Cerebrovascular pulsatility indicates preoperative subcortical cognitive impairment and an increased risk for postoperative delirium in elderly patients undergoing elective spine surgery.

Introduction: Advances in spine surgery enable safe interventions in elderly patients, but perioperative neurocognitive disorders (pNCD), such as post-operative delirium (POD) and cognitive dysfunction (POCD), remain a serious concern. Pre-operative cognitive impairment is a major risk factor for pNCD. Comprehensive pre-operative cognitive assessments are not feasible in clinical practice, making effective screening methods desirable. This study investigates whether pre-operative cerebrovascular duplex sonography can assess subcortical (vascular) cognitive impairment and the risk for POD. Methods: This prospective single-center study recruited patients aged ≥60 years scheduled for elective spine surgery at a German university hospital. Patients underwent pre-operative assessments including cognitive abilities (CERAD test battery), structural MRI, and cerebrovascular duplex sonography. POD screening was conducted three times daily for at least 3 days. The primary hypothesis, that the mean pulsatility index (PI) of both internal carotid arteries (ICA) predicts POD risk, was tested using logistic regression. Secondary analyses examined the association between POD risk and ICA flow (time-averaged peak velocities, TAPV) and correlations with cognitive profiles and MRI characteristics. Results: POD occurred in 22% of patients (n = 22/99) within three postoperative days. Patients with POD were significantly older (75.9 ± 5.4 vs. 70.0 ± 6.9 years, p < 0.01) but did not differ by gender (p = 0.51). ICA PI significantly predicted POD risk (OR = 5.46 [95%CI: 1.81-16.49], p = 0.003), which remained significant after adjustment for age and duration of surgery (ORadj = 6.38 [95% CI: 1.77-23.03], p = 0.005). TAPV did not inform the POD risk (p = 0.68). ICA PI Pre-operative cognitive scores were significantly associated with ICA PI (mean CERAD score: r = -0.32, p < 0.001). ICA PI was also significantly associated with total white matter lesion volume (τ = 0.19, p = 0.012) and periventricular white matter lesion volume (τ = 0.21, p = 0.007). Discussion: This is the first study to demonstrate that cerebrovascular duplex sonography can assess the risk for POD in elderly spine surgery patients. Increased ICA PI may indicate subcortical impairment, larger white matter lesion load, and lower white matter volume, predisposing factors for POD. Pre-operative cerebrovascular duplex sonography of the ICA is widely available, easy-to-use, and efficient, offering a promising screening method for POD risk. Increased ICA PI could supplement established predictors like age to adjust surgical and peri-operative procedures to individual risk profiles.

Drug administration via feeding tubes-a procedure that carries risks: systematic identification of critical factors based on commonly administered drugs in a cohort of stroke patients.

PURPOSE: Drug administration via feeding tubes is considered a process with many uncertainties. This review aimed to give a comprehensive overview of data available on feeding tube application and to carry out risk assessments for drug substances commonly administered to stroke patients. METHODS: Drugs frequently administered via feeding tubes were identified through a retrospective analysis of discharge letters from a stroke unit. Physicochemical, pharmacokinetic, and stability properties of these drugs and data on drug-enteral nutrition interactions were systematically searched for in the European Pharmacopoeia, Hagers Handbook of Pharmaceutical Practice, Birchers clinical-pharmacological data compilation, and the Martindale Complete Drug Reference, as well as from databases including DrugBank, DrugDex, PubChem, Google Scholar, and PubMed. RESULTS: Of the drugs most commonly administered via feeding tubes in the present stroke patient cohort, bisoprolol, candesartan, and ramipril could be considered the least critical due to their overall favourable properties. Acetylsalicylic acid, amlodipine, hydrochlorothiazide, omeprazole and esomeprazole, simvastatin, and torasemide pose risks based on pH or light-dependent instability or proposed food effects. The most critical drugs to be administered via feeding tubes are considered to be furosemide, levodopa, and levothyroxine as they show relevant instabilities under administration conditions and substantial food effects; the latter two even possess a narrow therapeutic index. However, little information is available on drug-tube and drug-formula interactions. CONCLUSION: Feeding tube administration of medications turned out to be a highly complex process with several unmet risks. Therefore, investigations that systematically assess these risk factors using clinically relevant model systems are urgently needed.

Association of Left Atrial Stiffness With Risk of Cryptogenic Ischemic Stroke in Young Adults.

Background: Incidence of cryptogenic ischemic stroke (CIS) in young adults is increasing. Early left atrial (LA) myopathy might be 1 of the underlying mechanisms, but this has only been scarcely explored. Objectives: The purpose of this study was to assess the association between increased LA stiffness and CIS in young adults. Methods: In the multicenter SECRETO (Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome) study, LA function was analyzed by speckle tracking echocardiography in 150 CIS patients (aged 18-49 years) and 150 age- and sex-matched controls. Minimum and maximum LA volumes, LA reservoir and contractile strain were measured. LA stiffness was calculated by the ratio: mitral peak E-wave velocity divided by mitral annular e' velocity (E/e')/LA reservoir strain and considered increased if ≥0.22. Increased LA volumes, LA stiffness, and/or reduced LA strain indicated LA myopathy. Logistic regression was used to determine the relation between LA stiffness and CIS and the clinical variables associated with LA stiffness. Results: Increased LA stiffness was found in 36% of patients and in 18% of controls (P < 0.001). Increased LA stiffness was associated with a 2.4-fold (95% CI: 1.1-5.3) higher risk of CIS after adjustment for age, sex, comorbidities, and echocardiographic confounders (P = 0.03). In patients, obesity, pre-CIS antihypertensive treatment, older age, and lower LA contractile strain were all related to increased LA stiffness (all P < 0.05). Conclusions: LA myopathy with increased LA stiffness and impaired LA mechanics more than doubles the risk of CIS in patients under the age of 50 years. This provides new insights into the link between LA dysfunction and CIS at young ages. (Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome [SECRETO]; NCT01934725).

Association between heavy alcohol consumption and cryptogenic ischaemic stroke in young adults: a case-control study.

BACKGROUND: The underlying risk factors for young-onset cryptogenic ischaemic stroke (CIS) remain unclear. This multicentre study aimed to explore the association between heavy alcohol consumption and CIS with subgroup analyses stratified by sex and age. METHODS: Altogether, 540 patients aged 18-49 years (median age 41; 47.2% women) with a recent CIS and 540 sex-matched and age-matched stroke-free controls were included. Heavy alcohol consumption was defined as >7 (women) and >14 (men) units per week or at least an average of two times per month ≥5 (women) and ≥7 (men) units per instance (binge drinking). A conditional logistic regression adjusting for age, sex, education, hypertension, cardiovascular diseases, diabetes, hypercholesterolaemia, current smoking, obesity, diet and physical inactivity was used to assess the independent association between alcohol consumption and CIS. RESULTS: Patients were twice as more often heavy alcohol users compared with controls (13.7% vs 6.7%, p<0.001), were more likely to have hypertension and they were more often current smokers, overweight and physically inactive. In the entire study population, heavy alcohol consumption was independently associated with CIS (adjusted OR 2.11; 95% CI 1.22 to 3.63). In sex-specific analysis, heavy alcohol consumption was associated with CIS in men (2.72; 95% CI 1.25 to 5.92), but not in women (1.56; 95% CI 0.71 to 3.41). When exploring the association with binge drinking alone, a significant association was shown in the entire cohort (2.43; 95% CI 1.31 to 4.53) and in men (3.36; 95% CI 1.44 to 7.84), but not in women. CONCLUSIONS: Heavy alcohol consumption, particularly binge drinking, appears to be an independent risk factor in young men with CIS.

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.

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.

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.

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.