Xabier Urra

Thrombectomy within 8 Hours after Symptom Onset in Ischemic Stroke

BACKGROUND We aimed to assess the safety and efficacy of thrombectomy for the treatment of stroke in a trial embedded within a population-based stroke reperfusion registry. METHODS During a 2-year period at four centers in Catalonia, Spain, we randomly assigned 206 patients who could be treated within 8 hours after the onset of symptoms of acute ischemic stroke to receive either medical therapy (including intravenous alteplase when eligible) and endovascular therapy with the Solitaire stent retriever (thrombectomy group) or medical therapy alone (control group). All patients had confirmed proximal anterior circulation occlusion and the absence of a large infarct on neuroimaging. In all study patients, the use of alteplase either did not achieve revascularization or was contraindicated. The primary outcome was the severity of global disability at 90 days, as measured on the modified Rankin scale (ranging from 0 [no symptoms] to 6 [death]). Although the maximum planned sample size was 690, enrollment was halted early because of loss of equipoise after positive results for thrombectomy were reported from other similar trials. RESULTS Thrombectomy reduced the severity of disability over the range of the modified Rankin scale (adjusted odds ratio for improvement of 1 point, 1.7; 95% confidence interval [CI], 1.05 to 2.8) and led to higher rates of functional independence (a score of 0 to 2) at 90 days (43.7% vs. 28.2%; adjusted odds ratio, 2.1; 95% CI, 1.1 to 4.0). At 90 days, the rates of symptomatic intracranial hemorrhage were 1.9% in both the thrombectomy group and the control group (P=1.00), and rates of death were 18.4% and 15.5%, respectively (P=0.60). Registry data indicated that only eight patients who met the eligibility criteria were treated outside the trial at participating hospitals. CONCLUSIONS Among patients with anterior circulation stroke who could be treated within 8 hours after symptom onset, stent retriever thrombectomy reduced the severity of post-stroke disability and increased the rate of functional independence. (Funded by Fundació Ictus Malaltia Vascular through an unrestricted grant from Covidien and others; REVASCAT ClinicalTrials.gov number, NCT01692379.).

The immunology of acute stroke

Recent clinical and experimental studies have highlighted a complex role for the immune system in the pathophysiological changes that occur after acute stroke. Sensors of the innate immune system such as Toll-like receptors, or effectors such as the lectin pathway of complement activation and innate immune cells, are activated by brain ischaemia and tissue damage, leading to amplification of the inflammatory cascade. Activation of the adaptive arm of the immune system, mediated by lymphocyte populations including T and B cells, regulatory T cells, and γδT cells, in response to stroke can lead to deleterious antigen-specific autoreactive responses but can also have cytoprotective effects. Increased incidence of infections is observed after acute stroke, and might result from activation of long-distance feedback loops between the CNS and peripheral immune organs, which are thought to play a part in stroke-induced immunodepression. Ongoing clinical trials are investigating whether the preventive use of antibiotics improves functional outcome after stroke. This Review discusses the multifaceted role of the immune system in the pathophysiology of acute stroke.

Infection after acute ischemic stroke: A manifestation of brain-induced immunodepression

Background and Purpose— Infection after experimental focal ischemia may result from brain-induced immunodepression, but it is unsettled whether a similar syndrome occurs in human stroke. Summary of Review— Many patients develop infections shortly after acute stroke regardless of optimal management. Mortality is higher in these patients and the severity of stroke is the strongest determinant of the infectious risk. However, it is controversial whether infections promote neurological worsening or alternatively represent a marker of severe disease. The brain and the immune system are functionally linked through neural and humoral pathways, and decreased immune competence with higher incidence of infections has been demonstrated in several acute neurological conditions. In experimental brain ischemia, infections are associated with the activation of the autonomous nervous system and neuroendocrine pathways, which increase the strength of anti-inflammatory signals. A strong cytokine-mediated anti-inflammatory response was recently observed in stroke patients at higher risk of infection, although infection could not demonstrate an independent association with the progression of the symptoms. Conclusions— The appearance of infection in patients with acute stroke obeys in part to immunological mechanisms triggered by acute brain injury. An excessive anti-inflammatory response is a key facilitating factor for the development of infection, and it is likely that this immunological response represents an adaptive mechanism to brain ischemia. Contrarily, it is unclear whether infection contributes independently to poor outcome in human stroke. Overall, a better understanding of the cross-talk between the brain and the immune system might lead to more effective therapies in patients with acute stroke.

Neuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation

Treatments for acute ischaemic stroke continue to evolve after the superior value of endovascular thrombectomy was confirmed over systemic thrombolysis. Unfortunately, numerous neuroprotective drugs have failed to show benefit in the treatment of acute ischaemic stroke, making the search for new treatments imperative. Increased awareness of the relevance of rigorous preclinical testing, and appropriate selection of study participants, might overcome the barriers to progress in stroke research. Relevant areas of interest include the search for safe and effective treatment strategies that combine neuroprotection reperfusion, better use of advanced brain imaging for patient selection, and wider implementation of prehospital conducted clinical trials. Randomised controlled trials of combination treatments completed within the past 5 years have included growth factors, hypothermia, minocycline, natalizumab, fingolimod, and uric acid; the latter two drugs with alteplase produced encouraging results. Blocking of excitotoxicity is also being reassessed in clinical trials with new approaches, such as the postsynaptic density-95 inhibitor NA-1, or peritoneal dialysis to remove excess glutamate. The findings of these randomised trials are anticipated to improve treatment options and clinical outcomes in of patients with acute stroke.

Monocyte subtypes predict clinical course and prognosis in human stroke

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.

Monocytes Are Major Players in the Prognosis and Risk of Infection After Acute Stroke

Background and Purpose— Monocytes participate in adaptive and innate immune responses. Monocyte numbers increase in patients with stroke associated infection (SAI) or severe stroke. Whether changes in monocytes are related to specific effects, or simply mark brain damage, remains unsettled. Methods— We used flow cytometry in 45 consecutive strokes and 12 healthy controls to assess the time course of monocytes, their phenotype, and the production of cytokines after stimulation. Cortisol, TNF-α, IFN-γ, and IL-10 were measured in serum and metanephrine in plasma. The effects of humoral and cellular parameters on the risk of SAI and poor outcome were tested in multivariate analyses adjusted for confounders (NIHSS score, age, and tube feeding). Results— Surface expression of human leukocyte antigen-DR, Toll-like receptor-2, and production of TNF-α in monocytes were independently associated with stroke. Distinct immune mechanisms were related with functional outcome and the risk of SAI; the signature of SAI included an increase of cortisol, metanephrine, and IL-10 in serum, and reduced production of TNF-α in monocytes; poor outcome was associated with increased expression of Toll-like receptor-4 in monocytes (OR, 9.61; 95% CI, 1.27–72.47). SAI did not predict poor outcome (OR, 5.63; 95% CI, 0.45–70.42; P=0.18). Conclusions— In human stroke, poor outcome is associated to innate responses mediated by Toll-like receptor-4 in monocytes. SAI may result from the immunosuppressive and antiinflammatory effects of corticoids, catecholamines, IL-10, and deactivated monocytes. Early treated SAI does not contribute significantly to additional brain damage. These findings encourage the exploration of strategies aimed to inhibit Toll-like receptor-4 signaling in acute stroke.

Genetically-Defined Deficiency of Mannose-Binding Lectin Is Associated with Protection after Experimental Stroke in Mice and Outcome in Human Stroke

Background The complement system is a major effector of innate immunity that has been involved in stroke brain damage. Complement activation occurs through the classical, alternative and lectin pathways. The latter is initiated by mannose-binding lectin (MBL) and MBL-associated serine proteases (MASPs). Here we investigated whether the lectin pathway contributes to stroke outcome in mice and humans. Methodology/Principal Findings Focal cerebral ischemia/reperfusion in MBL-null mice induced smaller infarctions, better functional outcome, and diminished C3 deposition and neutrophil infiltration than in wild-type mice. Accordingly, reconstitution of MBL-null mice with recombinant human MBL (rhMBL) enhanced brain damage. In order to investigate the clinical relevance of these experimental observations, a study of MBL2 and MASP-2 gene polymorphism rendering the lectin pathway dysfunctional was performed in 135 stroke patients. In logistic regression adjusted for age, gender and initial stroke severity, unfavourable outcome at 3 months was associated with MBL-sufficient genotype (OR 10.85, p = 0.008) and circulating MBL levels (OR 1.29, p = 0.04). Individuals carrying MBL-low genotypes (17.8%) had lower C3, C4, and CRP levels, and the proinflammatory cytokine profile was attenuated versus MBL-sufficient genotypes. Conclusions/Significance In conclusion, genetically defined MBL-deficiency is associated with a better outcome after acute stroke in mice and humans.

Final Infarct Volume Is a Stronger Predictor of Outcome Than Recanalization in Patients With Proximal Middle Cerebral Artery Occlusion Treated With Endovascular Therapy

Background and Purpose— The rationale for recanalization therapy in acute ischemic stroke is to preserve brain through penumbral salvage and thus improve clinical outcomes. We sought to determine the relationship between recanalization, clinical outcomes, and final infarct volumes in acute ischemic stroke patients presenting with middle cerebral artery occlusion who underwent endovascular therapy and post-procedure magnetic resonance imaging. Methods— We identified 201 patients with middle cerebral artery occlusion. Patients with other occlusive lesions were excluded. Baseline clinical/radiological characteristics, procedural outcomes (including thrombolysis in cerebral infarction scores), clinical outcome scores (modified Rankin scores), and final infarct volumes on diffusion weighted imaging were retrospectively analyzed from a prospectively collected database. Favorable outcome is defined as 90-day modified Rankin score ⩽2. Results— Successful recanalization (thrombolysis in cerebral infarction grade 2b or 3) was achieved in 63.2% and favorable outcomes in 46% of cases. Mean infarct volume was 50.1 mL in recanalized versus 133.9 mL in non-recanalized patients (P<0.01) and 40.4 mL in patients with favorable outcomes versus 111.8 in patients with unfavorable outcomes (P<0.01). In multivariate analysis, thrombolysis in cerebral infarction ≥2b, baseline National Institute of Health Stroke Scale, Alberta Stroke Program Early Computed Tomography scores, and age were identified as independent predictors of outcome. However, when infarct volumes were included in the analysis only final infarct volume and age remained significantly associated. Conclusions— Successful recanalization leads to improved functional outcomes through a reduction in final infarct volumes. In our series, age and final infarct volume but not recanalization were found to be independent predictors of outcome, supporting the use of final infarct volume as surrogate marker of outcome in acute stroke trials.

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.

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.