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Contains fulltext : 235277.pdf (Publisher’s version ) (Closed access) BACKGROUND: Balancing the risks of recurrent ischaemic stroke and intracranial haemorrhage is important for patients treated with antithrombotic therapy after ischaemic stroke or transient ischaemic attack. However, existing predictive models offer insufficient performance, particularly for assessing the risk of intracranial haemorrhage. We aimed to develop new risk scores incorporating clinical variables and cerebral microbleeds, an MRI biomarker of intracranial haemorrhage and ischaemic stroke risk. METHODS: We did a pooled analysis of individual-patient data from the Microbleeds International Collaborative Network (MICON), which includes 38 hospital-based prospective cohort studies from 18 countries. All studies recruited participants with previous ischaemic stroke or transient ischaemic attack, acquired baseline MRI allowing quantification of cerebral microbleeds, and followed-up participants for ischaemic stroke and intracranial haemorrhage. Participants not taking antithrombotic drugs were excluded. We developed Cox regression models to predict the 5-year risks of intracranial haemorrhage and ischaemic stroke, selecting candidate predictors on biological relevance and simplifying models using backward elimination. We derived integer risk scores for clinical use. We assessed model performance in internal validation, adjusted for optimism using bootstrapping. The study is registered on PROSPERO, CRD42016036602. FINDINGS: The included studies recruited participants between Aug 28, 2001, and Feb 4, 2018. 15 766 participants had follow-up for intracranial haemorrhage, and 15 784 for ischaemic stroke. Over a median follow-up of 2 years, 184 intracranial haemorrhages and 1048 ischaemic strokes were reported. The risk models we developed included cerebral microbleed burden and simple clinical variables. Optimism-adjusted c indices were 0·73 (95% CI 0·69-0·77) with a calibration slope of 0·94 (0·81-1·06) for the intracranial haemorrhage model and 0·63 (0·62-0·65) with a calibration slope of 0·97 (0·87-1·07) for the ischaemic stroke model. There was good agreement between predicted and observed risk for both models. INTERPRETATION: The MICON risk scores, incorporating clinical variables and cerebral microbleeds, offer predictive value for the long-term risks of intracranial haemorrhage and ischaemic stroke in patients prescribed antithrombotic therapy for secondary stroke prevention; external validation is warranted. FUNDING: British Heart Foundation and Stroke Association.

ObjectivesTo define the characteristics of post-traumatic headache with cluster headache phenotype (PTH-CH) and to compare these characteristics with primary CH.MethodsA retrospective study was conducted of patients seen between 2007 and 2017 in a headache centre and diagnosed with PTH-CH that developed within 7 days of head trauma. A control cohort included 553 patients with primary CH without any history of trauma who attended the headache clinic during the same period. Data including demographics, attack characteristics and response to treatments were recorded.ResultsTwenty-six patients with PTH-CH were identified. Multivariate analysis revealed significant associations between PTH-CH and family history of CH (OR 3.32, 95% CI 1.31 to 8.63), chronic form (OR 3.29, 95% CI 1.70 to 6.49), parietal (OR 14.82, 95% CI 6.32 to 37.39) or temporal (OR 2.04, 95% CI 1.10 to 3.84) location of pain, and presence of prominent cranial autonomic features during attacks (miosis OR 11.24, 95% CI 3.21 to 41.34; eyelid oedema OR 5.79, 95% CI 2.57 to 13.82; rhinorrhoea OR 2.65, 95% CI 1.26 to 5.86; facial sweating OR 2.53, 95% CI 1.33 to 4.93). Patients with PTH-CH were at a higher risk of being intractable to acute (OR 12.34, 95% CI 2.51 to 64.73) and preventive (OR 16.98, 95% CI 6.88 to 45.52) treatments and of suffering from associated chronic migraine (OR 10.35, 95% CI 3.96 to 28.82).ConclusionThis largest series of PTH-CH defines it as a unique entity with specific evolutive profile. Patients with PTH-CH are more likely to suffer from the chronic variant, have marked autonomic features, be intractable to treatment and have associated chronic migraine compared with primary CH.

The inherited cerebellar ataxias comprise of a genetic heterogeneous group of disorders. Pathogenic expansions of cytosine-adenine-guanine (CAG) encoding polyglutamine tracts account for the largest proportion of autosomal dominant cerebellar ataxias, while GAA expansion in the first introns of frataxin gene is the commonest cause of autosomal recessive cerebellar ataxias. Currently, there is no available treatment to alter the disease trajectory, with devastating consequences for affected individuals. Inter- and Intrafamily phenotypic variability suggest the existence of genetic modifiers, which may become targets amendable to treatment. Recent studies have demonstrated the importance of DNA repair pathways in modifying spinocerebellar ataxia with CAG repeat expansions. In this review, we discuss the mechanisms in which DNA repair pathways, epigenetics and other genetic factors may act as modifiers in cerebellar ataxias due to trinucleotide repeat expansions.

Background and purpose The prevalence of chronic kidney disease (estimated glomerular filtration rate (eGFR) 2 for ≥3 months, chronic kidney disease (CKD)) in ischemic stroke and transient ischemic attack (TIA) is unknown, as estimates have been based on single-point estimates of renal function. Studies investigating the effect of renal dysfunction (eGFR 2, renal dysfunction) on post-stroke outcomes are limited to hospitalized cohorts and have provided conflicting results. Methods We investigated rates, determinants and outcomes of renal dysfunction in ischemic stroke and TIA in the North Dublin Population Stroke Study. We also investigate the persistence of renal dysfunction in 90-day survivors to determine the prevalence of CKD. Ascertainment included hot and cold pursuit using multiple overlapping sources. Survival analysis was performed using Kaplan–Meier survival curves and Cox proportional hazards modeling. Results In 547 patients (ischemic stroke in 76.4%, TIA in 23.6%), the mean eGFR at presentation was 63.7 mL/min/1.73 m2 (SD 22.1). Renal dysfunction was observed in 44.6% (244/547). Among 90-day survivors, 31.2% (139/446) met criteria for CKD. After adjusting for age and stroke severity, eGFR 2 (hazard ratio 2.53, p = 0.01) independently predicted 28-day fatality but not at two years. Poor post-stroke functional outcome (Modified Rankin Scale 3–5) at two years was more common in those with renal dysfunction (52.5% vs. 20.6%, p Conclusion Renal dysfunction and CKD are common in ischemic stroke and TIA. Renal dysfunction is associated with considerable post-stroke morbidity and mortality. Further studies are needed to investigate if modifiable mechanisms underlie these associations.

Contains fulltext : 208975.pdf (Publisher’s version ) (Open Access) BACKGROUND: Cerebral microbleeds are a neuroimaging biomarker of stroke risk. A crucial clinical question is whether cerebral microbleeds indicate patients with recent ischaemic stroke or transient ischaemic attack in whom the rate of future intracranial haemorrhage is likely to exceed that of recurrent ischaemic stroke when treated with antithrombotic drugs. We therefore aimed to establish whether a large burden of cerebral microbleeds or particular anatomical patterns of cerebral microbleeds can identify ischaemic stroke or transient ischaemic attack patients at higher absolute risk of intracranial haemorrhage than ischaemic stroke. METHODS: We did a pooled analysis of individual patient data from cohort studies in adults with recent ischaemic stroke or transient ischaemic attack. Cohorts were eligible for inclusion if they prospectively recruited adult participants with ischaemic stroke or transient ischaemic attack; included at least 50 participants; collected data on stroke events over at least 3 months follow-up; used an appropriate MRI sequence that is sensitive to magnetic susceptibility; and documented the number and anatomical distribution of cerebral microbleeds reliably using consensus criteria and validated scales. Our prespecified primary outcomes were a composite of any symptomatic intracranial haemorrhage or ischaemic stroke, symptomatic intracranial haemorrhage, and symptomatic ischaemic stroke. We registered this study with the PROSPERO international prospective register of systematic reviews, number CRD42016036602. FINDINGS: Between Jan 1, 1996, and Dec 1, 2018, we identified 344 studies. After exclusions for ineligibility or declined requests for inclusion, 20 322 patients from 38 cohorts (over 35 225 patient-years of follow-up; median 1.34 years [IQR 0.19-2.44]) were included in our analyses. The adjusted hazard ratio [aHR] comparing patients with cerebral microbleeds to those without was 1.35 (95% CI 1.20-1.50) for the composite outcome of intracranial haemorrhage and ischaemic stroke; 2.45 (1.82-3.29) for intracranial haemorrhage and 1.23 (1.08-1.40) for ischaemic stroke. The aHR increased with increasing cerebral microbleed burden for intracranial haemorrhage but this effect was less marked for ischaemic stroke (for five or more cerebral microbleeds, aHR 4.55 [95% CI 3.08-6.72] for intracranial haemorrhage vs 1.47 [1.19-1.80] for ischaemic stroke; for ten or more cerebral microbleeds, aHR 5.52 [3.36-9.05] vs 1.43 [1.07-1.91]; and for >/=20 cerebral microbleeds, aHR 8.61 [4.69-15.81] vs 1.86 [1.23-1.82]). However, irrespective of cerebral microbleed anatomical distribution or burden, the rate of ischaemic stroke exceeded that of intracranial haemorrhage (for ten or more cerebral microbleeds, 64 ischaemic strokes [95% CI 48-84] per 1000 patient-years vs 27 intracranial haemorrhages [17-41] per 1000 patient-years; and for >/=20 cerebral microbleeds, 73 ischaemic strokes [46-108] per 1000 patient-years vs 39 intracranial haemorrhages [21-67] per 1000 patient-years). INTERPRETATION: In patients with recent ischaemic stroke or transient ischaemic attack, cerebral microbleeds are associated with a greater relative hazard (aHR) for subsequent intracranial haemorrhage than for ischaemic stroke, but the absolute risk of ischaemic stroke is higher than that of intracranial haemorrhage, regardless of cerebral microbleed presence, antomical distribution, or burden. FUNDING: British Heart Foundation and UK Stroke Association.

Background Few studies have directly compared stroke recurrence rates after stroke and transient ischemic attack, and the risk factors underlying early recurrence are poorly understood. We aimed to investigate risk factors for recurrent stroke after first stroke and transient ischemic attack in a population-based study. Methods The North Dublin Population Stroke Study applied multiple overlapping hot and cold pursuit methods, to ascertain hospital- and community-treated stroke and transient ischemic attack patients over a 12-month period. Inclusion criteria were: (1) Stroke-physician confirmed transient ischemic attack/ischemic stroke; (2) first-stroke/transient ischemic attack event within the ascertainment period. Patients were prospectively followed at 72 h, 7, 28 and 90 days. Results A total of 584 patients met eligibility criteria (172 transient ischemic attack, 412 stroke). More transient ischemic attack than stroke patients presented to medical attention with recurrent stroke (8.24% vs. 0.24%, p = 0.0002). Recurrent stroke was more common after transient ischemic attack than index stroke at each time-interval (at 72 h, 4.07% vs. 1.23%, p = 0.03; at 90 days, 13.45% vs. 5.72%, p = 0.002). Stroke recurrence at 90 days was also associated with delay seeking medical attention after the index event (OR 3.2, p = 0.001), delayed anti-platelet (OR 2.8, p = 0.001) and statin (OR 2.4, p = 0.009) treatment, carotid stenosis/occlusion (OR 2.4, p = 0.008). On multivariable analysis, transient ischemic attack as index event (adjusted OR 2.3, p = 0.02), delayed statin treatment (OR 2.5, p = 0.02), and carotid stenosis/occlusion (OR 2.4, p = 0.02) were independent predictors of 90-day recurrent stroke. Conclusion A combination of pathophysiological and behavioral factors was associated with early stroke recurrence risk. Improved public awareness to reduce delays to self-referral for transient ischemic attack symptoms is needed.

Background and Purpose— Few recent studies have investigated the rates and predictors of early and late stroke recurrence using prospective population–based methodology. We investigated recurrent stroke at 2 years in the North Dublin Population Stroke Study (NDPSS). Methods— Patients were ascertained from December 2005 to 2006 from overlapping community and hospital sources using hot and cold pursuit. Stroke recurrence, survival, and functional outcome were ascertained at 72 hours, 7 days, 28 days, 90 days, 1 year, and 2 years. Results— Of 567 patients, cumulative 2-year stroke recurrence rate was 10.8% and case fatality was 38.6%. Recurrence subtype was associated with initial stroke subtype ( P P =0.005) and prior stroke (adjusted hazard ratio, 2.92; P =0.01) were independent predictors of 2-year recurrence in 28-day survivors. Conclusions— Despite rigorous ascertainment, recurrent stroke rates were lower in current study than in earlier studies. Our data suggest that large sample sizes may be needed for future secondary prevention trials in patients treated with modern preventive medications.

Few population-based studies have assessed lipid adherence to international guidelines for primary and secondary prevention in stroke/transient ischaemic attack (TIA) patients. This study aims to evaluate adherence to lipid-lowering therapy (LLT) guidelines amongst patients with ischaemic stroke/TIA. Using hot and cold pursuit methods from multiple hospital/community sources, all stroke and TIA cases in North Dublin City were prospectively ascertained over a 1-year period. Adherence to National Cholesterol Education Programme (NCEP) III guidelines, before and after index ischaemic stroke/TIA, was assessed. Amongst 616 patients (428 ischaemic stroke, 188 TIA), total cholesterol was measured following the qualifying event in 76.5% (471/616) and low-density lipoprotein (LDL) in 60.1% (370/616). At initial stroke/TIA presentation, 54.1% (200/370) met NCEP III LDL goals. Compliance was associated with prior stroke (odds ratio [OR] 2.19, p = 0.02), diabetes (OR 1.91, p = 0.04), hypertension (OR 1.57, p = 0.03), atrial fibrillation (OR 1.78, p = 0.01), pre-event LLT (OR 2.85, p

Objective: We hypothesized that serum lipids, which experimental data suggest may be key initiators of carotid plaque inflammation, would be associated with plaque inflammation on 18 fluorodeoxyglucose (FDG)-PET in patients with acutely symptomatic carotid stenosis. Methods: In this cohort study, consecutive patients with acute symptomatic internal carotid artery (ICA) stenosis (≥50%) underwent carotid PET-CT. We quantified plaque FDG uptake as follows: (1) average maximum standardized uptake values (SUV max ) across 10 regions of interest (ROI); (2) highest single ROI SUV measure (SUV ROImax ); (3) averaged mean SUV across 10 ROIs (SUV mean ). Results: Sixty-one patients were included. Plaque inflammatory FDG SUV max was associated with increasing tertiles of low-density lipoprotein (LDL) (trend p = 0.004), total cholesterol ( p = 0.009), and triglycerides ( p = 0.01), and with lower high-density lipoprotein (HDL) ( p = 0.005). When analyzed as a continuous variable, LDL was associated with symptomatic ICA SUV mean (Spearman rho 0.44, p = 0.009), SUV ROImax (rho 0.33, p = 0.01), and SUV max (rho 0.35, p = 0.06). Total cholesterol was associated with SUV mean (rho 0.33, p = 0.009), with trends for SUV max (rho 0.24, p = 0.059) and SUV ROImax (rho 0.23, p = 0.08). Triglycerides were associated with SUV max (rho 0.32, p = 0.01) and SUV ROImax (rho 0.35, p = 0.005). HDL was associated with lower SUV max (rho −0.37, p = 0.004) and SUV ROImax (rho −0.44, p = 0.0004). On multivariable linear regression analysis adjusting for age, sex, degree of carotid stenosis, statins, and smoking, LDL ( p = 0.008) and total cholesterol ( p = 0.04) were independently associated with SUV max . Conclusion: Serum LDL and total cholesterol were associated with acutely symptomatic carotid plaque FDG uptake, supporting experimental data suggesting lipids may promote plaque inflammation, mediating rupture and clinical events.

Background: Following ischemic cerebrovascular accident (CVA) or transient ischemic attack (TIA) aggressive risk factor modification is undertaken to reduce the risk of recurrent events. Holter monitoring is advocated to facilitate the detection and treatment of Atrial Fibrillation (AF). Frequent Premature Atrial Contractions (PACs) are associated with the development of AF, but to date it is unknown whether the burden of PACs on Holters is of any prognostic importance following CVA/TIA. Objective: PACs on Holter monitoring may be a marker for recurrent cerebrovascular events post CVA/TIA. Methods: Retrospective analysis was performed on Holters of patients with CVA/TIA enrolled in a prior population based stroke study. Frequent PACs were defined as a rate of PACs ≥ 100 per 24 hours. The primary endpoint was recurrent CVA or TIA. Results: 84 cases (61.0% male) were reviewed. Mean age was 69.7 ± 12.4 years. Mean time to follow-up was 2514.6 ± 91.2 days. The average number of PACs in the frequent group (Hi-PAC, 21 patients) was 1610.8 ± 4541.4 compared with 21.8 ± 27.6 in those with less than 100 PACs (Lo-PAC, 63 patients). There was no statistically significant difference in age, gender, hypertension or diabetes between the two groups. On follow-up there were 20 recurrent events and 33 patients died. In the Hi-PAC group there were 8 (38.1%) recurrent events, and 16 (76.2%) patients died versus 12 (18.8%) and 17 (26.6%) respectively in Lo-PAC group. On Cox regression analysis the Hazard ratio (HR) for recurrent events was 2.75 (95% confidence interval (CI) 1.08 to 7.01). Kaplan Meier curves revealed a statistically significant difference in recurrance rates between the two groups (p < 0.05). There was also a statistically significant difference in overall mortality on Kaplan Meier survival analysis (p < 0.001), and with a hazard ratio on Cox regression analysis of 3.47 (95% CI 1.74 [[Unable to Display Character: –]] 6.91). There was no significant difference in incidence of MI or AF. Conclusion: Frequent PACs on Holter monitor represent a significant risk factor for both recurrent events and mortality following CVA/TIA. Further prospective studies should be performed to assess whether these patients may benefit from more aggressive anticoagulation, similar to those with AF.

Background: In suspected TIA, DWI hyperintensity confirms the diagnosis of brain ischemia and identifies those with 3-fold risk of early recurrent stroke. However, immediate MRI is expensive and may not be available in many healthcare settings. A simple validated blood test to objectively support the diagnosis of cerebral ischaemia after transient symptoms might have utility in clinical practice. We hypothesised that blood markers of inflammation may be associated with abnormal DWI following TIA. Methods: BIO-TIA was a multi-centre prospective study of consecutive patients with clinically-defined TIA, confirmed by a stroke physician. Phlebotomy and stroke protocol MRI were performed within 72 hours of symptoms. Patients with malignancy, active infection, trauma, surgery, definite transient non-ischaemic symptoms or recurrent stroke before phlebotomy/MRI were excluded. Plasma high-sensitivity CRP and interleukin-6 (IL-6) were measured by mass spectrometry. Results: In 201 included patients, mean age was 68 years (59% male). Carotid stenosis was present in 26.4% and atrial fibrillation in 29.1%. Mean ABCD2 score was 4.2 (SD 1.3). Acute DWI hyperintensity was observed in 37.8% (76/201). Median hsCRP was 1.78mg/L in DWI-negative, compared with 3.01mg/L in DWI-positive TIA (p=0.04). Median IL-6 was 3.76pg/ml (DWI-negative) versus 4.91pg/ml (DWI-positive) (p=0.04). When the highest quartiles of CRP and IL-6 distributions were compared with quartiles 1-3, the prevalence of DWI hyperintensity was 61.5% (Q4) versus 32.9% (Q1-3) for CRP (p=0.001), and 56.4% (Q4) versus 34.9% [Q1-3) for IL-6 (p=0.02). Thresholds of 4.78mg/L for CRP or 6.21pg/ml for IL-6 had at least 80% specificity for identification of abnormal DWI signal. IL-6 was associated with CRP (rho 0.58), age (rho 0.36), and ABCD2 score (rho 0.18) and carotid stenosis (p≤0.01 for all), but not statin use. Conclusion: Our preliminary findings require validation, but suggest that inexpensive, rapidly-measured blood markers are associated with acute DWI hyperintensity after TIA. If validated, blood markers may have utility to support the diagnosis of cerebral ischemia or select patients for early MRI.