general population. Proportional hazards regression analysis was used to examine associations between clinical variables and the occurrence of MI after TIA. Results— Average annual incidence of MI after TIA was 0.95%. Relative risk for incident MI in the TIA cohort compared to the general population was 2.09 (95% CI, 1.52–2.81). This was highest in patients younger than 60 years old (relative risk, 15.1; 95% CI, 4.11–38.6). Increasing age (hazard ratio, 1.51 per 10 years; 95% CI, 1.14–2.01), male sex (hazard ratio, 2.19; 95% CI, 1.18–4.06), and the use of lipid-lowering therapy at the time of TIA (hazard ratio, 3.10; 95% CI, 1.20–8.00) were independent risk factors for MI after TIA. Conclusions— Average annual incidence of MI after TIA is ≈1%, approximately double that of the general population. The relative risk increase is especially high in patients younger than 60 years old. These data are useful for identifying subgroups of patients with TIA at highest risk for subsequent MI.

White matter hyperintensity (WMH) may be a marker of an underlying cerebral microangiopathy. Therefore, we hypothesized that WMH would be most severe in patients with lacunar stroke and intracerebral hemorrhage (ICH), 2 types of stroke in which cerebral small vessel (SV) changes are pathophysiologically relevant.We determined WMH volume (WMHV) in cohorts of prospectively ascertained patients with acute ischemic stroke (AIS) (Massachusetts General Hospital [MGH], n = 628, and the Ischemic Stroke Genetics Study [ISGS], n = 263) and ICH (MGH, n = 122).Median WMHV was 7.5 cm³ (interquartile range 3.4-14.7 cm³) in the MGH AIS cohort (mean age 65 ± 15 years). MGH patients with larger WMHV were more likely to have lacunar stroke compared with cardioembolic (odds ratio [OR] = 1.87 per SD normally transformed WMHV), large artery (OR = 2.25), undetermined (OR = 1.87), or other (OR = 1.85) stroke subtypes (p0.03). These associations were replicated in the ISGS cohort (p = 0.03). In a separate analysis, greater WMHV was seen in ICH compared with lacunar stroke (OR = 1.2, p0.02) and in ICH compared with all ischemic stroke subtypes combined (OR = 1.34, p0.007).Greater WMH burden was associated with SV stroke compared with other ischemic stroke subtypes and, even more strongly, with ICH. These data, from 2 independent samples, support the model that increasing WMHV is a marker of more severe cerebral SV disease and provide further evidence for links between the biology of WMH and SV stroke.

We sought to examine the relationship of the QTc interval with mortality and functional outcome after acute ischemic stroke, and determine whether a threshold cutoff is present beyond which risk of death increases.The QTc interval was measured for all patients presenting to the emergency department. The outcomes were mortality at 90 days and functional outcome at hospital discharge. The cutoffs were determined plotting martingale residuals.Patients with a prolonged QTc interval were more likely to die within 90 days compared with patients without a prolonged interval (relative risk [RR] 2.5; 95% confidence interval [CI] 1.5-4.1; P.001). The estimated survival at 90 days was 70.5% and 87.1%, respectively. This association retained statistical significance after adjusting for age and National Institutes of Health Stroke Scale score (RR 1.7; 95% CI 1.0-2.9; P = .043). Patients with a prolonged QTc interval were also more likely to have poor functional status compared with patients without a prolonged interval (odds ratio 1.8; 95% CI 1.2-3.0; P = .006). This association was not statistically significant after adjusting for age and National Institutes of Health Stroke Scale score (odds ratio 1.2; 95% CI 0.7-2.4). The identified threshold cutoffs for increased risk of death at 90 days were 440 milliseconds for women and 438 milliseconds for men.There appears to be an increased risk of early death in patients with acute ischemic stroke and a prolonged QTc interval at the time of emergency department presentation. Prognosis appears to be worse with QTc intervals longer than 440 milliseconds in women and longer than 438 milliseconds in men.

Background The Joint Commission (JC) certifies primary stroke centers in the United States. Whether certification promotes enrollment of study subjects into stroke research studies is not known. We examined whether enrollment performance of centers was related to JC certification status. Methods The 51 US Siblings with Ischemic Stroke Study (SWISS) centers were characterized by JC certification status, year of certification, year initiated into SWISS, center location, and whether the center had a vascular/stroke neurology fellowship program accredited by the Accreditation Council for Graduate Medical Education. Performance measures included days elapsed from initiation to first enrollment, total enrollments within 12 months after initiation, and annual rate of enrollment thereafter. Results In all, 36 of 51 SWISS sites (71%) were JC certified. A total of 32 (63%) were initiated into the study from 2000 through 2002, and 19 (37%) were initiated from 2005 through May 2008. Comparison of certified and noncertified sites showed no significant difference in the time to first enrollment (median, 77.5 v 115 days; P = .90), total enrollees in the first year (median, 3 v 2 probands; P = .69), or annual enrollment rate (median, 1.9 v 1.8 probands; P = .72). The rate of enrollment or time to first enrollment was not different between 2000-to-2002 and 2005-to-2008 sites. Early-initiated centers tended to have better year-1 enrollment than later-initiated centers (3 v 2 probands; P = .056). Conclusions JC certification did not have a significant effect on SWISS center enrollment. The JC should encourage the research mission among certified stroke centers.