Effectiveness of Thrombectomy in Stroke According to Baseline Prognostic Factors: Inverse Probability of Treatment Weighting Analysis of a Population-Based Registry

Background and Purpose In real-world practice, the benefit of mechanical thrombectomy (MT) is uncertain in stroke patients with very favorable or poor prognostic profiles at baseline. We studied the effectiveness of MT versus medical treatment stratifying by different baseline prognostic factors. Methods Retrospective analysis of 2,588 patients with an ischemic stroke due to large vessel occlusion nested in the population-based registry of stroke code activations in Catalonia from January 2017 to June 2019. The effect of MT on good functional outcome (modified Rankin Score 85 years, National Institutes of Health Stroke Scale [NIHSS] >25, time from onset >6 hours, Alberta Stroke Program Early CT Score 3), good (if NIHSS <6 or distal occlusion, in the absence of poor prognostic factors), or reference (not meeting other groups' criteria). Results Patients receiving MT (n=1,996, 77%) were younger, had less pre-stroke disability, and received systemic thrombolysis less frequently. These differences were balanced after the IPTW stratified by prognosis. MT was associated with good functional outcome in the reference (odds ratio [OR], 2.9; 95% confidence interval [CI], 2.0 to 4.4), and especially in the poor baseline prognostic stratum (OR, 3.9; 95% CI, 2.6 to 5.9), but not in the good prognostic stratum. MT was associated with survival only in the poor prognostic stratum (OR, 2.6; 95% CI, 2.0 to 3.3). Conclusions Despite their worse overall outcomes, the impact of thrombectomy over medical management was more substantial in patients with poorer baseline prognostic factors than patients with good prognostic factors

Identificación de la presencia de antígenos neurales en el tejido linfoide de los pacientes con ictus y análisis de su eventual implicación patogénica en la respuesta inmune adaptativa tras el daño cerebral

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Identificación de la presencia de antígenos neurales en el tejido linfoide de los pacientes con ictus y análisis de su eventual implicación patogénica en la respuesta inmune adaptativa tras el daño cerebral

INTRODUCCION: En condiciones fisiológicas existe un drenaje de solutos y células del sistema inmune desde el sistema nervioso central hacia el tejido linfoide secundario, pudiendo desarrollarse una respuesta inmune de tipo adaptativo frente a dichos antígenos. Ciertas moléculas coadyuvantes como heat shock protein 70(Hsp-70) pueden facilitar y modular los procesos de presentación antigénica y la propia respuesta inmune. Hsp-70 es producida en gran cantidad durante la isquemia cerebral. En los pacientes con ictus isquémico podría haber una mayor llegada de antígenos cerebrales y moléculas coadyuvantes al tejido linfoide secundario que en sujetos controles y de este modo favorecerse respuestas inmunes que influyan en la evolución y pronóstico del ictus. MÉTODOS: Estudio de tejido linfoide en pacientes con ictus agudo mediante toma de biopsias de amígdala palatina y análisis de muestras de sangre, así como en sujetos control. Así mismo, toma de muestras de amígdala palatina y ganglio linfático cervical en necropsias de pacientes con ictus y necropsias control. Se estudiaron las diferentes subpoblaciones linfocitarias, marcadores de activación linfocitaria, presencia de antígenos cerebrales y la proteína Hsp-70, y estructura del tejido linfoide mediante técnicas de citometría de flujo, inmunofluorescencia y western blot, realizándose un análisis cuantitativo. Se analizó la síntesis local tanto de antígenos como Hsp-70 mediante técnica de PCR. RESULTADOS: No se observaron diferencias ni en la estructura del tejido linfoide ni en las diferentes subpoblaciones linfocitarias entre pacientes y controles. Los antígenos cerebrales y Hsp-70 se encontraron en mayor cantidad en pacientes con ictus. Ambos estaban localizados en células presentadoras de antígenos con capacidad para activar el sistema inmune. Dichas células portadoras de antígenos cerebrales se encuentran preferentemente localizadas próximas a la trama fibroreticular del tejido linfoide y podían llevar a cabo algún grado de activación linfocitaria. Los pacientes que presentaban mas antígenos neurales presentaban mejor pronostico, mientras que aquellos con mayor presencia de antígenos mielínicos tenían un mayor volumen de infarto y peor pronóstico. CONCLUSIONES: En los pacientes con ictus isquémico se observa un incremento de antígenos cerebrales en el tejido linfoide secundario. La respuesta inmune frente a ellos puede influir en la evolución y pronóstico de la enfermedad.INTRODUCTION: Under physiological conditions solutes and immune system cells drain from the central nervous system to the secondary lymphoid tissue. An immune response against these antigens can be developed. Certain adjuvant molecules as heat shock protein 70 (HSP -70) can facilitate and modulate the process of antigen presentation and the immune responses. Hsp -70 is produced in large quantities during cerebral ischemia . In patients with ischemic stroke there could be a increased arrival of brain antigens and adjuvant molecules to the secondary lymphoid tissue and this could favor the development of immune responses that could have a role in the evolution and prognosis of stroke. METHODS: We performed a biopsy of palatine tonsil to acute stroke patients and control subjects. We also obtained samples of palatine tonsil and cervical lymph node from necropsies of patients with stroke and controls. Different lymphocyte subsets, lymphocyte activation markers, presence of brain antigens and Hsp -70 protein, and lymphoid tissue structure were studied by flow cytometry, immunofluorescence and western blot techniques. RESULTS: No differences were observed in either the structure of lymphoid tissue or in different lymphocyte subpopulations between patients and controls. Brain antigens and Hsp -70 were increased in the lymphoid tissue of patients with stroke. Both were located on antigen-presenting cells with ability to activate the immune system. These antigen-presenting cells carrying brain antigens were preferably located near the fibroreticular mesh of the lymphoid tissue and performed some degree of lymphocyte activation. Patients who had more neural antigens showed better prognosis, whereas those with greater presence of myelinated antigens had an increased infarct volume and worse prognosis. CONCLUSIONS: We observed that brain antigens were increased in the secondary lymphoid tissue of stroke patients . The development of an immune response against them could influence the evolution and prognosis of the disease

Identificación de la presencia de antígenos neurales en el tejido linfoide de los pacientes con ictus y análisis de su eventual implicación patogénica en la respuesta inmune adaptativa tras el daño cerebral

[spa] INTRODUCCION: En condiciones fisiológicas existe un drenaje de solutos y células del sistema inmune desde el sistema nervioso central hacia el tejido linfoide secundario, pudiendo desarrollarse una respuesta inmune de tipo adaptativo frente a dichos antígenos. Ciertas moléculas coadyuvantes como heat shock protein 70(Hsp-70) pueden facilitar y modular los procesos de presentación antigénica y la propia respuesta inmune. Hsp-70 es producida en gran cantidad durante la isquemia cerebral. En los pacientes con ictus isquémico podría haber una mayor llegada de antígenos cerebrales y moléculas coadyuvantes al tejido linfoide secundario que en sujetos controles y de este modo favorecerse respuestas inmunes que influyan en la evolución y pronóstico del ictus. MÉTODOS: Estudio de tejido linfoide en pacientes con ictus agudo mediante toma de biopsias de amígdala palatina y análisis de muestras de sangre, así como en sujetos control. Así mismo, toma de muestras de amígdala palatina y ganglio linfático cervical en necropsias de pacientes con ictus y necropsias control. Se estudiaron las diferentes subpoblaciones linfocitarias, marcadores de activación linfocitaria, presencia de antígenos cerebrales y la proteína Hsp-70, y estructura del tejido linfoide mediante técnicas de citometría de flujo, inmunofluorescencia y western blot, realizándose un análisis cuantitativo. Se analizó la síntesis local tanto de antígenos como Hsp-70 mediante técnica de PCR. RESULTADOS: No se observaron diferencias ni en la estructura del tejido linfoide ni en las diferentes subpoblaciones linfocitarias entre pacientes y controles. Los antígenos cerebrales y Hsp-70 se encontraron en mayor cantidad en pacientes con ictus. Ambos estaban localizados en células presentadoras de antígenos con capacidad para activar el sistema inmune. Dichas células portadoras de antígenos cerebrales se encuentran preferentemente localizadas próximas a la trama fibroreticular del tejido linfoide y podían llevar a cabo algún grado de activación linfocitaria. Los pacientes que presentaban mas antígenos neurales presentaban mejor pronostico, mientras que aquellos con mayor presencia de antígenos mielínicos tenían un mayor volumen de infarto y peor pronóstico. CONCLUSIONES: En los pacientes con ictus isquémico se observa un incremento de antígenos cerebrales en el tejido linfoide secundario. La respuesta inmune frente a ellos puede influir en la evolución y pronóstico de la enfermedad.[eng] INTRODUCTION: Under physiological conditions solutes and immune system cells drain from the central nervous system to the secondary lymphoid tissue. An immune response against these antigens can be developed. Certain adjuvant molecules as heat shock protein 70 (HSP -70) can facilitate and modulate the process of antigen presentation and the immune responses. Hsp -70 is produced in large quantities during cerebral ischemia . In patients with ischemic stroke there could be a increased arrival of brain antigens and adjuvant molecules to the secondary lymphoid tissue and this could favor the development of immune responses that could have a role in the evolution and prognosis of stroke. METHODS: We performed a biopsy of palatine tonsil to acute stroke patients and control subjects. We also obtained samples of palatine tonsil and cervical lymph node from necropsies of patients with stroke and controls. Different lymphocyte subsets, lymphocyte activation markers, presence of brain antigens and Hsp -70 protein, and lymphoid tissue structure were studied by flow cytometry, immunofluorescence and western blot techniques. RESULTS: No differences were observed in either the structure of lymphoid tissue or in different lymphocyte subpopulations between patients and controls. Brain antigens and Hsp -70 were increased in the lymphoid tissue of patients with stroke. Both were located on antigen-presenting cells with ability to activate the immune system. These antigen-presenting cells carrying brain antigens were preferably located near the fibroreticular mesh of the lymphoid tissue and performed some degree of lymphocyte activation. Patients who had more neural antigens showed better prognosis, whereas those with greater presence of myelinated antigens had an increased infarct volume and worse prognosis. CONCLUSIONS: We observed that brain antigens were increased in the secondary lymphoid tissue of stroke patients . The development of an immune response against them could influence the evolution and prognosis of the disease

Presence of heat shock protein 70 in secondary lymphoid tissue correlates with stroke prognosis

Heat shock protein 70 (Hsp-70) can act as a danger signal and activate immune responses. We studied the presence of Hsp-70 in lymphoid tissue and plasma of acute stroke patients and asymptomatic controls free of neurological disease. Immunofluorescence, Western blotting, qRT-PCR and flow cytometry studies were performed. Plasma Hsp-70 concentration at day 7 was similar in patients and controls, whereas patients disclosed stronger immunoreactivity to Hsp-70 in lymphoid tissue than controls. Most Hsp-70. + cells were antigen presenting cells located in T cell zones. Stronger immunoreactivity to Hsp-70 was associated with smaller infarctions and better functional outcome. © 2014 Elsevier B.V.This work was supported by grants from the ‘Instituto de Salud Carlos III’ (ISCIII) (PI09/1313), the Spanish Ministry of Science and Innovation (SAF2011-30492), the ERANET-NEURON project (PRI-PIMNEU-2011-1342) of the European Community, and a donation by the Doctor Melchor Colet Foundation. We are indebted to IDIBAPS Biobank, Xarxa de Bancs de Tumors de Catalunya (XBTC) financed by ‘Pla Director d’Oncologia de Catalunya’ and Red Nacional de Biobancos (RNBB, ReTBioH) financed by ISCIII (RETIC RD09-0076/0038)Peer Reviewe

Monocyte subtypes predict clinical course and prognosis in human stroke

et al.The number of circulating monocytes increases after stroke. In this study, we assessed the time course and phenotype of monocyte subsets and their relationship with the clinical course and outcome in 46 consecutive stroke patients and 13 age-matched controls. The proportion of the most abundant ‘classical’ CD14highCD16− monocytes did not change after stroke, whereas that of CD14highCD16+ monocytes increased and CD14dimCD16+ monocytes decreased. CD14highCD16+ monocytes had the highest expression of TLR2, HLA-DR and the angiogenic marker, Tie-2; CD14dimCD16+ monocytes had the highest expression of costimulatory CD86 and adhesion molecule CD49d. Platelet–monocyte interactions were highest in CD14highCD16− monocytes and lowest in CD14dimCD16+ monocytes. In adjusted models, 1/CD14highCD16− monocytes were associated with poor outcome (OR: 1.38), higher mortality (OR: 1.40) and early clinical worsening (OR: 1.29); 2/CD14highCD16+ monocytes were inversely related to mortality (OR: 0.32); and 3/CD14dimCD16+ monocytes were inversely related to poor outcome (OR: 0.74) and infarction size (r=−0.45; P=0.02). These results illustrate that the predominant monocyte subtype conveys harmful effects after stroke, which include stronger interaction with platelets. Alternatively, rarer subpopulations of monocytes are beneficial with a phenotype that could promote tissue repair and angiogenesis. Therefore, monitoring of monocyte subtypes may emerge as a useful tool at the bedside for stroke patients.Peer reviewe

Uric acid levels are relevant in patients with stroke treated with thrombolysis

Background and Purpose: Uric acid (UA) is a neuroprotective antioxidant that improves the benefits of alteplase in experimental ischemia. However, it is unknown whether endogenous UA also influences the response to thrombolysis in patients with stroke. Methods-A total of 317 consecutive patients treated with thrombolysis were included in a prospective stroke registry. Demographics, laboratory data, neurological course, and infarction volume were prospectively collected. Excellent outcome was defined as achieving a modified Rankin Scale score <2 at 90 days. Binary and ordinal logistic regression models were used to analyze modified Rankin Scale score at 90 days. Results-UA levels were significantly higher in patients with an excellent outcome than in patients with a poor outcome (5.82 [1.39] versus 5.42 [1.81], P=0.029). In multivariate models, increased UA levels (OR, 1.23; 95% CI, 1.03 to 1.49; P=0.025) were associated with an excellent outcome and with an increased risk of shifting to a better category across the modified Rankin Scale (OR, 1.19; 95% CI, 1.04 to 1.38; P=0.014) independently of the effect of confounders. The levels of UA and the volume of final infarction were inversely correlated (r=-0.216, P<0.001) and the inverse correlation remained after adjustment for age, sex, and baseline National Institutes of Health Stroke Scale score (t value=-2.54, P=0.01). Significantly lower UA levels were found in patients with malignant middle cerebral artery infarction and parenchymal hemorrhage postthrombolysis. Conclusions: Increased UA serum levels are associated with better outcome in patients with stroke treated with reperfusion therapies. These results support the assessment of the potential neuroprotective role of the exogenous administration of UA in patients with stroke treated with thrombolysis. © 2010 American Heart Association, Inc.The study was supported by the Fondo de Investigaciones Sanitarias (FIS) of the Spanish Ministry of Health EC07-90276 and the Fundación Melchor Colet. Xabier Urra is a Fellow of the FIS.Peer Reviewe

Brain-derived antigens in lymphoid tissue of patients with acute stroke

In experimental animals, the presence of brain-derived constituents in cervical lymph nodes has been associated with the activation of local lymphocytes poised to minimize the inflammatory response after acute brain injury. In this study, we assessed whether this immune crosstalk also existed in stroke patients. We studied the clinical course, neuroimaging, and immunoreactivity to neuronal derived Ags (microtubule-associated protein-2 and N-methyl d-aspartate receptor subunit NR-2A), and myelin-derived Ags (myelin basic protein and myelin oligodendrocyte glycoprotein) in palatine tonsils and cervical lymph nodes of 28 acute stroke patients and 17 individuals free of neurologic disease. Stroke patients showed greater immunoreactivity to all brain Ags assessed compared with controls, predominantly in T cell zones. Most brain immunoreactive cells were CD68(+) macrophages expressing MHC class II receptors. Increased reactivity to neuronal-derived Ags was correlated with smaller infarctions and better long-term outcome, whereas greater reactivity to myelin basic protein was correlated with stroke severity on admission, larger infarctions, and worse outcome at follow-up. Patients also had more CD69(+) T cells than controls, indicative of T cell activation. Overall, the study showed in patients with acute stroke the presence of myelin and neuronal Ags associated with lymph node macrophages located near activated T cells. Whether the outcome of acute stroke is influenced by Ag-specific activation of immune responses mediated by CD69 lymphocytes deserves further investigation.This work was supported by grants from the Fondo de Investigaciones Sanitarias of the Spanish Ministry of Health (PI09/1313), the Spanish Ministry of Science and Innovation (SAF2008-04515), the European Community (Project FP7/2007-2013, Grant Agreement 201024), and the Doctor Melchor Collet Foundation.Peer Reviewe

Course of matrix metalloproteinase-9 isoforms after the administration of uric acid in patients with acute stroke: a proof-of-concept study

The final publication is available at www.springerlink.comOxidative stress as well as expression and activity of matrix metalloproteinase 9 (MMP-9) are rapidly enhanced after cerebral ischemia. The magnitude of these effects is related to stroke outcome. In human stroke, the extent of oxidative stress correlates well with increased MMP-9 expression. The aim of this study was to evaluate whether treatment with the antioxidant molecule uric acid (UA) decreased the levels of MMP-9 in stroke patients treated with rtPA. The patients were part of a pilot, double-blind, randomized, vehiclecontrolled study of patients with acute stroke treated with rtPA (< 3 h) and randomized to receive an intravenous infusion of UA (n = 16) or vehicle (n = 8). Total matrix metalloproteinase (tMMP)-9 and active (aMMP-9) levels were measured in serum at baseline (< 3 h), at the end of study treatment infusion (< 5.5 h), and at 48 hours. Total MMP-9 and aMMP-9 increased very early after stroke onset in patients allocated vehicle after rtPA therapy. Lower increments of aMMP-9 were associated with better outcome at 3 months. UA treatment was associated with reduced levels of aMMP-9 at T1 (p < 0.02) in multivariate models adjusted for age, NIHSS score, and baseline aMMP-9 levels. The decline of aMMP-9 attained after UA administration supports further clinical assessment of UA therapy in patients with acute stroke.The study was supported by the Fondo de Investigaciones Sanitarias (FIS) (Grant: EC07-90276), the CICYT (Grant: SAF 2005-05793-CO2-01) and the Fundación Melchor Colet. Sergio Amaro, Álvaro Cervera, Xabier Urra and Manuel Gómez-Choco are Fellows of the FIS of the Spanish Ministry of Health.Peer reviewe