Cranial nerve injuries post carotid endarterectomy: a 15-year prospective study with routine otolaryngologist and neurological evaluation.

OBJECTIVE: The aim of this prospective monocentric cohort study was to analyze the risk of otolaryngologist-assessed cranial nerve injuries (CNIs) following carotid endarterectomy (CEA) in our academic center during a 15-year period, and to identify possible risk factors for CNI development. METHODS: From January 2007 to December 2022, 3749 consecutive CEAs were performed and their data prospectively recorded in a dedicated database. CNIs were assessed and defined according to a standardized protocol. Instrumental ear, nose, and throat (ENT) evaluations were conducted within 30 days before intervention and before discharge. Preoperative neurological assessments were carried out in all patients with symptomatic carotid stenosis, whereas postoperative neurological evaluations were performed in all patients. Patients with newly onset CNIs underwent follow-up assessments at 30 days and, if necessary, at 6, 12, and 24 months. Perioperative results, including mortality, major central neurological events, and postoperative CNIs, were analyzed. Regression or persistence of lesions during follow-up visits was assessed, and multivariate analysis (binary logistic regression) was conducted to evaluate clinical, anatomical, and surgical technique factors influencing the occurrence of CNIs. RESULTS: CEAs were performed more frequently in male patients (2453 interventions; 65.5%) than in females (1296 interventions; 34.5%). The interventions were performed in asymptomatic patients in 3078 cases (82%). In 66 cases, the interventions followed a previous ipsilateral CEA. At preoperative ENT evaluation, no cases of ipsilateral pre-existent CNI were recorded. The 30-day stroke and death rate was 1%. In 113 patients (3%), a postoperative neck bleeding requiring surgical revision and drainage was noted. Pre-discharge ENT evaluations identified 259 motor CNIs, accounting for 6.9% of the entire study group. Eighteen patients had lesions in more than one cranial nerve. ENT and neurological evaluations at 30 days showed the complete resolution of 161 lesions, whereas in 98 cases (2.6%), the CNI persisted. At 1 year, the rate of persistent CNI was 0.4% (10 patients), whereas at 2 years, it was 0.25% (6 cases), in all but one asymptomatic. At multivariate analysis, urgent intervention in unstable patients, secondary intervention, a clamping time >40 minutes, a hematoma requiring revision, and a postoperative stroke were independent predictors of CNIs. CONCLUSIONS: Data from this prospective monocentric cohort study showed that the occurrence of CNI following CEA was low, even when an independent multi-specialist evaluation was performed. The percentage of persistent lesions at 2 years was negligible and, in most cases, asymptomatic.

Prevalence of non-stenotic vulnerable carotid plaques in embolic stroke of undetermined source.

INTRODUCTION: The latest research in ischaemic stroke pathogenesis is directed to unveil what is inside embolic stroke of undetermined source (ESUS). Whether vulnerable non stenotic carotid plaques (NSTEPS), i.e. atherosclerotic lesions in carotid arteries determining a stenosis lower than 50%, may represent a cause of stroke in ESUS is a matter of debate. We aimed to study the prevalence of NSTEPS in an ESUS population. PATIENTS AND METHODS: We retrospectively identified a consecutive ESUS population admitted to the Stroke-Unit of Careggi Hospital, Italy from 2019 to 2022. Characteristics of atherosclerotic plaques (thickness, ulceration, hypodensity) and their location (ipsilateral versus contralateral to the stroke) were studied on carotid CT angiography (CTA). Follow-up data were recorded up to 24 months after stroke. RESULTS: We identified 57 ESUS patients with unilateral ischaemic lesions studied with CTA; 53 (93%) had an ipsilateral carotid plaque, 81% contralateral, (p = 0.754) and 74% both. Plaques ipsilateral to stroke were ≥ 3 mm thick in 15 (28%) patients; hypodense in 14 (26%) and ulcerated in 5 (9%). The frequency of hypodensity was higher in ipsilateral compared to contralateral plaques (26% vs. 13%, p = 0.039) and ulceration was around four times more frequent, although not statistically significant (9% vs. 2%, p = 0.219). At follow-up, six patients had stroke recurrence (11%), 2 of them were in the same vascular territory of the former. DISCUSSION AND CONCLUSIONS: Our data suggest that plaques ipsilateral to stroke seem to be more frequently vulnerable and consequently more prone to embolization. Prospective data are needed to clarify the causal role of NSTEPS in ESUS.

Nuclear Magnetic Resonance-Based Metabolomics to Predict Early and Late Adverse Outcomes in Ischemic Stroke Treated with Intravenous Thrombolysis.

Metabolic perturbations and inflammatory mediators play a fundamental role in both early and late adverse post-acute ischemic stroke outcomes. Using data from the observational MAGIC (MArker bioloGici nell'Ictus Cerebrale) study, we evaluated the effect of 130 serum metabolic features, using a nuclear magnetic spectroscopy approach, on the following outcomes: hemorrhagic transformation at 24 h after stroke, non-response to intravenous thrombolytic treatment with the recombinant tissue plasminogen activator (rt-PA), and the 3 month functional outcome. Blood circulating metabolites, lipoproteins, and inflammatory markers were assessed at the baseline and 24 h after rt-PA treatment. Adjusting for the major determinants for unfavorable outcomes (i.e., age, sex, time onset-to-treatment, etc.), we found that acetone and 3-hydroxybutyrate were associated with symptomatic hemorrhagic transformation and with non-response to rt-PA; while 24 h after rt-PA, levels of triglycerides high-density lipoprotein (HDL) and triglycerides low-density lipoprotein (LDL) were associated with 3 month mortality. Cholesterol and phospholipids levels, mainly related to smaller and denser very low-density lipoprotein (VLDL) and LDL subfractions were associated with 3 month poor functional outcomes. We also reported associations between baseline 24 h relative variation (Δ) in VLDL subfractions and ΔC-reactive protein, Δinterleukin-10 levels with hemorrhagic transformation. All observed metabolic changes reflect a general condition of energy failure, oxidative stress, and systemic inflammation that characterize the development of adverse outcomes.

Elective or Urgent Carotid Endarterectomy in Symptomatic Patients: Analysis Based on the Type and Timing of Neurological Symptoms.

BACKGROUND: The aim of this study was to retrospectively analyse perioperative and long-term outcomes of carotid endarterectomy (CEA) performed in symptomatic patients in a high-volume academic vascular centre, stratifying them according to the type of preoperative symptoms and the timing of surgery with respect to the indexed neurological event. METHODS: From January 2014 to December 2020, 1,369 consecutive CEAs were performed at our institution. Data concerning these interventions were prospectively collected in a dedicated database including data concerning preoperative assessment, surgical details, perioperative (<30 days) outcomes, and long-term outcomes. A retrospective analysis of the database was performed, and 213 interventions performed in symptomatic patients were found. We identified 2 subgroups of patients: patients with stable neurological symptoms (not recent transient ischemic attack (TIA) or stable major disabling stroke, stable group, and 157 patients) and patients with unstable neurological symptoms (recent TIA, crescendo TIAs, stroke in evolution, acute/recent minor stroke, unstable group, and 56 patients). Perioperative outcomes were analysed in terms of mortality, major neurological events, and local or systemic complications The results were compared using the χ2 test; these were also analysed on the basis of the presenting symptom (isolated TIA, crescendo TIA, stroke in evolution, acute/recent minor stroke, stabilized stroke) and the timing of the intervention relative to the onset of the symptom. Long term results were analysed using the life-table analysis and Kaplan-Meier curves in terms of survival, stroke-free survival, absence of neurological symptoms, and absence of significant restenosis. RESULTS: Overall, 30-day stroke and death rate were 4.2%. (3.1% vs. 7%, P = 0.2). Two deaths occurred at 30 days, both in the stable group (mortality 1.2%, P = 0.4 compared to the unstable group), but no fatal strokes were recorded in the overall sample. No differences were found in terms of new perioperative neurological events and local complications between the 2 groups. We found a trend toward poorer perioperative results in patients operated on within 48 hr from the indexed event and in patients operated on for stroke in evolution or acute/recent stroke, whereas we found a trend toward better results in favour of patients operated on between 8 and 14 days (P = 0.08). The median duration of follow-up was 24.8 months (range 1-78); at 5 years we did not find significant differences in terms of survival and stroke-free survival rates between 2 groups. CONCLUSIONS: In our experience, carotid surgery in symptomatic patients provided satisfactory results, particularly in patients with stable neurological status. Among unstable patients, the rate of complications significantly increases, mainly among treated in the very early (<48 hr) period for stroke in evolution or acute/recent stroke. Once the perioperative risk is overcome, the results in the long-term setting are similarly good, both in stable and in unstable patients.

Carotid revascularization and cognitive impairment: the neglected role of cerebral small vessel disease.

Carotid atherosclerosis is a pathological process that leads to narrowing of the vessel lumen and a consequent risk of stroke. Revascularization procedures such as carotid endarterectomy (CEA) and carotid stenting aim to reduce occurrence of stroke in selected patients. Due to the proven benefit and low intraoperative risk, CEA is currently the preferred choice in candidates for carotid revascularization. However, the risk of cognitive impairment subsequent to CEA has not been fully elucidated and is unclear whether certain conditions, such as frailty, may increase this risk. There is consistent evidence that shows that frail patients have higher risk of cognitive impairment after surgical procedure. Moreover, brain pre-existing conditions may play a role in cognitive impairment after CEA. Cerebral small vessel disease (SVD) is a pathology that involves microcirculation and is detectable with computed tomography or magnetic resonance. SVD shares common vascular risk factors with carotid atherosclerosis, is a major contributor to vascular cognitive impairment and vascular dementia, and has been proposed as a marker of brain frailty. In this review, we discuss the current evidence about the link between carotid revascularization and cognitive impairment and advance the hypothesis that SVD may play a relevant role in development of cognitive impairment after carotid revascularization.

Analysis of Metabolite and Lipid Association Networks Reveals Molecular Mechanisms Associated with 3-Month Mortality and Poor Functional Outcomes in Patients with Acute Ischemic Stroke after Thrombolytic Treatment with Recombinant Tissue Plasminogen Activator.

Here, we present an integrated multivariate, univariate, network reconstruction and differential analysis of metabolite-metabolite and metabolite-lipid association networks built from an array of 18 serum metabolites and 110 lipids identified and quantified through nuclear magnetic resonance spectroscopy in a cohort of 248 patients, of which 22 died and 82 developed a poor functional outcome within 3 months from acute ischemic stroke (AIS) treated with intravenous recombinant tissue plasminogen activator. We explored differences in metabolite and lipid connectivity of patients who did not develop a poor outcome and who survived the ischemic stroke from the related opposite conditions. We report statistically significant differences in the connectivity patterns of both low- and high-molecular-weight metabolites, implying underlying variations in the metabolic pathway involving leucine, glycine, glutamine, tyrosine, phenylalanine, citric, lactic, and acetic acids, ketone bodies, and different lipids, thus characterizing patients' outcomes. Our results evidence the promising and powerful role of the metabolite-metabolite and metabolite-lipid association networks in investigating molecular mechanisms underlying AIS patient's outcome.

Blood-brain barrier leakage and hemorrhagic transformation: The Reperfusion Injury in Ischemic StroKe (RISK) study.

BACKGROUND AND PURPOSE: In patients with acute ischemic stroke treated with reperfusion therapy we aimed to evaluate whether pretreatment blood-brain barrier (BBB) leakage is associated with subsequent hemorrhagic transformation (HT). METHODS: We prospectively screened patients with acute ischemic stroke treated with intravenous thrombolysis and/or endovascular treatment. Before treatment, each patient received computed tomography (CT), CT angiography, and CT perfusion. We assessed pretreatment BBB leakage within the ischemic area using the volume transfer constant (Ktrans ) value. Our primary outcome was relevant HT, defined as hemorrhagic infarction type 2 or parenchymal hemorrhage type 1 or 2. We evaluated independent associations between BBB leakage and HT using logistic regression, adjusting for age, sex, baseline stroke severity, Alberta Stroke Program Early CT Score (ASPECTS) ≥ 6, treatment type, and onset-to-treatment time. RESULTS: We enrolled 171 patients with available assessment of BBB leakage. The patients' mean (±SD) age was 75.5 (±11.8) years, 86 (50%) were men, and the median (interquartile range) National Institutes of Health Stroke Scale score was 18 (12-23). A total of 32 patients (18%) received intravenous thrombolysis, 102 (60%) underwent direct endovascular treatment, and 37 (22%) underwent both. Patients with relevant HT (N = 31;18%) had greater mean BBB leakage (Ktrans 0.77 vs. 0.60; p = 0.027). After adjustment in the logistic regression model, we found that BBB leakage was associated both with a more than twofold risk of relevant HT (odds ratio [OR] 2.50; 95% confidence interval [CI] 1.03-6.03 per Ktrans point increase; OR 2.34; 95% CI 1.06-5.17 for Ktrans values > 0.63 [mean BBB leakage value]) and with symptomatic intracerebral hemorrhage (OR 4.30; 95% CI 1.13-13.77 per Ktrans point increase). CONCLUSION: Pretreatment BBB leakage before reperfusion therapy was associated with HT, and may help to identify patients at risk of HT.

Aphasia predicts unfavorable outcome in mild ischemic stroke patients and prompts thrombolytic treatment.

BACKGROUND: Patients with an acute ischemic stroke rated as mild, and for this reason not submitted to thrombolysis, have an unfavorable outcome in a non-negligible proportion. Whether selective presentation features help identify those at risk of bad outcome, and whether it could be recommended to treat only patients with such features, is poorly elucidated. We report our experience based on retrospective evaluation of a consecutive series of patients scoring 6 or less on baseline National Institutes of Health Stroke Scale (NIHSS), some of whom received thrombolysis. METHODS: From the prospective Careggi Hospital Stroke Registry, Florence, Italy, we selected a series of patients who fulfilled the following criteria: (1) screening for treatment within 3 hours of symptom onset; (2) mild symptoms, defined as a score of 6 or less on NIHSS, with or without rapid improvement; (3) no other reason for exclusion from thrombolysis; (4) no previous disability; and (5) admission to the stroke unit. We choose a modified Rankin scale score of less than 2 to define a good 3-month functional outcome. We studied as potential outcome predictors: age, baseline NIHSS score, isolated aphasia, motor impairment with or without aphasia, thrombolysis, previous stroke or transient ischemic attack, and interactions between each of these factors and thrombolysis. RESULTS: Between February 2004 and June 2011, 128 patients fulfilled the selection criteria: 47 (36.7%) received tissue plasminogen activator, 81 (63.3%) did not. At 3 months, of the 81 patients not receiving tissue plasminogen activator, 14 (17.3%) had an unfavorable outcome, compared with 6 (12.8%) among the 47 treated. Hemorrhagic complications or death occurred in neither group. Adjusting for major confounders and for thrombolysis, the presence of aphasia on early assessment proved the only independent predictor of worse outcome. NIHSS score variation showed no effect. CONCLUSIONS: Aphasia is an early marker of unfavorable outcome in mild ischemic stroke patients. In these patients thrombolysis should be considered beyond the NIHSS scoring.

MMP9 variation after thrombolysis is associated with hemorrhagic transformation of lesion and death.

BACKGROUND AND PURPOSE: Experimentally, matrix metalloproteinases (MMPs) play a detrimental role related to hemorrhagic transformation and severity of an ischemic brain lesion. Tissue-type plasminogen activator (tPA) enhances such effects. This study aimed to expand clinical evidence in this connection. METHODS: We measured MMPs 1, 2, 3, 7, 8, 9, and tissue inhibitors of metalloproteinases 1, 2, 4 circulating level in blood taken before and 24 hours after tPA from 327 patients (mean age, 68.9±12.1 years; median National Institutes of Health Stroke Scale, 11) with acute ischemic stroke. Delta median values ([24 hours post tPA-pre tPA]/pre tPA) of each MMP or tissue inhibitors of metalloproteinase were analyzed across subgroups of patients undergoing symptomatic intracerebral hemorrhage, 3-month death, or 3-month modified Rankin Scale score 3 to 6. RESULTS: Adjusting for major clinical determinants, only matrix metalloproteinase-9 variation proved independently associated with death (odds ratio [95% confidence interval], 1.58 [1.11-2.26]; P=0.045) or symptomatic intracerebral hemorrhage (odds ratio [95% confidence interval], 1.40 [1.02-1.92]; P=0.049). Both matrix metalloproteinase-9 and tissue inhibitors of metalloproteinase-4 changes were correlated with baseline, 24 hours, and 7 days National Institutes of Health Stroke Scale (Spearman P from <0.001 to 0.040). CONCLUSIONS: Our clinical evidence corroborates the detrimental role of matrix metalloproteinase-9 during ischemic stroke treated with thrombolysis, and prompts clinical trials testing agents antagonizing its effects.

Intravenous thrombolysis for acute ischemic stroke associated to extracranial internal carotid artery occlusion: the ICARO-2 study.

BACKGROUND AND PURPOSES: In a case-control study in patients with acute ischemic stroke and extracranial internal carotid artery (eICA) occlusion, thrombolytic treatment was associated with increased mortality. The aim of this cohort study was to assess the efficacy and safety of thrombolysis in patients with eICA occlusion compared to those without eICA occlusion. METHODS: Consecutive patients treated with intravenous tissue-type plasminogen activator within 4.5 h from symptom onset included in the Safe Implementation of Thrombolysis in Stroke - International Stroke Thrombolysis Registry (SITS-ISTR) in 20 Italian centres were analyzed. Acute carotid occlusion was diagnosed using ultrasound examination, angio-CT scan or angio-MRI. Since the SITS-ISTR database did not plan to report the site of vessel occlusion, each participating center provided the code of the patient with eICA occlusion. Patients were divided into 2 groups, those with and those without eICA occlusion. Main outcome measures were: death, disability (modified Rankin Scale, mRS, 3-6) and any intracranial bleeding at 3 months. Multiple logistic regression analysis was performed to reveal predictors for main outcomes. The following variables of interest were included in the analysis: presence of eICA occlusion, age, gender, diabetes mellitus, hyperlipidemia, atrial fibrillation, congestive heart failure, previous stroke, current smoking, antiplatelet treatment at stroke onset, baseline NIHSS score, baseline blood glucose, cholesterol and blood pressure, history of hypertension and stroke onset to treatment time. RESULTS: A total of 1,761 patients without eICA occlusion and 137 with eICA occlusion were included in the study. At 3 months, 42 patients were lost to follow-up (3 with eICA occlusion). Death occurred in 30 (22.4%) patients with eICA occlusion and in 175 (10.2%) patients without (p < 0.0001). Death or disability at 3 months occurred in 91 of 134 patients with eICA occlusion (67.9%) compared with 654 of 1,722 patients without eICA occlusion (37.9%, p < 0.0001). No or minimal disability at 3 months (mRS 0-1) was reported in 25 (18.7%) patients with eICA occlusion and in 829 (48.2%) patients without (p < 0.0001). Any intracranial bleeding detected by CT or MRI at posttreatment imaging was seen in 16 (11.7%) patients with eICA occlusion and in 314 (17.8%) of those without (p = 0.09). The proportion of symptomatic intracerebral hemorrhage was 5.8% for patients with eICA occlusion and 8.0% for patients without (p = 0.16). At logistic regression analysis, eICA occlusion was associated with mortality (odds ratio, OR 5.7; 95% confidence interval, CI 2.9-11.1) and mortality or disability (OR 5.0; 95% CI 2.9-8.7) at 90 days. CONCLUSIONS: This cohort study in patients with acute ischemic stroke treated with thrombolysis showed an association between eICA occlusion and adverse outcome.

Small Vessel Disease Is Associated with Tissue Inhibitor of Matrix Metalloproteinase-4 After Ischaemic Stroke.

Small vessel disease (SVD) is frequent in aging and stroke patients. Inflammation and remodeling of extracellular matrix have been suggested as concurrent mechanisms of SVD. We investigated the relationship between imaging features of SVD and circulating metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in patients with ischaemic stroke. In patients treated with intravenous thrombolysis, we took blood samples before intravenous thrombolysis and 90 days after the acute stroke and analysed levels of MMPs and TIMPs. We assessed leukoaraiosis, number of lacunes and brain atrophy on pre-treatment CT scan and graded global SVD burden combining such features. We investigated associations between single features, global SVD and MMPs and TIMPs at baseline and at follow-up, retaining univariate statistically significant associations in multivariate linear regression analysis and adjusting for clinical confounders. A total of 255 patients [mean (±SD) = 68.6 (± 12.7) years, 154 (59%) males] were included, 107 (42%) had no signs of SVD; 47 (19%) had from moderate to severe SVD burden. A total of 107 (42%) patients had no signs of SVD; 47 (19%) had from moderate to severe SVD burden. After adjustment, only TIMP-4 proved associations with SVD features. Brain atrophy was associated with baseline TIMP-4 (ß = 0.20;p = 0.019) and leukoaraiosis with 90 days TIMP-4 (ß = 0.19; p = 0.013). Global SVD score was not associated with baseline TIMP-4 levels (ß = 0.10; p = 0.072), whereas was associated with 90 days TIMP-4 levels (ß = 0.21; p = 0.003). Total SVD burden was associated with higher TIMP-4 levels 90 days after stroke, whereas was not during the acute phase. Our results support a biological relationship between SVD grade and TIMP-4.

Small vessel disease and biomarkers of endothelial dysfunction after ischaemic stroke.

INTRODUCTION: Although pathogenesis of small vessel disease is poorly understood, increasing evidence suggests that endothelial dysfunction may have a relevant role in development and progression of small vessel disease. In this cross-sectional study, we investigated the associations between imaging signs of small vessel disease and blood biomarkers of endothelial dysfunction at two different time points in a population of ischaemic stroke patients. PATIENTS AND METHODS: In stroke patients treated with intravenous thrombolysis, we analysed blood levels of von Willebrand factor, intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and vascular endothelial growth factor. Three reviewers independently assessed small vessel disease features using computed tomography. At baseline and 90 days after the index stroke, we tested the associations between single and combined small vessel disease features and levels of blood biomarkers using linear regression analysis adjusting for age, sex, hypertension, diabetes, smoke. RESULTS: A total of 263 patients were available for the analysis. Mean age (±SD) was 69 (±13) years, 154 (59%) patients were male. We did not find any relation between small vessel disease and endothelial dysfunction at baseline. At 90 days, leukoaraiosis was independently associated with intercellular adhesion molecule-1 (ß = 0.21; p = 0.016) and vascular cell adhesion molecule-1 (ß = 0.22; p = 0.009), and lacunes were associated with vascular endothelial growth factor levels (ß = 0.21; p = 0.009) whereas global small vessel disease burden was associated with vascular endothelial growth factor (ß = 0.26; p = 0.006). DISCUSSION: Leukoaraiosis and lacunes were associated with endothelial dysfunction, which could play a key role in pathogenesis of small vessel disease. CONCLUSIONS: Small vessel disease features and total burden were associated with endothelial dysfunction 90 days after the stroke, whereas there was no relation during the acute phase. Our results suggest that endothelial dysfunction, particularly vascular endothelial growth factor, is involved in pathological process of small vessel disease.

Reperfusion Injury after ischemic Stroke Study (RISKS): single-centre (Florence, Italy), prospective observational protocol study.

INTRODUCTION: Treatments aiming at reperfusion of the acutely ischaemic brain tissue may result futile or even detrimental because of the so-called reperfusion injury. The processes contributing to reperfusion injury involve a number of factors, ranging from blood-brain barrier (BBB) disruption to circulating biomarkers. Our aim is to evaluate the relative effect of imaging and circulating biomarkers in relation to reperfusion injury. METHODS AND ANALYSIS: Observational hospital-based study that will include 140 patients who had ischaemic stroke, treated with systemic thrombolysis, endovascular treatment or both. BBB disruption will be assessed with CT perfusion (CTP) before treatment, and levels of a large panel of biomarkers will be measured before intervention and after 24 hours. Relevant outcomes will include: (1) reperfusion injury, defined as radiologically relevant haemorrhagic transformation at 24 hours and (2) clinical status 3 months after the index stroke. We will investigate the separate and combined effect of pretreatment BBB disruption and circulating biomarkers on reperfusion injury and clinical status at 3 months. Study protocol is registered at http://www.clinicaltrials.gov (ClinicalTrials.gov ID: NCT03041753). ETHICS AND DISSEMINATION: The study protocol has been approved by ethics committee of the Azienda Ospedaliero Universitaria Careggi (Università degli Studi di Firenze). Informed consent is obtained by each patient at time of enrolment or deferred when the participant lacks the capacity to provide consent during the acute phase. Researchers interested in testing hypotheses with the data are encouraged to contact the corresponding author. Results from the study will be disseminated at national and international conferences and in medical thesis. TRIAL REGISTRATION NUMBER: NCT03041753.

Inflammatory and metalloproteinases profiles predict three-month poor outcomes in ischemic stroke treated with thrombolysis.

Inflammatory mediators and metalloproteinases are altered in acute ischemic stroke (AIS) and play a detrimental effect on clinical severity and hemorrhagic transformation of the ischemic brain lesion. Using data from the Italian multicenter observational MAGIC (MArker bioloGici nell'Ictus Cerebrale) Study, we evaluated the effect of inflammatory and metalloproteinases profiles on three-month functional outcome, hemorrhagic transformation and mortality in 327 patients with AIS treated with intravenous thrombolys in according to SITS-MOST (Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy) criteria. Circulating biomarkers were assessed at baseline and 24 h after thrombolysis. Adjusting for age, sex, baseline glycemia and National Institute of Health Stroke Scale, history of atrial fibrillation or congestive heart failure, and of inflammatory diseases or infections, baseline alpha-2macroglobulin (A2M), baseline serum amyloid protein (SAP) and pre-post tissue-plasminogen activator (tPA) variations (Δ) of metalloproteinase 9, remained significantly and independently associated with three-month death [OR (95% CI):A2M:2.99 (1.19-7.53); SAP:5.46 (1.64-18.74); Δmetalloproteinase 9:1.60 (1.12-2.27)]. The addition of baseline A2M and Δmetalloproteinase 9 or baseline SAP and Δmetalloproteinase 9 (model-2 or model-3) to clinical variables (model-1) significantly improved the area under curve for prediction of death [model-2 with A2M: p = 0.0205; model-3 with SAP: p = 0.001]. In conclusion, among AIS patients treated with thrombolysis, circulating A2M, SAP and Δmetalloproteinase 9 are independent markers of poor outcome. These results may prompt controlled clinical research about agents antagonizing their effect.

Unbalanced Metalloproteinase-9 and Tissue Inhibitors of Metalloproteinases Ratios Predict Hemorrhagic Transformation of Lesion in Ischemic Stroke Patients Treated with Thrombolysis: Results from the MAGIC Study.

BACKGROUND: Experimentally, metalloproteinases (MMPs) play a detrimental role related to the severity of ischemic brain lesions. Both MMPs activity and function in tissues reflect the balance between MMPs and tissue inhibitors of metalloproteinases (TIMPs). We aimed to evaluate the role of MMPs/TIMPs balance in the setting of rtPA-treated stroke patients. METHODS: Blood was taken before and 24-h after rtPA from 327 patients (mean age 68 years, median NIHSS 11) with acute ischemic stroke. Delta median values of each MMP/TIMP ratio [(post rtPA MMP/TIMP-baseline MMP/TIMP)/(baseline MMP/TIMP)] were analyzed related to symptomatic intracranial hemorrhage (sICH) according to NINDS criteria, relevant hemorrhagic transformation (HT) defined as confluent petechiae within the infarcted area or any parenchymal hemorrhage, stroke subtypes (according to Oxfordshire Community Stroke Project) and 3-month death. The net effect of each MMP/TIMP ratio was estimated by a logistic regression model including major clinical determinants of outcomes. RESULTS: Adjusting for major clinical determinants, only increase in MMP9/TIMP1 and MMP9/TIMP2 ratios remained significantly associated with sICH (odds ratio [95% confidence interval], 1.67 [1.17-2.38], p = 0.005; 1.74 [1.21-2.49], p = 0.003, respectively). Only relative increase in MMP9/TIMP1 ratio proved significantly associated with relevant HT (odds ratio [95% confidence interval], 1.74 [1.17-2.57], p = 0.006) with a trend toward significance for MMP9/TIMP2 ratio (p = 0.007). DISCUSSION: Our data add substantial clinical evidence about the role of MMPs/TIMPs balance in rtPA-treated stroke patients. These results may serve to generate hypotheses on MMPs inhibitors to be administered together with rtPA in order to counteract its deleterious effect.

Bone marrow-derived progenitor cells in the early phase of ischemic stroke: relation with stroke severity and discharge outcome.

A limited number of studies suggested that in ischemic stroke patients, the number of bone marrow circulating progenitor cells (CPCs), either endothelial progenitor cells (EPCs) or CPCs, was negatively correlated with the number of infarcts as well as with the outcome. The aim of this study was to simultaneously measure CPCs and EPCs in the acute phase of ischemic stroke, and to establish whether a relationship exists with stroke severity and discharge outcome. In 67 (40 M; 27 F) ischemic stroke patients with a median age of 73 (21 to 91) years, the number of CPCs and EPCs was measured by flow cytometry and analyzed in relation to baseline NIH Stroke Scale score, ischemic stroke syndromes, and discharge outcome. Patients with partial anterior circulation syndrome showed a higher CPCs' number with respect to patients with total anterior circulation syndrome. Moreover, a negative relationship between National Institutes of Health Stroke Scale score at the admission and CPCs number was observed. When the outcome was considered, patients discharged to home had a higher number of CPCs, but not of EPCs, compared with those moved to a rehabilitation unit. We report an association between the number of CPCs measured in the early phase after stroke presentation, neurologic severity, and discharge outcome.