Carlos Laredo

Uric Acid Therapy Improves Clinical Outcome in Women With Acute Ischemic Stroke

Background and Purpose— It is unknown whether women and men with acute ischemic stroke respond similar to an antioxidant regimen administered in combination with thrombolysis. Here, we investigated the independent effect of sex on the response to uric acid (UA) therapy in patients with acute stroke treated with alteplase. Methods— In the Efficacy Study of Combined Treatment With Uric Acid and rtPA in Acute Ischemic Stroke (URICO-ICTUS) trial, 206 women and 205 men were randomized to UA 1000 mg or placebo. In this reanalysis of the trial, the primary outcome was the rate of excellent outcome at 90 days (modified Rankin Scale, 0–1, or 2, if premorbid score of 2) in women and men using regression models adjusted for confounders associated with sex. The interaction of UA levels by treatment on infarct growth was assessed in selected patients. Results— Excellent outcome occurred in 47 of 111 (42%) women treated with UA, and 28 of 95 (29%) treated with placebo, and in 36 of 100 (36%) men treated with UA and 38 of 105 (34%) treated with placebo. Treatment and sex interacted significantly with excellent outcome (P=0.045). Thus, UA therapy doubled the effect of placebo to attain an excellent outcome in women (odd ratio [95% confidence interval], 2.088 [1.050–4.150]; P=0.036), but not in men (odd ratio [95% confidence interval], 0.999 [0.516–1.934]; P=0.997). The interactions between treatment and serum UA levels (P<0.001) or allantoin/UA ratio (P<0.001) on infarct growth were significant only in women. Conclusions— In women with acute ischemic stroke treated with alteplase, the administration of UA reduced infarct growth in selected patients and was better than placebo to reach excellent outcome. Clinical Trial Registration— URL: https://clinicaltrials.gov. Unique identifier: NCT00860366.

Uric acid improves glucose‐driven oxidative stress in human ischemic stroke

A study was undertaken to test in a subgroup reanalysis of the URICO‐ICTUS trial whether uric acid is superior to placebo in improving the functional outcome in patients with acute stroke and hyperglycemia.

Relevance of Blood–Brain Barrier Disruption After Endovascular Treatment of Ischemic Stroke Dual-Energy Computed Tomographic Study

Background and Purpose— Computed tomographic (CT) high attenuation (HA) areas after endovascular therapy for acute ischemic stroke are a common finding indicative of blood–brain barrier disruption. Dual-energy CT allows an accurate differentiation between HA areas related to contrast staining (CS) or to brain hemorrhage (BH). We sought to evaluate the prognostic significance of the presence of CS and BH after endovascular therapy. Methods— A prospective cohort of 132 patients treated with endovascular therapy was analyzed. According to dual-energy CT findings, patients were classified into 3 groups: no HA areas (n=53), CS (n=32), and BH (n=47). The rate of new hemorrhagic transformations was recorded at follow-up neuroimaging. Clinical outcome was evaluated at 90 days with the modified Rankin Scale (poor outcome, 3–6). Results— Poor outcome was associated with the presence of CS (odds ratio [OR], 11.3; 95% confidence interval, 3.34–38.95) and BH (OR, 10.4; 95% confidence interval, 3.42–31.68). The rate of poor outcome despite complete recanalization was also significantly higher in CS (OR, 9.7; 95% confidence interval, 2.55–37.18) and BH (OR, 15.1; 95% confidence interval, 3.85–59.35) groups, compared with the no-HA group. Patients with CS disclosed a higher incidence of delayed hemorrhagic transformation at follow-up (OR, 4.5; 95% confidence interval, 1.22–16.37) compared with no-HA patients. Conclusions— Blood–brain barrier disruption, defined as CS and BH on dual-energy CT, was associated with poor clinical outcomes in patients with stroke treated with endovascular therapies. Moreover, isolated CS was associated with delayed hemorrhagic transformation. These results support the clinical relevance of blood–brain barrier disruption in acute stroke.

Uric Acid Therapy Prevents Early Ischemic Stroke Progression: A Tertiary Analysis of the URICO-ICTUS Trial (Efficacy Study of Combined Treatment With Uric Acid and r-tPA in Acute Ischemic Stroke).

Background and Purpose— Identification of neuroprotective therapies in acute ischemic stroke is imperative. We report a predefined analysis of the URICO-ICTUS trial (Efficacy Study of Combined Treatment With Uric Acid and r-tPA in Acute Ischemic Stroke) assessing the efficacy of uric acid (UA) compared with placebo to prevent early ischemic worsening (EIW) and the relevance of collateral circulation. Methods— URICO-ICTUS was a double-blind, placebo-controlled, phase 2b trial where a total of 411 patients treated with alteplase within 4.5 hours of stroke onset were randomized (1:1) to receive UA 1000 mg (n=211) or placebo (n=200) before the end of alteplase infusion. EIW defined an increment ≥4 points in the National Institutes of Health Stroke Scale score within 72 hours of treatment in the absence of hemorrhage or recurrent stroke. Logistic regression models assessed the interaction between therapy and the collateral circulation in 112 patients who had a pretreatment computed tomographic angiography. Results— EIW occurred in 2 of 149 (1%) patients with good outcome and 23 of 262 (9%) patients with poor outcome (&khgr;2; P=0.002). EIW occurred in 7 of 204 (3%) patients treated with UA and in 18 of 200 (9%) patients treated with placebo (&khgr;2; P=0.01). There was a significant interaction between the efficacy of UA to prevent EIW and collaterals (P=0.029), with lower incidence in patients with good collaterals treated with UA compared with placebo (2% versus 15%, respectively; P=0.048). Conclusions— UA therapy may prevent EIW after acute stroke in thrombolysed patients. Optimal access of UA to its molecular targets through appropriate collaterals may modify the magnitude of the neuroprotective effect. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00860366.

Vessel Wall Enhancement and Blood–Cerebrospinal Fluid Barrier Disruption After Mechanical Thrombectomy in Acute Ischemic Stroke

Background and Purpose— Less than half of acute ischemic stroke patients treated with mechanical thrombectomy obtain permanent clinical benefits. Consequently, there is an urgent need to identify mechanisms implicated in the limited efficacy of early reperfusion. We evaluated the predictors and prognostic significance of vessel wall permeability impairment and its association with blood–cerebrospinal fluid barrier (BCSFB) disruption after acute stroke treated with thrombectomy. Methods— A prospective cohort of acute stroke patients treated with stent retrievers was analyzed. Vessel wall permeability impairment was identified as gadolinium vessel wall enhancement (GVE) in a 24- to 48-hour follow-up contrast-enhanced magnetic resonance imaging, and severe BCSFB disruption was defined as subarachnoid hemorrhage or gadolinium sulcal enhancement (present across >10 slices). Infarct volume was evaluated in follow-up magnetic resonance imaging, and clinical outcome was evaluated with the modified Rankin Scale at day 90. Results— A total of 60 patients (median National Institutes of Health Stroke Scale score, 18) were analyzed, of whom 28 (47%) received intravenous alteplase before mechanical thrombectomy. Overall, 34 (57%) patients had GVE and 27 (45%) had severe BCSFB disruption. GVE was significantly associated with alteplase use before thrombectomy and with more stent retriever passes, along with the presence of severe BCSFB disruption. GVE was associated with poor clinical outcome, and both GVE and severe BCSFB disruption were associated with increased final infarct volume. Conclusions— These findings may support the clinical relevance of direct vessel damage and BCSFB disruption after acute stroke and reinforce the need for further improvements in reperfusion strategies. Further validation in larger cohorts of patients is warranted.

Complete reperfusion is required for maximal benefits of mechanical thrombectomy in stroke patients

A mTICI 2b or a mTICI 3 score are currently considered success following mechanical thrombectomy (MT) in acute stroke but is undetermined whether the two scores translate equivalent outcomes. We present a single-center, retrospective cohort of patients with anterior circulation stroke treated with MT and achieving a final mTICI score 2b or 3. A multimodal CT at baseline and a multimodal MRI at 24 hours assessed the growth of the infarct, and the modified Rankin Scale (mRS) assessed functional outcome at 90 days. The primary outcome was the shift analysis of the mRS at day 90 in ordinal regression adjusted for covariates (age, sex, pretreatment NIHSS score, target occlusion, infarct core, pretreatment alteplase), and the collateral score. Infarct growth was explored in a similarly adjusted multiple linear regression model. MT was started within a median of 285 minutes of symptom onset; 51 (41%) patients achieved a mTICI 2b, and 74 (59%), a mTICI 3. mTICI 3 resulted in better mRS score transitions than mTICI 2b (odds ratio 2.018 [95% CI 1.033–3.945], p = 0. 040), and reduced infarct growth (p = 0.002). We conclude that in patients with acute stroke receiving MT, success should be redefined as achieving a mTICI 3 score.

Perfusion Deficits and Mismatch in Patients with Acute Lacunar Infarcts Studied with Whole-Brain CT Perfusion

BACKGROUND AND PURPOSE: The incidence and significance of perfusion abnormalities on brain imaging in patients with lacunar infarct are controversial. We studied the diagnostic yield of CTP and the type of perfusion abnormalities in patients presenting with a lacunar syndrome and in those with MR imaging–confirmed lacunar infarcts. MATERIALS AND METHODS: A cohort of 33 patients with lacunar syndrome underwent whole-brain CTP on admission. Twenty-eight patients had an acute ischemic lesion at follow-up MR imaging; 16 were classified as lacunar infarcts. Two independent readers evaluated NCCT and CTP to compare their diagnostic yield. In patients with DWI-confirmed lacunar infarcts and visible deficits on CTP, the presence of mismatch tissue was measured by using different perfusion thresholds. RESULTS: The symptomatic acute lesion was seen on CTP in 50% of patients presenting with a lacunar syndrome compared with only 17% on NCCT, and in 62% on CTP compared with 19% on NCCT, respectively, in patients with DWI-confirmed lacunar infarcts. CTP was more sensitive in supratentorial than in infratentorial lesions. In the nonblinded analysis, a perfusion deficit was observed in 12/16 patients with DWI-confirmed lacunar infarcts. The proportion of mismatch tissue was similar in patients with lacunar infarcts or nonlacunar strokes (32% versus 36%, P = .734). CONCLUSIONS: Whole-brain CTP is superior to NCCT in identifying small ischemic lesions, including lacunar infarcts, in patients presenting with a lacunar syndrome. Perfusion deficits and mismatch are frequent in lacunar infarcts, but larger studies are warranted to elucidate the clinical significance of these CTP findings.

Neuroanatomical correlates of stroke-associated infection and stroke-induced immunodepression

BACKGROUND Infections represent the most frequent medical complications in stroke patients. Their main determinants are dysphagia and a transient state of immunodepression. We analyzed whether distinct anatomical brain regions were associated with the occurrence of stroke-associated infections or immunodepression. MATERIALS AND METHODS In 106 patients with acute ischemic stroke, we evaluated the incidence of pneumonia, urinary tract infection, or other infections together with the characterization of biomarkers of immunodepression. Twenty control subjects served to provide reference values. Using voxel-based lesion-symptom mapping, the involvement of gray and white matter structures was correlated with clinical and laboratory findings in crude analyses and in volume adjusted models to rule out associations reflecting differences in the size of the infarction. RESULTS Stroke-associated infection occurred in 22 (21%) patients and prevailed in patients with larger infarcts. Volume adjusted voxel-based lesion-symptom mapping revealed the involvement of the superior and middle temporal gyri, the orbitofrontal cortex, the superior longitudinal fasciculus and the inferior fronto-occipital fasciculus amongst infected patients. These associations were similar for pneumonia but not for urinary tract infections. Lymphopenia was associated with lesions of the superior and middle temporal gyri. Laterality did not influence stroke-associated infections or the presence of immunodepressive traits after volume control. The greatest overlap in the neuroanatomical correlates occurred between pneumonia and dysphagia. CONCLUSION Infarct volume plays a relevant role in the occurrence of stroke-associated infections, but lesions in specific brain locations such as the superior and lateral temporal lobe and the orbitofrontal cortex are also associated with increased infectious risk, especially pneumonia.

Brain hemorrhage after endovascular reperfusion therapy of ischemic stroke: a threshold-finding whole-brain perfusion CT study

Endovascular reperfusion therapy is increasingly used for acute ischemic stroke treatment. The occurrence of parenchymal hemorrhage is clinically relevant and increases with reperfusion therapies. Herein we aimed to examine the optimal perfusion CT-derived parameters and the impact of the duration of brain ischemia for the prediction of parenchymal hemorrhage after endovascular therapy. A cohort of 146 consecutive patients with anterior circulation occlusions and treated with endovascular reperfusion therapy was analyzed. Recanalization was assessed at the end of reperfusion treatment, and the rate of parenchymal hemorrhage at follow-up neuroimaging. In regression analyses, cerebral blood volume and cerebral blood flow performed better than Delay Time maps for the prediction of parenchymal hemorrhage. The most informative thresholds (receiver operating curves) for relative cerebral blood volume and relative cerebral blood flow were values lower than 2.5% of normal brain. In binary regression analyses, the volume of regions with reduced relative cerebral blood volume and/or relative cerebral blood flow was significantly associated with an increased risk of parenchymal hemorrhage, as well as delayed vessel recanalization. These results highlight the relevance of the severity and duration of ischemia as drivers of blood-brain barrier disruption in acute ischemic stroke and support the role of perfusion CT for the prediction of parenchymal hemorrhage.

Adrenal hormones and circulating leukocyte subtypes in stroke patients treated with reperfusion therapy

Ischemic stroke sets in motion a dialogue between the central nervous and the immune systems that includes the sympathetic/adrenal system. We investigated the course of immune cells and adrenocortical and adrenomedullary effectors in a cohort of 51 patients with acute stroke receiving reperfusion therapy (intravenous alteplase or mechanical thrombectomy) and its correlation with stroke outcomes and infarct growth. Cortisol increased rapidly and fleetingly after stroke, but 39% of patients who had larger infarctions on admission showed a positive delta cortisol at day 1. It was associated with enhanced infarct growth (p = 0.002) and poor outcome [OR (95% CI) 5.30 (1.30-21.69)], and correlated with less lymphocytes and T cells at follow up. Likewise, fewer circulating lymphocytes, T cells, and Tregs were associated with infarct growth. By contrast, metanephrines did not increase at clinical onset, and decreased over time. Higher levels of NMN correlated with more Treg and B cells. Eventually, complete reperfusion at the end of therapy headed the identification of more circulating Tregs at day 1. Then activation of cortical or medullar compartments of the adrenal gland result in specific signatures on leukocyte subpopulations. Manipulation of the adrenal gland hormone levels warrants further investigation.