Structural integrity of the insula and emotional facial recognition performance following stroke.

The role of the human insula in facial emotion recognition is controversially discussed, especially in relation to lesion-location-dependent impairment following stroke. In addition, structural connectivity quantification of important white-matter tracts that link the insula to impairments in facial emotion recognition has not been investigated. In a case-control study, we investigated a group of 29 stroke patients in the chronic stage and 14 healthy age- and gender-matched controls. Lesion location of stroke patients was analysed with voxel-based lesion-symptom mapping. In addition, structural white-matter integrity for tracts between insula regions and their primarily known interconnected brain structures was quantified by tractography-based fractional anisotropy. Our behavioural analyses showed that stroke patients were impaired in the recognition of fearful, angry and happy but not disgusted expressions. Voxel-based lesion mapping revealed that especially lesions centred around the left anterior insula were associated with impaired recognition of emotional facial expressions. The structural integrity of insular white-matter connectivity was decreased for the left hemisphere and impaired recognition accuracy for angry and fearful expressions was associated with specific left-sided insular tracts. Taken together, these findings suggest that a multimodal investigation of structural alterations has the potential to deepen our understanding of emotion recognition impairments after stroke.

Long-term risk of recurrent vascular events and mortality in young stroke patients: Insights from a multicenter study.

BACKGROUND: Although the incidence of stroke in the young is rising, data on long-term outcomes in these patients are scarce. We thus aimed to investigate the long-term risk of recurrent vascular events and mortality in a multicenter study. METHODS: We followed 396 consecutive patients aged 18-55 years with ischemic stroke (IS) or transient ischemic attack (TIA) enrolled in three European centers during the period 2007-2010. A detailed outpatient clinical follow-up assessment was performed between 2018 and 2020. When an in-person follow-up visit was not possible, outcome events were assessed using electronic records and registry data. RESULTS: During a median follow-up of 11.8 (IQR 10.4-12.7) years, 89 (22.5%) patients experienced any recurrent vascular event, 62 (15.7%) had any cerebrovascular event, 34 (8.6%) had other vascular events, and 27 (6.8%) patients died. Cumulative 10-year incidence rate per 1000 person-years was 21.6 (95% CI 17.1-26.9) for any recurrent vascular event and 14.9 (95% CI 11.3-19.3) for any cerebrovascular event. The prevalence of cardiovascular risk factors increased over time, and 22 (13.5%) patients lacked any secondary preventive medication at the in-person follow-up. After adjustment for demographics and comorbidities, atrial fibrillation at baseline was found to be significantly associated with recurrent vascular events. CONCLUSIONS: This multicenter study shows a considerable risk of recurrent vascular events in young IS and TIA patients. Further studies should investigate whether detailed individual risk assessment, modern secondary preventive strategies, and better patient adherence may reduce recurrence risk.

Duration of Surgery and Intraoperative Blood Pressure Management Are Modifiable Risk Factors for Postoperative Neurocognitive Disorders After Spine Surgery: Results of the Prospective CONFESS Study.

STUDY DESIGN: Prospective quasi-experimental observational study. OBJECTIVE: The objective of this study was to evaluate whether duration of surgery is a modifiable risk factor for postoperative delirium (POD) after spine surgery and explore further modifiable risk factors. In addition, we sought to investigate the association between POD and postoperative cognitive dysfunction and persistent neurocognitive disorders. SUMMARY OF BACKGROUND DATA: Advances in spine surgery enable technically safe interventions in elderly patients with disabling spine disease. The occurrence of POD and delayed neurocognitive complications ( e.g. postoperative cognitive dysfunction/persistent neurocognitive disorder) remain a concern since these contribute to inferior functional outcomes and long-term care dependency after spine surgery. MATERIALS AND METHODS: This prospective single-center study recruited patients aged 60 years or above and scheduled for elective spine surgery between February 2018 and March 2020. Functional (Barthel Index, BI) and cognitive outcomes [Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test battery; telephone Montréal Cognitive Assessment] were assessed at baseline, three (V3), and 12 months postoperatively. The primary hypothesis was that the duration of surgery predicts POD. Multivariable predictive models of POD included surgical and anesthesiological parameters. RESULTS: Twenty-two percent of patients developed POD (n=22/99). In a multivariable model, duration of surgery [OR adj =1.61/h (95% CI, 1.20-2.30)], age [OR adj =1.22/yr (95% CI, 1.10-1.36)], and baseline deviations of intraoperative systolic blood pressure [25th percentile: OR adj =0.94/mm Hg (95% CI, 0.89-0.99); 90th percentile: OR adj =1.07/mm Hg (95% CI, 1.01-1.14)] were significantly associated with POD. Postoperative cognitive scores generally improved (V3, ΔCERAD total z -score: 0.22±0.63). However, this positive group effect was counteracted by POD [beta: -0.87 (95% CI, -1.31 to 0.42)], older age [beta: -0.03/yr (95% CI, -0.05 to 0.01)], and lack of functional improvement [ΔBI; beta: -0.04/point (95% CI, -0.06 to 0.02)]. Cognitive scores at twelve months remained inferior in the POD group, adjusted for baseline cognition/age. CONCLUSIONS: This study identified distinct neurocognitive effects after spine surgery, which are influenced by perioperative risk factors. Potential cognitive benefits are counteracted by POD, rendering its prevention critical in an aging population.

Predictors of post-stroke delirium incidence and duration: Results of a prospective observational study using high-frequency delirium screening.

BACKGROUND: Post-stroke delirium (PSD) is a modifiable predictor for worse outcome in stroke. Knowledge of its risk factors would facilitate clinical management of affected patients, but recently updated national guidelines consider available evidence insufficient. AIMS: The study aimed to establish risk factors for PSD incidence and duration using high-frequency screening. METHODS: We prospectively investigated patients with ischemic stroke admitted within 24 h. Patients were screened twice daily for the presence of PSD throughout the treatment period. Sociodemographic, treatment-related, and neuroimaging characteristics were evaluated as predictors of either PSD incidence (odds ratios (OR)) or duration (PSD days/unit of the predictor, b), using logistic and linear regression models, respectively. RESULTS: PSD occurred in 55/141 patients (age = 73.8 ± 10.4 years, 61 female, National Institutes of Health Stroke Scale (NIHSS) = 6.4 ± 6.5). Age (odds ratio (OR) = 1.06 (95% confidence interval (CI): 1.02-1.10), b = 0.08 (95% CI = 0.04-0.13)), and male gender (b = 0.99 (95% CI = 0.05-1.93)) were significant non-modifiable risk factors. In a multivariable model adjusted for age and gender, presence of pain (OR < sub > mvar = 1.75 (95% CI = 1.12-2.74)), urinary catheter (OR < sub > mvar = 3.16 (95% CI = 1.10-9.14)) and post-stroke infection (PSI; OR < sub > mvar = 4.43 (95% CI = 1.09-18.01)) were predictors of PSD incidence. PSD duration was impacted by presence of pain (b < sub > mvar = 0.49 (95% CI = 0.19-0.81)), urinary catheter (b < sub > mvar = 1.03 (95% CI = 0.01-2.07)), intravenous line (b < sub > mvar = 0.36 (95% CI = 0.16-0.57)), and PSI (b < sub > mvar = 1.60 (95% CI = 0.42-2.78)). PSD (OR = 3.53 (95% CI = 1.48-5.57)) and PSI (OR = 5.29 (95% CI = 2.92-7.66)) independently predicted inferior NIHSS at discharge. Insular and basal ganglia lesions increased the PSD risk about four- to eight-fold. DISCUSSION/CONCLUSION: This study identified modifiable risk factors, the management of which might reduce the negative impact PSD has on outcome.

Obesity and the Risk of Cryptogenic Ischemic Stroke in Young Adults.

OBJECTIVES: We examined the association between obesity and early-onset cryptogenic ischemic stroke (CIS) and whether fat distribution or sex altered this association. MATERIALS AND METHODS: This prospective, multi-center, case-control study included 345 patients, aged 18-49 years, with first-ever, acute CIS. The control group included 345 age- and sex-matched stroke-free individuals. We measured height, weight, waist circumference, and hip circumference. Obesity metrics analyzed included body mass index (BMI), waist-to-hip ratio (WHR), waist-to-stature ratio (WSR), and a body shape index (ABSI). Models were adjusted for age, level of education, vascular risk factors, and migraine with aura. RESULTS: After adjusting for demographics, vascular risk factors, and migraine with aura, the highest tertile of WHR was associated with CIS (OR for highest versus lowest WHR tertile 2.81, 95%CI 1.43-5.51; P=0.003). In sex-specific analyses, WHR tertiles were not associated with CIS. However, using WHO WHR cutoff values (>0.85 for women, >0.90 for men), abdominally obese women were at increased risk of CIS (OR 2.09, 95%CI 1.02-4.27; P=0.045). After adjusting for confounders, WC, BMI, WSR, or ABSI were not associated with CIS. CONCLUSIONS: Abdominal obesity measured with WHR was an independent risk factor for CIS in young adults after rigorous adjustment for concomitant risk factors.

Global Differences in Risk Factors, Etiology, and Outcome of Ischemic Stroke in Young Adults-A Worldwide Meta-analysis: The GOAL Initiative.

BACKGROUND AND OBJECTIVES: There is a worldwide increase in the incidence of stroke in young adults, with major regional and ethnic differences. Advancing knowledge of ethnic and regional variation in causes and outcomes will be beneficial in implementation of regional health care services. We studied the global distribution of risk factors, causes, and 3-month mortality of young patients with ischemic stroke, by performing a patient data meta-analysis from different cohorts worldwide. METHODS: We performed a pooled analysis of individual patient data from cohort studies that included consecutive patients with ischemic stroke aged 18-50 years. We studied differences in prevalence of risk factors and causes of ischemic stroke between different ethnic and racial groups, geographic regions, and countries with different income levels. We investigated differences in 3-month mortality by mixed-effects multivariable logistic regression. RESULTS: We included 17,663 patients from 32 cohorts in 29 countries. Hypertension and diabetes were most prevalent in Black (hypertension, 52.1%; diabetes, 20.7%) and Asian patients (hypertension 46.1%, diabetes, 20.9%). Large vessel atherosclerosis and small vessel disease were more often the cause of stroke in high-income countries (HICs; both p < 0.001), whereas "other determined stroke" and "undetermined stroke" were higher in low and middle-income countries (LMICs; both p < 0.001). Patients in LMICs were younger, had less vascular risk factors, and despite this, more often died within 3 months than those from HICs (odds ratio 2.49; 95% confidence interval 1.42-4.36). DISCUSSION: Ethnoracial and regional differences in risk factors and causes of stroke at young age provide an understanding of ethnic and racial and regional differences in incidence of ischemic stroke. Our results also highlight the dissimilarities in outcome after stroke in young adults that exist between LMICs and HICs, which should serve as call to action to improve health care facilities in LMICs.

Relationship between trajectories of post-stroke disability and self-rated health (NeuroAdapt): protocol for a prospective observational study.

INTRODUCTION: Stroke is the leading neurological cause of adult long-term disability in Europe. Even though functional consequences directly related to neurological impairment are well studied, post-stroke trajectories of functional health according to the International Classification of Functioning, Disability and Health are poorly understood. Particularly, no study investigated the relationship between post-stroke trajectories of activities of daily living (ADL) and self-rated health (SRH). However, such knowledge is of major importance to identify patients at risk of unfavourable courses. This prospective observational study aims to investigate trajectories of ADL and SRH, and their modifying factors in the course of the first year after stroke. METHODS AND ANALYSIS: The study will consecutively enrol 300 patients admitted to a tertiary care hospital with acute ischaemic stroke or transient ischaemic attack (TIA; Age, Blood Pressure, Clinical Features, Duration of symptoms, Diabetes score ≥3). Patient inclusion is planned from May 2021 to September 2022. All participants will complete an interview assessing ADL, SRH, mental health, views on ageing and resilience-related concepts. Participants will be interviewed face-to-face 1-5 days post-stroke/TIA in the hospital; and will be followed up after 6 weeks, 3 months, 6 months and 12 months via telephone. The 12-month follow-up will also include a neurological assessment. Primary endpoints are ADL operationalised by modified Rankin Scale scores and SRH. Secondary outcomes are further measures of ADL, functional health, physical activity, falls and fatigue. Views on ageing, social support, resilience-related concepts, affect, frailty, illness perceptions and loneliness will be examined as modifying factors. Analyses will investigate the bidirectional relationship between SRH and ADL using bivariate latent change score models. ETHICS AND DISSEMINATION: The study has been approved by the institutional review board of the University Medicine Greifswald (Ref. BB 237/20). The results will be disseminated through scientific publications, conferences and media. Moreover, study results and potential implications will be discussed with patient representatives. TRIAL REGISTRATION NUMBER: NCT04704635.

Association between Migraine and Cryptogenic Ischemic Stroke in Young Adults.

OBJECTIVE: To assess the association between migraine and cryptogenic ischemic stroke (CIS) in young adults, with subgroup analyses stratified by sex and presence of patent foramen ovale (PFO). METHODS: We prospectively enrolled 347 consecutive patients aged 18 to 49 years with a recent CIS and 347 age- and sex-matched (±5 years) stroke-free controls. Any migraine and migraine with (MA) and migraine without aura (MO) were identified by a screener, which we validated against a headache neurologist. We used conditional logistic regression adjusting for age, education, hypertension, diabetes, waist-to-hip ratio, physical inactivity, current smoking, heavy drinking, and oral estrogen use to assess independent association between migraine and CIS. The effect of PFO on the association between migraine and CIS was analyzed with logistic regression in a subgroup investigated with transcranial Doppler bubble screen. RESULTS: The screener performance was excellent (Cohen kappa > 0.75) in patients and controls. Compared with nonmigraineurs, any migraine (odds ratio [OR] = 2.48, 95% confidence interval [CI] = 1.63-3.76) and MA (OR = 3.50, 95% CI = 2.19-5.61) were associated with CIS, whereas MO was not. The association emerged in both women (OR = 2.97 for any migraine, 95% CI = 1.61-5.47; OR = 4.32 for MA, 95% CI = 2.16-8.65) and men (OR = 2.47 for any migraine, 95% CI = 1.32-4.61; OR = 3.61 for MA, 95% CI = 1.75-7.45). Specifically for MA, the association with CIS remained significant irrespective of PFO. MA prevalence increased with increasing magnitude of the right-to-left shunt in patients with PFO. INTERPRETATION: MA has a strong association with CIS in young patients, independent of vascular risk factors and presence of PFO. ANN NEUROL 2021;89:242-253.

Course and Recognition of Poststroke Delirium: A Prospective Noninferiority Trial of Delirium Screening Tools.

BACKGROUND AND PURPOSE: Poststroke delirium (PSD) is an independent predictor of unfavorable outcome. Despite its individual and socioeconomic burden, its frequency, clinical course, and routine detection remain unresolved. This study aimed to assess psychometric properties of established delirium screening tools and investigate the natural course of PSD. METHODS: This study investigated patients presenting with high-risk transient ischemic attacks or ischemic stroke within 24 hours during a 3-month period. Twice-daily screenings for PSD were done using the confusion assessment method, nursing delirium scale, and rapid delirium assessment, and evaluated for noninferiority against Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria. We investigated demographic and stroke characteristics as predictors of PSD, neurological deficits as predictors of false screening results, and conducted a simulation study to estimate the best timing to identify PSD. RESULTS: We enrolled 141 patients (73.8±10.4 years of age, 61 female) with a mean National Institutes of Health Stroke Scale score of 6.4±6.5. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition based PSD incidence was 39%, which manifested within 24 hours in 25% and 72 hours in almost all cases. The confusion assessment method was the only screening tool noninferior to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ratings providing a sensitivity of 82% and specificity of 80%. Age (odds ratio, 1.07 [1.02-1.13] per year, P=0.004) and National Institutes of Health Stroke Scale (odds ratio, 1.24 [1.15-1.34] per point, P<0.001) were predictors of PSD. False-positive screening results were associated with stroke-induced disorientation (odds ratio, 6.1 [3.2-11.61], P<0.001) and neglect (odds ratio, 2.17 [1.22-3.87], P=0.008). Simulations revealed that one in 4 cases is missed with less than daily screenings. CONCLUSIONS: PSD is a common complication of stroke and transient ischemic attack. Detection is challenged by confounding effects such as focal neurological deficits and the necessity for at least daily screenings. Future studies are required to investigate implementation of these findings in clinical routine. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03930719.

Stroke-Induced Modulation of Myeloid-Derived Suppressor Cells (MDSCs) and IL-10-Producing Regulatory Monocytes.

Background: Stroke patients are at risk of acquiring secondary infections due to stroke-induced immune suppression (SIIS). Immunosuppressive cells comprise myeloid-derived suppressor cells (MDSCs) and immunosuppressive interleukin 10 (IL-10)-producing monocytes. MDSCs represent a small but heterogeneous population of monocytic, polymorphonuclear (or granulocytic), and early progenitor cells ("early" MDSC), which can expand extensively in pathophysiological conditions. MDSCs have been shown to exert strong immune-suppressive effects. The role of IL-10-producing immunosuppressive monocytes after stroke has not been investigated, but monocytes are impaired in oxidative burst and downregulate human leukocyte antigen-DR isotype (HLA-DR) on the cell surface. Objectives: The objective of this work was to investigate the regulation and function of MDSCs as well as the immunosuppressive IL-10-producing monocytes in experimental and human stroke. Methods: This longitudinal, monocentric, non-interventional prospective explorative study used multicolor flow cytometry to identify MDSC subpopulations and IL-10 expression in monocytes in the peripheral blood of 19 healthy controls and 27 patients on days 1, 3, and 5 post-stroke. Quantification of intracellular STAT3p and Arginase-1 by geometric mean fluorescence intensity was used to assess the functionality of MDSCs. In experimental stroke induced by electrocoagulation in middle-aged mice, monocytic (CD11b+Ly6G-Ly6Chigh) and polymorphonuclear (CD11b+Ly6G+Ly6Clow) MDSCs in the spleen were analyzed by flow cytometry. Results: Compared to the controls, stroke patients showed a relative increase in monocytic MDSCs (percentage of CD11b+ cells) in whole blood without evidence for an altered function. The other MDSC subgroups did not differ from the control. Also, in experimental stroke, monocytic, and in addition, polymorphonuclear MDSCs were increased. The numbers of IL-10-positive monocytes did not differ between the patients and controls. However, we provide a new insight into monocytic function post-stroke since we can report that a differential regulation of HLA-DR and PD-L1 was found depending on the IL-10 production of monocytes. IL-10-positive monocytes are more activated post-stroke, as indicated by their increased HLA-DR expression. Conclusions: MDSC and IL-10+ monocytes can induce immunosuppression within days after stroke.

Corrigendum: Clinical Improvement Following Stroke Promptly Reverses Post-stroke Cellular Immune Alterations.

[This corrects the article DOI: 10.3389/fneur.2019.00414.].

Correction: Evaluating Mechanisms of Postoperative Delirium and Cognitive Dysfunction Following Elective Spine Surgery in Elderly Patients (CONFESS): Protocol for a Prospective Observational Trial.

[This corrects the article DOI: 10.2196/15488.].

Evaluating Mechanisms of Postoperative Delirium and Cognitive Dysfunction Following Elective Spine Surgery in Elderly Patients (CONFESS): Protocol for a Prospective Observational Trial.

BACKGROUND: Elderly people are at particular high risk for postoperative delirium (POD) following spine surgery, which is associated with longer hospital stays, higher costs, risk for delayed complications, long-term care dependency, and cognitive dysfunction (POCD). It is insufficiently understood which mechanisms and risk factors contribute to the development of POD and POCD following these major but plannable surgeries. OBJECTIVE: This study aims to identify modifiable risk factors in spine surgery. A better understanding thereof would help adapt medical management and surgical strategies to individual risk profiles. METHODS: This is a single-center observational study jointly conducted by the departments of neurosurgery, neurology, and anesthesiology at a tertiary care hospital in Germany. All patients aged 60 years and older presenting to the neurosurgery outpatient clinic or ward for elective spine surgery are screened for eligibility. Exclusion criteria include presence of neurodegenerative or history of psychiatric disease and medication with significant central nervous system activity (eg, antidepressants, antipsychotics, sedatives). Surgical and anesthetic procedures including duration of surgery as primary end point of this study are thoroughly documented. All patients are furthermore evaluated for their preoperative cognitive abilities by a number of tests, including the Consortium to Establish a Registry for Alzheimer's Disease Plus test battery. Physical, mental, and social health and well-being are assessed using the Patient-Reported Outcome Measurement Information System Profile 29 and Hospital Anxiety and Depression Scale. Patients additionally receive preoperative cerebrovascular ultrasound and structural and functional brain imaging. The immediate postoperative period includes screening for POD using the Nursing Delirium Screening Scale and validation through Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, criteria. We furthermore investigate markers of (neuro)inflammation (eg, interleukins, C-reactive protein, tumor necrosis factor alpha). Preoperative examinations are repeated 3 months postoperatively to investigate the presence of POCD and its mechanisms. Statistical analyses will compare delirious and nondelirious patients for predictors of immediate (POD) and delayed (POCD) cognitive dysfunction. RESULTS: This is the first study to prospectively evaluate risk factors for POD and POCD in spine surgery. Recruitment is ongoing, and data collection is estimated to be finished with the inclusion of 200 patients by mid-2020. CONCLUSIONS: The identification of mechanisms, possibly common, underlying POD and POCD would be a major step toward defining effective interventional strategies early in or even before the postoperative period, including the adaptation of surgical strategies to individual risk profiles. TRIAL REGISTRATION: ClinicalTrials.gov NCT03486288; https://clinicaltrials.gov/ct2/show/NCT03486288. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/15488.

Clinical Improvement Following Stroke Promptly Reverses Post-stroke Cellular Immune Alterations.

Background and Purpose: Stroke induces immediate profound alterations of the peripheral immune system rendering patients more susceptible to post-stroke infections. The precise mechanisms maintaining stroke-induced immune alterations (SIIA) remain unknown. High-Mobility-Group-Protein B1 (HMGB-1) is elevated for at least 7 days post-stroke and has been suggested to mediate SIIA. Patients with rapid clinical recovery of neurological deficits rarely develop severe infections. We therefore investigated whether rapid neurological recovery (either spontaneous or secondary to neurovascular recanalization therapy) alters the course of SIIA. National Institutes of Health Stroke Scale (NIHSS) served as surrogate marker for neurological improvement. Methods: Fluorescence-activated cell sorting was used to define leukocyte subpopulations. C-reactive protein (CRP), procalcitonin (PCT), HMGB-1, GM-CSF; IFN-ß, IFN-γ, IL-1ß, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-17, IL-17F, IL-18, TNF-α, MIF, IL-8, MCP-1, MCP-4, MIP-3α, MIP-3ß, Eotaxin, soluble IL-6 receptor, E-selectin, and P-selectin were analyzed by ELISA or Multiplex Assays. Serum miRNA expression changes were analyzed by qPCR. Results: Cellular parameters were similar in the improved and non-improved cohort on admission. In patients with rapid clinical recovery absolute and relative leukocyte, neutrophil, and lymphocyte numbers normalized promptly overnight. In contrast, HMGB-1 serum levels did not differ between the two groups. Nine miRNA were found to be differentially expressed between improved and non-improved patients. Conclusions: SIIA are detectable on admission of acute stroke patients. While it was assumed that post-stroke immunosuppression is rapidly reversed with improvement this is the first data set that shows that improvement actually is associated with a rapid reversal of SIIA demonstrating that SIIA require a constant signal to persist. The observation that HMGB-1 serum concentrations were similar in improved and non-improved cohorts argues against a role for this pro-inflammatory mediator in the maintenance of SIIA. Serum miRNA observed to be regulated in stroke in other publications was counter regulated with improvement in our cohort.

Intrathecal inflammation in young stroke.

OBJECTIVES: Correct identification of inflammatory etiologies of stroke is of outmost importance as they require treatment of the underlying disease. Aim of this study was to determine the prevalence of inflammatory changes in cerebrospinal fluid (CSF) observed in young cryptogenic stroke patients. MATERIALS AND METHODS: Of 6476 records of patients diagnosed with ischemic stroke, 278 had confirmed ischemia in brain imaging and received lumbar puncture. A total of 122 were classified as young stroke (≤55 years), and 156 were classified as older stroke patients; lumbar puncture in this cohort was indicated due to atypical clinical presentation. RESULTS: An infectious etiology was detected in 2.5% of young stroke patients (n = 3: vasculitis due to opportunistic infection, vasculitis due to neuroborreliosis, secondary vasospasm after viral meningitis) and in 1.9% (n = 3) in the older stroke cohort (vasculitis due to neurotuberculosis, septic embolic ischemia, vasculitis post-haemophilus influenza meningoencephalitis). Isolated vasculitis was evident in one patient of the older stroke cohort (0.6%). Non-specific alterations in CSF included increased cell count in 10% in young and in 9.3% in the older stroke cohort. Intrathecal Ig synthesis was present in 3.4% of the younger and in 4% of the older stroke cohort. CONCLUSIONS: The prevalence of an infectious etiology in young stroke is modest but slightly higher in comparison with older stroke patients. As brain imaging is not always sufficient for suspecting vasculitis, we recommend implementation of lumbar puncture in young cryptogenic stroke patients. If an infectious disease is present in ischemic stroke, it is of high therapeutic relevance.

Dolichoectasia and Small Vessel Disease in Young Patients With Transient Ischemic Attack and Stroke.

BACKGROUND AND PURPOSE: We evaluated whether basilar dolichoectasia is associated with markers of cerebral small vessel disease in younger transient ischemic attack and ischemic stroke patients. METHODS: We used data from the SIFAP1 study (Stroke in Young Fabry Patients), a large prospective, hospital-based, screening study for Fabry disease in young (<55 years) transient ischemic attack/stroke patients in whom detailed clinical data and brain MRI were obtained, and stroke subtyping with TOAST classification (Trial of ORG 10172 in Acute Stroke Treatment) was performed. RESULTS: Dolichoectasia was found in 508 of 3850 (13.2%) of patients. Dolichoectasia was associated with older age (odds ratio per decade, 1.26; 95% confidence interval, 1.09-1.44), male sex (odds ratio, 1.96; 95% confidence interval, 1.59-2.42), and hypertension (odds ratio, 1.39; 95% confidence interval, 1.13-1.70). Dolichoectasia was more common in patients with small infarctions (33.9% versus 29.8% for acute lesions, P=0.065; 29.1% versus 16.5% for old lesions, P<0.001), infarct location in the brain stem (12.4% versus 6.9%, P<0.001), and in white matter (27.8% versus 21.1%, P=0.001). Microbleeds (16.3% versus 4.7%, P=0.001), higher grades of white matter hyperintensities (P<0.001), and small vessel disease subtype (18.1% versus 12.4%, overall P for differences in TOAST (P=0.018) were more often present in patients with dolichoectasia. CONCLUSIONS: Dolichoectasia is associated with imaging markers of small vessel disease and brain stem localization of acute and old infarcts in younger patients with transient ischemic attack and ischemic stroke. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00414583.

Posterior versus Anterior Circulation Stroke in Young Adults: A Comparative Study of Stroke Aetiologies and Risk Factors in Stroke among Young Fabry Patients (sifap1).

BACKGROUND: Although 20-30% of all strokes occur in the posterior circulation, few studies have explored the characteristics of patients with strokes in the posterior compared to the anterior circulation so far. Especially data on young patients is missing. METHODS: In this secondary analysis of data of the prospective multi-centre European sifap1 study that investigated stroke and transient ischemic attack (TIA) patients aged 18-55 years, we compared vascular risk factors, stroke aetiology, presence of white matter hyperintensities (WMH) and cerebral microbleeds (CMB) between patients with ischaemic posterior circulation stroke (PCS) and those having suffered from anterior circulation stroke (ACS) based on cerebral MRI. RESULTS: We diagnosed PCS in 612 patients (29.1%, 407 men, 205 women) and ACS in 1,489 patients (70.9%). Their age (median 46 vs. 47 years, p = 0.205) and stroke severity (modified Rankin Scale: both 2, p = 0.375, Barthel Index 90 vs. 85, p = 0.412) were similar. PCS was found to be more frequent among the male gender (66.5 vs. 60.1% with ACS, p = 0.003). Vertebral artery (VA) dissection was more often the cause of PCS (16.8%) than was carotid artery dissection of ACS (7.9%, p < 0.001). Likewise, small vessel disease (Trial of Org 10172 in Acute Stroke Treatment [TOAST] = 3, PCS: 14.7%, ACS: 11.8%) and stroke of other determined aetiology (TOAST = 4, PCS: 24.5%, ACS: 16.0%) were more frequent in those with PCS. Furthermore, patent foramen ovale (PFO; PCS: 31.1%, ACS: 25.4%, p = 0.029) was more often detected in patients with PCS. In contrast, large-artery atherosclerosis (TOAST = 1, PCS: 15.4%, ACS: 22.2%) and cardio-embolic stroke (TOAST = 2, PCS: 15.6%, ACS: 18.0%) were less frequent in those with PCS (p < 0.001) as were preceding cerebrovascular events (10.1 vs. 14.1%, p = 0.014), TIA (4.8 vs. 7.7%, p = 0.016) and smoking (53.2 vs. 61.0%, p = 0.001). The presence, extent, and location of WMH and CMB did not differ between the 2 groups. CONCLUSIONS: Our data suggested a different pattern of aetiology and risk factors in young patients with PCS compared to those with ACS. These findings especially call for a higher awareness of VA dissection and potentially for more weight of a PFO as a risk factor in young patients with PCS. Clinical trial registration-URL: http://www.clinicaltrials.gov; NCT00414583.

Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Triggers, Causes, and Outcome (SECRETO): Rationale and design.

BACKGROUND: Worldwide, about 1.3 million annual ischaemic strokes (IS) occur in adults aged <50 years. Of these early-onset strokes, up to 50% can be regarded as cryptogenic or associated with conditions with poorly documented causality like patent foramen ovale and coagulopathies. KEY HYPOTHESES/AIMS: (1) Investigate transient triggers and clinical/sub-clinical chronic risk factors associated with cryptogenic IS in the young; (2) use cardiac imaging methods exceeding state-of-the-art to reveal novel sources for embolism; (3) search for covert thrombosis and haemostasis abnormalities; (4) discover new disease pathways using next-generation sequencing and RNA gene expression studies; (5) determine patient prognosis by use of phenotypic and genetic data; and (6) adapt systems medicine approach to investigate complex risk-factor interactions. DESIGN: Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome (SECRETO; NCT01934725) is a prospective multi-centre case-control study enrolling patients aged 18-49 years hospitalised due to first-ever imaging-proven IS of undetermined etiology. Patients are examined according to a standardised protocol and followed up for 10 years. Patients are 1:1 age- and sex-matched to stroke-free controls. Key study elements include centralised reading of echocardiography, electrocardiography, and neurovascular imaging, as well as blood samples for genetic, gene-expression, thrombosis and haemostasis and biomarker analysis. We aim to have 600 patient-control pairs enrolled by the end of 2018. SUMMARY: SECRETO is aiming to establish novel mechanisms and prognosis of cryptogenic IS in the young and will provide new directions for therapy development for these patients. First results are anticipated in 2019.

Patent Foramen Ovale and Cryptogenic Strokes in the Stroke in Young Fabry Patients Study.

BACKGROUND AND PURPOSE: A patent foramen ovale (PFO) is disproportionately prevalent in patients with cryptogenic stroke. Without alternative explanations, it is frequently considered to be causative. A detailed stratification of these patients may improve the identification of incidental PFO. METHODS: We investigated the PFO prevalence in 3497 transient ischemic attack and ischemic stroke patients aged 18 to 55 years in the prospective multicenter SIFAP1 study (Stroke in Young Fabry Patients 1) using the ASCO classification. Patients without an obvious cause for transient ischemic attack/stroke (ASCO 0) were divided into subgroups with and without vascular risk factors (ASCO 0+ and 0-). In addition, we looked for PFO-related magnetic resonance imaging lesion patterns. RESULTS: PFO was identified in 25% of patients. Twenty percent of patients with a definite or probable cause of transient ischemic attack/stroke (≥1 grade 1 or 2 ASCO criterion; n=1769) had a PFO compared with 29% of cryptogenic stroke patients (ASCO 0 and 3; n=1728; P<0,001); subdivision of cryptogenic strokes revealed a PFO in 24% of 978 ASCO 3 patients (n.s. versus ASCO 1 and 2) and a higher prevalence of 36% in 750 ASCO 0 cases (P<0.001 versus ASCO 3 and versus ASCO 1 and 2). PFO was more commonly observed in ASCO 0- (n=271) than in ASCO 0+ patients (n=479; 48 versus 29%; P<0.001). There was no PFO-associated magnetic resonance imaging lesion pattern. CONCLUSIONS: Cryptogenic stroke patients demonstrate a heterogeneous PFO prevalence. Even in case of less conclusive diseases like nonstenotic arteriosclerosis, patients should preferentially be considered to have a non-PFO-mediated stroke. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00414583.

Reduced Numbers and Impaired Function of Regulatory T Cells in Peripheral Blood of Ischemic Stroke Patients.

BACKGROUND AND PURPOSE: Regulatory T cells (Tregs) have been suggested to modulate stroke-induced immune responses. However, analyses of Tregs in patients and in experimental stroke have yielded contradictory findings. We performed the current study to assess the regulation and function of Tregs in peripheral blood of stroke patients. Age dependent expression of CD39 on Tregs was quantified in mice and men. METHODS: Total FoxP3(+) Tregs and CD39(+)FoxP3(+) Tregs were quantified by flow cytometry in controls and stroke patients on admission and on days 1, 3, 5, and 7 thereafter. Treg function was assessed by quantifying the inhibition of activation-induced expression of CD69 and CD154 on T effector cells (Teffs). RESULTS: Total Tregs accounted for 5.0% of CD4(+) T cells in controls and <2.8% in stroke patients on admission. They remained below control values until day 7. CD39(+) Tregs were most strongly reduced in stroke patients. On day 3 the Treg-mediated inhibition of CD154 upregulation on CD4(+) Teff was impaired in stroke patients. CD39 expression on Treg increased with age in peripheral blood of mice and men. CONCLUSION: We demonstrate a loss of active FoxP3(+)CD39(+) Tregs from stroke patient's peripheral blood. The suppressive Treg function of remaining Tregs is impaired after stroke.